Effects of CGS 21680, a selective A2A adenosine receptor agonist,on cardiac output and vascular resistance in acute heart failure in the anaesthetized rat

1. The effects of CGS 21680, a selective A_2A adenosine receptor agonist, on cardiac output, blood pressure, mean circulatory filling pressure (P_mcf), arterial and venous resistances, heart rate and left ventricular end-diastolic pressure were assessed in rats with acute heart failure by means of coronary artery occlusion.
2. Animals (n=6 in each group) were divided into five groups: group I, sham-operated vehicle-treated (0.9% saline; 0.018 mL min⁻¹); groups II-V, subject to coronary artery occlusion and treated with vehicle (0.9% saline; 0.018 ml min⁻¹) and CGS 21680 (0.1, 0.3 and 1.0 μg kg⁻¹ min⁻¹), respectively. Haemodynamic measurements were taken one hour after completion of surgery, ninety minutes after coronary artery occlusion (except in group I), and fifteen minutes after infusion of saline or CGS 21680.
3. Baseline haemodynamic measurements before occlusion were found not to differ significantly between the different groups of animals. However, after occlusion, cardiac output, rate of rise in left ventricular pressure (+dP/dt) and blood pressure were significantly reduced when compared to corresponding values in sham-operated animals. In addition, occlusion of the coronary artery resulted in a significant elevation in venous resistance, P_mcf and left ventricular end-diastolic pressure as compared to corresponding values in sham-operated animals.
4. Infusion with CGS 21680 at the highest dose significantly reduced blood pressure, arterial resistance and left ventricular end-diastolic pressure when compared to occluded vehicle-treated animals (group II). Administration of CGS 21680 at the highest dose also significantly increased cardiac output (28%) and heart rate (10%) in comparison to occluded vehicle-treated animals. In addition, the highest dose of CGS 21680 significantly reduced P_mcf (9%) and venous resistance (62%) in comparison to occluded vehicle-treated animals. Administration of CGS 21680 did not significantly affect +dP/dt when compared to occluded vehicle-treated animals.
5. The results from the present investigation indicate that occlusion of the coronary artery in rats results in a state of heart failure characterized by reduced arterial pressure and cardiac output, and increased venous resistance, P_mcf and left ventricular end-diastolic pressure. Administration of CGS 21680 to animals with acute heart failure resulted in increased cardiac output which was due to reduced venous resistance, as well as increased heart rate.

     

Effects of long-term treatment with trandolapril on sarcoplasmic reticulum function of cardiac muscle in rats with chronic heart failure following myocardial infarction

1. Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca²⁺ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction.
2. CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF.
3. The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25–1 min with 10⁻⁵ M Ca²⁺ (48–88%) and when preloaded with 10⁻⁶ M Ca²⁺ and then exposed to 0.1–1 mM caffeine (45–93%).
4. The [³H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca²⁺ released from SR is decreased due to a reduced rate of SR Ca²⁺ uptake and a downregulation of the SR Ca²⁺-release channel.
5. Rats were treated orally with 3 mg kg⁻¹ day⁻¹ trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF.
6. It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca²⁺ release channel.

     

Systemic,pulmonary and coronary haemodynamic actions of the novel dopamine receptor agonist in awake pigs at rest and during treadmill exercise Z1046

1. In view of the potential therapeutic application of specific dopamine receptor agonists in the treatment of hypertension and left ventricular dysfunction, we investigated the cardiovascular actions of the novel mixed D₁/D₂ dopamine receptor agonist Z1046 in awake pigs at rest and during treadmill exercise.
2. Thirteen swine were chronically instrumented under sterile conditions for measurement of systemic, pulmonary, and coronary haemodynamics. Regional blood flows were determined with the radioactive microsphere technique.
3. Z1046 (1, 10, 100 μg kg⁻¹, i.v.) produced dose-dependent reductions in central aortic blood pressure (up to 27±3%, P⩽0.05) in awake resting pigs which was accompanied by only minimal reflex activation of the sympathetic nervous system. The hypotensive response was principally the result of peripheral vasodilatation (system vascular resistance decreased up to 35±4%, P⩽0.05), which was located in the cerebral, coronary, renal, mesenteric, adrenal, splenic and skeletal muscular vascular beds (vascular resistance decreased up to 30–40% after the highest dose in these beds). Only in the cerebral and mesenteric bed was the vasodilatation sufficiently large to overcome the decrease in blood pressure and result in an increased blood flow; the vasodilatation in the coronary bed was most likely due to autoregulation as neither coronary blood flow nor myocardial oxygen demand were changed significantly by Z1046. The systemic vasodilatation that was caused by the highest i.v. dose (100 μg kg⁻¹) was accompanied by transient and minor increases in heart rate (15±5%, P⩽0.05) and cardiac output (15±5%, P⩽0.05) whereas after 10 μg kg⁻¹, i.v., a slight decrease in cardiac output also contributed to the hypotension. Z1046 had no effect on pulmonary vascular resistance.
4. The systemic vasodilator responses to Z1046 (100 μg kg⁻¹, i.v.) were sustained during treadmill exercise (2–4 km h⁻¹ which produced heart rates of up to 233±10 beats min⁻¹), but with increasing treadmill speed attenuation of the exercise-induced increase in heart rate (−11±3%, P⩽0.05) and hence cardiac output (−10±3%, P⩽0.05) (as stroke volume was not altered by Z1046) contributed significantly to a lower aortic blood pressure (−20±3%, P⩽0.05). Z1046 had no effect on pulmonary vascular resistance during exercise.
5. Oral administration of Z1046 (0.5, 1.5 mg kg⁻¹) produced a fall in central aortic blood pressure (up to 15±3%, P⩽0.05), which developed gradually during the first 90 min and lasted up to 4 h after administration, again with negligible changes in heart rate and LVdP/dt_max.
6. Neither non-selective α- and β-adrenoceptor blockade, nor selective α₂-adrenoceptor blockade altered the vasodilator actions of Z1046, but non-selective α- and β-adrenoceptor blockade abolished the cardiac responses to dopamine receptor stimulation, suggesting that its cardiac actions were principally caused by D₂-receptor-mediated inhibition of catecholamine release, whereas the vasodilator response was probably the result of vascular D₁-receptor stimulation.
7. In conclusion, the novel dopamine receptor agonist Z1046 is an effective blood pressure lowering agent that elicits minimal reflex activation of the sympathetic nervous system in awake resting pigs. Systemic vasodilatation was not affected by combined α- and β-adrenoceptor blockade, which is consistent with a predominantly D₁ receptor-dependent vasodilator mechanism. The hypotensive effect is maintained during treadmill exercise during which systemic vasodilatation and a lower cardiac output both contribute to the blood pressure lowering actions of Z1046. The cardiovascular profile of this orally active compound warrants further investigation of this class of drugs in experimental and clinical hypertension.

     

Resuscitating effect of melanocortin peptides after prolonged respiratory arrest

1. The resuscitating activity of melanocortin peptides (MSH-ACTH peptides) was tested in an experimental model of prolonged respiratory arrest.
2. Anaesthetized, endotracheally intubated rats subjected to a 5 min period of ventilation interruption, invariably died from cardiac arrest within 6–9 min of resumption of ventilation.
3. When resumption of ventilation was associated with the simultaneous intravenous (i.v.) injection of a melanocortin peptide (α-MSH or ACTH-(1–24)) (160 μg kg⁻¹) there was an almost immediate (within 1 min), impressive increase in cardiac output, heart rate, mean arterial pressure (+560% of the before-treatment value) and pulse pressure (+356% of the before-treatment value), with full recovery of electroencephalogram after 30–45 min. Blood gases and pH were normalized within 15–60 min after treatment, and all treated animals eventually recovered completely and survived indefinitely (= more than 15 days).
4. The same response was observed in adrenalectomized animals, as well as in animals pretreated with a β₁-adrenoceptor blocking agent (atenolol, 3 mg kg⁻¹, i.v.), or with an α₁-adrenoceptor blocking agent (prazosin, 0.1 mg kg⁻¹, i.v.), or with an adrenergic neurone blocking agent (guanethidine, 10 mg kg⁻¹, intraperitoneally).
5. An effect quite similar to that produced by melanocortins was obtained with ouabain (0.1 mg kg⁻¹, i.v.); the antioxidant drug, glutathione (75 mg kg⁻¹, i.v.) also produced 100% resuscitation, but the effect was slower in onset. On the other hand, adrenaline (0.005 mg kg⁻¹, i.v.) was able to resuscitate only 1 out of 8 rats and dobutamine (0.02 mg kg⁻¹, i.v.) resuscitated 4 out of 8 rats; moreover, the effect of both catecholamines was much slower in onset than that of melanocortins and the initial, impressive stimulation of cardiovascular function was absent.
6. These results show that melanocortin peptides have a resuscitating effect in a pre-terminal condition produced in rats by prolonged asphyxia. This effect seems primarily due to the restoration of cardiac function, not mediated by catecholamines. These data also suggest that these peptides may have potential therapeutic value in conditions of transient cardiac hypoxia and re-oxygenation such as occur in coronary artery disease.

     

The effect of chronic treatment with trandolapril on cyclic AMP- and cyclic GMP-dependent relaxations in aortic segments of rats with chronic heart failure

1. Characteristics of cyclic GMP- and cyclic AMP-mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation.
2. Cardiac output indices of coronary artery-ligated and sham-operated rats were 125±8 and 189±10 ml min⁻¹ kg⁻¹, respectively (P<0.05), indicating the development of CHF at this period.
3. The maximal relaxant response of aortic segments to 10 μM acetylcholine in rats with CHF and sham-operated rats was 64.0±5.7 and 86.9±1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham-operated rats.
4. In endothelium-intact segments of rats with CHF, the maximal relaxant response to 10 μM isoprenaline (44.5±6.7%) was lower that sham-operated rats (81.3±2.5%, P<0.05) and the concentration-response curve for NKH477, a water-soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline-induced relaxation of aortic segments was attenuated by N^G-nitro-L-arginine methyl ester (L-NAME) in sham-operated rats, but not in rats with CHF. Relaxation to 30 μM dibutyryl cyclic AMP in rats with CHF (26.8±2.7%) was lower than that in sham-operated rats (63.4±11.8%, P<0.05).
5. Trandolapril (3 mg kg⁻¹ day⁻¹) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5±3.6 ml min⁻¹) was lower than that of sham-operated rats (55.0±3.0 ml min⁻¹), and this reduction was reversed (54.1±3.4 ml min⁻¹) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril-treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7±1.0%; that to isoprenaline, 80.5±2.8%; that to dibutyryl cyclic AMP, 54.7±6.2%). However, aortic segments of trandolapril-treated rats with CHF, L-NAME did not attenuate isoprenaline-induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged.
6. The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP-mediated signal transduction, was partially restored by long-term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF-induced endothelial dysfunction.

     

Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5-HT receptor antagonists in a mouse model of allergic asthma

1. Since both histamine and 5-hydroxytryptamine (5-HT) can be released by murine mast cells, we investigated the possible role of these autacoids on airway hyperresponsiveness (AHR), eosinophil infiltration and serum-IgE levels in a murine model of allergic asthma.
2. Ovalbumin-sensitized mice were exposed to either ovalbumin (2 mg ml⁻¹) or saline aerosols on 8 consecutive days. Starting one day before the challenge, animals were injected i.p. twice a day with a 5-HT-type 1 (5-HT₁) or type 2 (5-HT₂) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg⁻¹ and ketanserin, 12 mg kg⁻¹, respectively) or a histamine-type 1 (H₁) or type 2 (H₂) receptor antagonist (mepyramine, 12 or 20 mg kg⁻¹ and cimetidine, 10 or 25 mg kg⁻¹, respectively). Furthermore, animals were injected with a combination of cimetidine and ketanserin or with an α-adrenoceptor antagonist (phentolamine, 5 mg kg⁻¹).
3. In vehicle-treated ovalbumin-challenged animals airway responsiveness to intravenous injections of methacholine in vivo was significantly (9 fold increase, P<0.01) increased when compared to vehicle-treated saline-challenged animals. Furthermore, ovalbumin challenge of vehicle-treated animals induced a significant increase in both eosinophil numbers in bronchoalveolar lavage (BAL) fluid (0±0, vehicle/saline and 15.0±5.9×10⁴ cells vehicle/ovalbumin, P<0.05) and ovalbumin-specific IgE levels in serum (157±69 and 617±171 units ml⁻¹, respectively, P<0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected in saline-challenged animals after all different treatments.
4. Treatment with ketanserin or cimetidine resulted in a partial but significant decrease of the ovalbumin-induced AHR compared to ovalbumin-challenged controls (P<0.05) and reduced eosinophil infiltration after ovalbumin challenge by 60% and 58%, respectively. The combination of cimetidine and ketanserin almost completely abolished AHR whereas eosinophilia was decreased by 49%. No effects of these antagonists were observed on IL-16 levels in BAL fluid or on serum antigen-specific IgE levels. Treatment with either the H₁-receptor, the 5-HT₁-receptor or the α-adrenoceptor antagonist, did not decrease the observed ovalbumin-induced airway responsiveness or eosinophilia in vehicle-treated animals. Higher doses of either methiotepine (2.0 mg kg⁻¹) or mepyramine (20 mg kg⁻¹) did decrease ovalbumin-induced eosinophil infiltration (by 67%, P<0.05 and 73%, respectively), whereas no effects of these antagonists were observed on ovalbumin-specific IgE levels in serum.
5. From these data it can be concluded that both histamine and 5-HT play a role in antigen-induced AHR and eosinophilia in the mouse.

     

Effects of adenosine and adenosine analogues on mean circulatory filling pressure and cardiac output in anesthetized rats

The effects of adenosine and adenosine analogues, 2-[p-(2-[carboxyethyl) phenethylamino]-5’-N-ethylcarboxamidoadenosine (CGS 21680) and N⁶-2-(4-aminophenyl)-ethyladenosine (APNEA), on mean arterial pressure, cardiac output, mean circulatory filling pressure, arterial resistance, venous resistance and heart rate in untreated or treated (with ganglion-blockers mecamylamine and atropine) pentobarbital-anesthetized rats were examined. Infusion of adenosine (100, 300 and 900 μg/kg/min), CGS 21680 (0.1, 0.3 and 0.9 μg/kg/ min) or APNEA (1.0, 3.0 and 9.0 μg/kg/min) reduced mean arterial pressure and arterial resistance in all groups. Adenosine and APNEA also reduced mean circulatory filling pressure, venous resistance and heart rate in untreated animals. Furthermore, APNEA but not adenosine reduced cardiac output. In contrast, CGS 21680 increased cardiac output and heart rate but did not have any effect on mean circulatory filling pressure or venous resistance. In ganglion-blocked rats, APNEA reduced cardiac output, mean circulatory filling pressure and heart rate, while adenosine did not have any effect on these parameters. In addition, APNEA and adenosine reduced arterial resistance but were unable to alter venous resistance while CGS 21680 reduced mean circulatory filling pressure and arterial resistance but did not further affect cardiac output, heart rate and venous resistance in ganglion-blocked animals. The results of the present study suggest that adenosine and APNEA dilate arterioles and vein, whereas CGS 21680 causes arterial dilatation but not venodilatation in untreated animals due to hypotension-induced sympathetic activation. A possible explanation for the present observations could be differences in the distribution of vascular A₂ versus A₃ adenosine receptors in the venous circulation. Reza Tabrizchi Received: 17 September 1996 / Accepted: 27 March 1997     

Down-regulation of aortic and cardiac AT1 receptor gene expression in transgenic (mRen-2) 27 rats

1. Transgenic(TG) (mRen-2) rats overexpressing the mouse renin gene develop fulminant hypertension and cardiac hypertrophy. Since the activation of AT₁ receptor by angiotensin II is involved in blood pressure regulation, cardiac performance and myocardial growth, we investigated the biological effects of angiotensin II and the regulation of the AT₁ receptor in the heart and aorta of TGR (mRen-2)27 rats in comparison to control animals.
2. Contraction studies on isolated cardiac muscle strips reveal that angiotensin II exerts no positive inotropic effect on the left ventricular myocardium of both, transgenic and control rats. In contrast, angiotensin II leads via AT₁ receptor activation in the left atrium of control rats to a significant contraction (130±5% of basal contraction) which is not detectable in left atrium preparations of the transgenic animals. Furthermore, AT₁ receptor activation causes a profound contraction of aortic rings isolated from control rats amounting to 1.39±0.2 mN mg⁻¹ wet weight, whereas aortic rings from TGR (mRen-2)27 rats contract only minimally upon angiotensin II stimulation (0.2±0.02 mN mg⁻¹ wet weight).
3. These altered physiological responses of angiotensin II in the transgenic rats are in part due to a marked down-regulation of the AT₁ receptor in atrial, ventricular and aortic tissue of these transgenic animals in comparison to control Sprague-Dawley rats, as shown by radioligand binding assays and quantitative polymerase chain reaction (PCR) experiments. The AT₁ receptor density B_max in the left atrium was 1.3±0.08 fmol mg⁻¹ protein in control rats (K_D 1.1±0.18 nmol l⁻¹) and 0.94±0.15 fmol mg⁻¹ protein (K_D 2.1±0.3 nmol l⁻¹. In the aorta B_max values were 15.1±0.5 fmol mg⁻¹ protein (K_D 1.9±0.27 nmol l⁻¹) for control rats and 11.3±0.76 fmol mg⁻¹ protein (K_D 1.9±0.27 nmol l⁻¹) for the TGR(mRen-2)27 rats AT₁ receptor mRNA was reduced in the transgenic animals to 46±3% in the left atrium, 50±11% in the left ventricle and 40±3% in the aorta, respectively.
4. Together, the AT₁ receptor is down-regulated in TGR (mRen-2)27 rats in comparison to wildtype Sprague Dawley rats leading to a profoundly decreased response of cardiac and aortic tissue upon stimulation with angiotensin II.

     

Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats

1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A₁-receptor agonist N⁶-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals.
2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and β-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously.
3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 μg kg⁻¹ in 5 min and 15 min, and 120 μg kg⁻¹ in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean±s.e., n=19) were E_max: −80±2% (% change from baseline), EC₅₀: 22±2 ng ml⁻¹, and Hill factor: 2.2±0.2.
4. In another group, given 400 μg kg⁻¹ SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal E_max model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC₅₀ values (mean±s.e., n=6) were 131±31 ng ml⁻¹ and 20±3 ng ml⁻¹ for heart rate and NEFA lowering effect, respectively.
5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

     

The protective effects of CP-060S on ischaemia- and reperfusion-induced arrhythmias in anaesthetized rats

1. CP-060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP-060S against ischaemia- and reperfusion-induced arrhythmia was evaluated in anesthetized rats.
2. Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion-induced arrhythmia model) or 30 min without (an ischaemia-induced arrhythmia model). All drugs were intravenously administered 1 min before the onset of occlusion.
3. In the reperfusion-induced arrhythmia model, the animals in the vehicle-treated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP-060S (30–300 μg kg⁻¹) dose-dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 μg kg⁻¹ in VF (incidence: 42%) and mortality (8%), and at 300 μg kg⁻¹ in VT (50%), VF (33%) and mortality (8%). This protective effect of CP-060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30–1000 μg kg⁻¹) we tested, in terms of effective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel blocking activity of CP-060S would not seem to be sufficient to explain its potency.
4. In the same model, co-administration of ineffective doses of diltiazem (300 μg kg⁻¹) and a sodium and calcium overload inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"R56865","term_id":"826971","term_text":"R56865"}}R56865 (100 μg kg⁻¹), produced significant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-administration of {"type":"entrez-nucleotide","attrs":{"text":"R56865","term_id":"826971","term_text":"R56865"}}R56865 at the same dose with CP-060S (300 μg kg⁻¹) did not add to the effect of a single treatment of CP-060S.
5. In the ischaemia-induced arrhythmia model, CP-060S (300 μg kg⁻¹) significantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg⁻¹) was ineffective.
6. These results suggest that CP-060S inhibits both ischaemia- and reperfusion-induced arrhythmia. The combination of the calcium channel blocking effect and the calcium overload inhibition was hypothesized to contribute to these potently protective effects.

     

The role of tachykinin NK1 and NK2 receptors in atropine-resistant colonic propulsion in anaesthetized guinea-pigs

1. The role of endogenous tachykinins on guinea-pig colonic propulsion was investigated by using potent and selective tachykinin NK₁ and NK₂ receptor antagonists. Colonic propulsion and contractions were determined by means of a balloon-catheter device, inserted into the rectum of guanethidine (68 μmol kg⁻¹, s.c., 18 and 2 h before)-pretreated, urethane-anaesthetized guinea-pigs. Propulsion of the device (dynamic model) was determined by measuring the length of the catheter expelled during 60 min filling of the balloon (flow rate 5 μl  min⁻¹).
2. In control conditions the tachykinin NK₁ receptor antagonist SR 140333 (1 μmol kg⁻¹, i.v.) did not affect either colonic propulsion or the amplitude of contractions. The tachykinin NK₂ receptor antagonists MEN 10627 and MEN 11420 (1 μmol kg⁻¹, i.v.) increased colonic propulsion at 10 min (+120% and 150%, respectively) but at 60 min the effect was significant only for MEN 10627 (+84%). SR 48968 (1 μmol kg⁻¹, i.v.) did not significantly enhance the colonic propulsion. None of these tachykinin NK₂ receptor antagonists modified the amplitude of colonic contractions. In contrast, both atropine (6 μmol kg⁻¹, i.v., plus infusion of 1.8 μmol h⁻¹) and hexamethonium (55 μmol kg⁻¹, i.v., plus infusion of 17 μmol h⁻¹) abolished propulsion (81% and 87% inhibition, respectively) and decreased the amplitude of contractions (68% inhibition for either treatment).
3. In atropine-treated animals (6 μmol kg⁻¹, i.v., plus infusion of 1.8 μmol h⁻¹), apamin (30 nmol kg⁻¹, i.v.) restored colonic propulsion (+416%) and increased the amplitude of contractions (+367% as compared to atropine alone). Hexamethonium (55 μmol kg⁻¹, i.v., plus infusion of 17 μmol h⁻¹) abolished the apamin-induced, atropine-resistant colonic propulsion (97% inhibition) and reduced the amplitude of the atropine-resistant contractions (52% inhibition).
4. The apamin-induced, atropine-resistant colonic propulsion was inhibited by SR 140333 (−69% at 1 μmol kg⁻¹), SR 48968 (−78% at 1 μmol kg⁻¹), MEN 11420 (−59% at 1 μmol kg⁻¹) and MEN 10627 (−50% at 1 μmol kg⁻¹), although the latter effect was not statistically significant. The combined administration of SR 140,333 and MEN 10,627 (1 μmol kg⁻¹ for each antagonist) almost completely abolished colonic propulsion (90% inhibition). The amplitude of colonic contractions was also reduced by SR 140333 (−42%), SR 48968 (−29%), MEN 11420 (−45%) but not by MEN 10627 (−16%). The combined administration of SR 140333 and MEN 10,627 reduced the amplitude of contractions by 47%. SR 140603 (1 μmol kg⁻¹, i.v.), the less potent enantiomer of SR 140333, was inactive.
5. In control animals, apamin (30 nmol kg⁻¹, i.v.) enhanced colonic propulsion (+84%) and increased the amplitude of contractions (+68%), as compared to the vehicle. Hexamethonium (55 μmol kg⁻¹, i.v. plus infusion of 17 μmol h⁻¹) inhibited propulsion (86% inhibition) and decreased the amplitude of contractions (49% inhibition). SR 140333, SR 48968, MEN 11420, MEN 10627, or the coadministration of SR 140333 and MEN 10627 had no effect.
6. In a separate series of experiments, the mean amplitude of colonic contractions was also recorded under isovolumetric conditions through the balloon-catheter device kept in place at 75 mm from the anal sphincter (static model). In control conditions, neither SR 140333 nor MEN 11420 modified the amplitude of contractions. In atropine-pretreated guinea-pigs, SR 140333 and MEN 11420 (0.1–1 μmol kg⁻¹) dose-dependently decreased the amplitude of contractions. In apamin- and atropine-pretreated animals, only the highest (1 μmol kg⁻¹) dose of SR 140333 or MEN 11420 significantly decreased the amplitude of contractions. The inhibitory potency of atropine (0.3–1 μmol kg⁻¹) was similar in apamin-pretreated animals and in controls.
7. It was concluded that, in anaesthetized guinea-pigs, endogenous tachykinins, acting through both NK₁ and NK₂ receptors, act as non-cholinergic excitatory neurotransmitters in promoting an apamin-evoked reflex propulsive activity of the distal colon.

     

An endogenous A2B adenosine receptor coupled to cyclic AMP generation in human embryonic kidney (HEK 293) cells

1. Cyclic AMP generation by adenosine analogues was examined in human embryonic kidney (HEK 293) cells by use of a [³H]-adenine pre-labelling methodology.
2. Adenosine analogues showed the following rank order of potency (pD₂ value): 5′-N-ethylcarboxamidoadenosine (NECA, 5.24)>2-chloroadenosine (4.41) ⩾ adenosine (4.19)=N⁶-(2-(4-aminophenyl)-ethylamino)adenosine (APNEA, 4.11). The A_2A-selective agonist {"type":"entrez-protein","attrs":{"text":"CGS21680","term_id":"878113053","term_text":"CGS21680"}}CGS21680 failed to elicit a significant stimulation of cyclic AMP generation at concentrations below 30 μM.
3. Of these agents, NECA was observed to exhibit the greatest intrinsic activity, while in comparison maximal responses to adenosine (76±8% NECA response), 2-chloroadenosine (70±6%) and APNEA (40±3%) were significantly reduced.
4. Antagonists of the NECA-evoked cyclic AMP generation showed the rank order of apparent affinity (apparent pA₂ value): CGS 15943 (7.79)=XAC (7.74)>DPCPX (7.01)=PD115199 (6.93)=8FB-PTP (6.80)>KF 17837 (5.98)>3-propylxanthine (5.13).
5. Agarose gel electrophoresis of the products of the polymerase chain reaction, with cDNA generated from HEK 293 cell total RNA showed virtually identical patterns and nucleotide sizes in comparison with the vector for the full length human brain A_2B adenosine receptor.
6. We concluded that HEK 293 cells express an endogenous adenosine receptor coupled to cyclic AMP generation which is of the A_2B subtype.

     

Effect of DMPPO,a phosphodiesterase type 5 inhibitor,on hypoxic pulmonary hypertension in rats

1. Cyclic guanosine 3′–5′-monophosphate (cyclic GMP) is the second messenger of important physiologically active mediators controlling the pulmonary vascular tone. To potentiate the effects of cyclic GMP on the pulmonary vasculature, we used DMPPO, a new selective PDE-5 inhibitor, and examined its action in a rat model of hypoxic pulmonary hypertension.
2. Levels of cyclic GMP measured during baseline conditions at 5 and 60 min of perfusion were similar in the perfusate of isolated lungs from normoxic and chronically hypoxic rats and did not differ with time. Pretreatment with DMPPO (1 μM) induced a larger increase in cyclic GMP concentration in the perfusate from chronically hypoxic rat lungs (319±36 at 5 min to 1821±83 pmol ml⁻¹ at 60 min) than in normoxic rat lungs (329±20 to 1281±127 pmol ml⁻¹, P<0.05).
3. In isolated lungs preconstricted with U-46619, pretreatment with DMPPO (1 μM) potentiated the vasodilator effects of atrial natriuretic peptide (100 pM–10 nM) and sodium nitroprusside (1 pM–10 nM), but did not alter vasodilation to isoproterenol.
4. In conscious rats previously exposed to 15 days hypoxia and studied under 10% O₂, DMPPO (0.01, 0.05 and 0.1 mg kg⁻¹, i.v. bolus) caused a dose-dependent decrease in pulmonary arterial pressure (Pap) with no change in systemic artery pressure (Sap) and cardiac output.
5. Continuous infusion of DMPPO (0.1 mg kg⁻¹ h⁻¹ i.v. by osmotic pumps) in rats exposed to 10% O₂ during 2-weeks reduced the Pap (P<0.05) and the degree of muscularization of pulmonary vessels at the alveolar wall (P<0.01) and alveolar duct levels (P<0.05) despite no significant change in right ventricular hypertrophy.
6. These results suggest that cyclic GMP phosphodiesterase inhibition may selectively dilate pulmonary circulation during chronic hypoxia.

     

Effect of chronic bradykinin B2 receptor blockade on blood pressure of conscious Dahl salt-resistant rats

1. In this study 3 protocols were utilized to determine the role of endogenous kinins in the resistance of the inbred Dahl (Rapp) salt-resistant (SR/Jr) rats to high salt diet-induced blood pressure elevation.
2. The bradykinin B₂ receptor antagonist, Hoe 140 (D-Arg[Hyp³, Thi⁵, D-Tic⁷, Oic⁸]-bradykinin) at doses of either 10–20 or 20–40 nmol day⁻¹ (subcutaneously (s.c), via osmotic minipumps, for either 1 or 3 weeks during a high (8%) salt diet) effectively blocked or attenuated the hypotensive responses to 100–1000 ng of bradykinin.
3. In the first protocol, 5 week old SR/Jr rats treated with Hoe 140 (10–20 nmol day⁻¹, n=9, s.c., via osmotic minipumps) for 3 weeks and concomitantly fed high (8%) NaCl diet had significantly higher conscious tail cuff blood pressures (BPc) at 1 and 3 weeks when compared with rats treated with vehicle (0.9% NaCl, n=6). The differences in BPc between the 2 groups were 13 mmHg (P<0.001) after 1 week and 8 mmHg (P<0.05) after 3 weeks of treatment.
4. In the second protocol, 5 week old SR/Jr rats were treated with Hoe 140 (20–40 nmol day⁻¹, n=8, s.c., via osmotic minipumps) or vehicle (n=8) for 3 weeks. During the first week of treatment the rats were fed normal (0.8%) NaCl diet. The rats were then switched to 8% NaCl for 2 remaining weeks of the protocol. The mean BPc of Hoe 140-treated rats was not significantly different from that of the vehicle-treated rats when fed 0.8% NaCl diet. In contrast, rats treated with Hoe 140 and concomitantly fed high (8%) NaCl diet had significantly increased BPc (123±2 vs 111±1 mmHg, P<0.001 for the Hoe 140- and vehicle-treated rats, respectively).
5. In the third protocol, treatment with Hoe 140 (20–40 nmol day⁻¹, s.c., via osmotic minipumps) during high salt diet did not increase BPc in rats that were pre-exposed to the high salt diet for 2 weeks.
6. At the end of 3 weeks of study, blood pressure was measured via an arterial catheter during pentobarbitone-induced anaesthesia. Rats treated with Hoe 140 for 1 or 3 weeks had significantly lower mean arterial blood pressures than the vehicle-treated rats.
7. Our findings suggest that in SR/Jr rats, kinin activation of bradykinin B₂ receptors at least partially contributes to early regulatory mechanisms that resist an increase in blood pressure following exposure to a high salt diet. The mechanism underlying the decreased blood pressure during pentobarbitone anaesthesia of SR/Jr rats chronically treated with Hoe 140 has yet to be elucidated.

     

Direct cardiac and vascular actions of adrenomedullin in conscious sheep

1. Adrenomedullin (ADM) is a recently characterized circulating hormone which affects haemodynamic, renal and pituitary function in mammals. We have shown previously that in sheep, ADM produces vasodilatation together with increases in cardiac output and contractility. However, whether these effects are direct or mediated by autonomic reflexes is unclear. The present study examined the cardiovascular actions of an intravenous infusion of ADM in conscious, chronically instrumented sheep with either sympathetic, parasympathetic or autonomic ganglion blockade, to determine the role of the autonomic nervous system in mediating these cardiovascular changes.
2. Human ADM (1–52) was infused for 60 min at 2 μg kg⁻¹ h⁻¹ following: (1) saline control, (2) combined α/β-adrenoceptor (sympathetic) blockade (proporanolol 0.4 mg kg⁻¹ h⁻¹+phentolamine 0.15 mg kg⁻¹ h⁻¹ for 20 h), (3) muscarinic (parasympathetic) blockade (methscopolamine 0.05 mg kg⁻¹ h⁻¹ for 20 h) or (4) ganglion blockade (hexamethonium 3 mg kg⁻¹ h⁻¹ for 4 h). Measurements were made of mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), maximal aortic flow (Fmax) and maximal rate of change of aortic flow (dF/dt).
3. ADM reduced MAP by 3±1 mmHg, and increased CO (1.2±0.2 l min⁻¹), HR (14±2 beats min⁻¹), TPC (21±3 ml min⁻¹ mmHg⁻¹), Fmax (2.3±0.8 l min⁻¹) and dF/dt (86±21 l min⁻¹ s⁻¹) in normal sheep. In animals with α/β blockade, similar changes were observed with ADM. However, during muscarinic blockade, the increases in HR (32±4 beats min⁻¹), CO (2.1±0.4 l min⁻¹), TPC (31±4 ml min⁻¹ mmHg⁻¹), Fmax (4.0±0.6 l min⁻¹), and dF/dt (150±12 l min⁻¹ s⁻¹) produced by ADM were enhanced. During ganglion blockade, ADM produced a greater reduction in MAP (−10±2 mmHg) compared to controls (−3±1 mmHg). However, there was no increase in HR. The changes in CO, TPC and contractility were similar to those observed in control animals.
4. These results suggest that the vasodilator effects of ADM on the periphery and its ability to increase CO and cardiac contractility are not mediated by the autonomic nervous system, but are probably the result of direct actions of ADM on the heart and vasculature.

     

Cigarette smoke-inhibition of neurogenic bronchoconstriction in guinea-pigs in vivo: involvement of exogenous and endogenous nitric oxide

1. We investigated the effect of acute inhalation of cigarette smoke on subsequent non-adrenergic, non-cholinergic (NANC) neural bronchoconstriction in anaesthetized guinea-pigs in vivo by use of pulmonary insufflation pressure (PIP) as an index of airway tone. The contribution of endogenous nitric oxide (NO) was investigated with the NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME). The contribution of plasma exudation to the response was investigated with Evans blue dye as a plasma marker.
2. Inhalation of 50 tidal volumes of cigarette smoke or air had no significant effect on baseline PIP. In the presence of propranolol and atropine (1 mg kg⁻¹ each), electrical stimulation of the vagus nerves in animals given air 30 min previously induced a frequency-dependent increase in PIP above sham stimulated controls (16 fold increase at 2.5 Hz, 24 fold increase at 10 Hz). In contrast, in smoke-exposed animals, the increase in subsequent vagally-induced PIP was markedly less than in the air controls (90% less at 2.5 Hz, 76% less at 10 Hz).
3. L-NAME (10 mg kg⁻¹), given 10 min before air or smoke, potentiated subsequent vagally-induced (2.5 Hz) NANC bronchoconstriction by 338% in smoke-exposed animals, but had no significant effect in air-exposed animals. The inactive enantiomer D-NAME (10 mg kg⁻¹) had no effect, and the potentiation by L-NAME was partially reversed by the NO-precursor L-arginine (100 mg kg⁻¹). Vagal stimulation did not affect the magnitude of vagally-induced bronchoconstriction 30 min later.
4. Cigarette smoke exposure reduced the magnitude of subsequent bronchoconstriction induced by neurokinin A (NKA) by 37% compared with the effect of NKA in air-exposed animals. L-NAME had no significant effect on the smoke-induced inhibition of NKA-induced bronchoconstriction.
5. Vagally-induced plasma exudation in the main bronchi was greater in smoke-exposed animals compared with air-exposed animals (120% greater at 2.5 Hz, 82% greater at 10 Hz).
6. We conclude that cigarette smoke-induced inhibition of subsequent NANC neurogenic bronchoconstriction is not associated with inhibition of airway plasma exudation and is mediated in part via exogenous smoke-derived NO, or another bronchoprotective molecule, and by endogenous NO.

     

A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity

1. Intraplantar injection of carrageenan (150 μl, 1–3% w/v) in the rat resulted in a dose-related increase in hindpaw weight (oedema) characterized by a rapid ‘early'' phase (up to 2.5 h) response followed by a more sustained ‘late'' phase (2–6 h) response. No change in weight of either the contralateral (i.e. noninjected) hindpaw or hindpaws injected with saline was observed.
2. Six hours after intraplantar injection of carrageenan (1–3% w/v) hindpaw constitutive (i.e. calcium-dependent) nitric oxide synthase (cNOS) activity (determined ex vivo as the conversion of radiolabelled L-arginine to radiolabelled citrulline) was increased (e.g. 2% w/v; 0.64±0.08 pmol citrulline mg⁻¹ protein 15 min⁻¹ c.f. 0.08±0.04 pmol citrulline mg⁻¹ protein 15 min⁻¹ in saline-injected, control animals, n=4, P<0.05). Carrageenan injection also resulted in the appearance in hindpaw homogenates of inducible (i.e. calcium-independent) nitric oxide synthase (iNOS, e.g. 2% w/v; 0.67±0.14 pmol citrulline mg⁻¹ protein 15 min⁻¹, n=4). Hindpaw cyclic GMP concentration was also significantly increased 6 h after intraplantar injection of carrageenan (e.g. 2% w/v; 379.6±26.8 fmol mg⁻¹ protein c.f. 261.8±42.2 fmol mg⁻¹ protein, in saline-injected, control animals, n=4, P<0.05).
3. Pretreatment (5–25 mg kg⁻¹, i.p., 30 min before carrageenan, 2% w/v) of animals with L-N^G nitro arginine methyl ester (L-NAME; isoform nonselective inhibitor of NOS) or 7-nitro indazole (7-NI; inhibitor of neuronal NOS, nNOS) caused dose-related inhibition of both the early (2 h) and late (6 h) phase hindpaw oedema, associated with reduced hindpaw iNOS and cNOS activity and cyclic GMP concentration in animals killed at 6 h. Administration of 7-NI (5–25 mg kg⁻¹, i.p.) to animals 2.5 h after intraplantar carrageenan (2% w/v) injection (i.e. at the end of the early phase oedema response) produced dose-related inhibition of the late phase response.
4. Pretreatment (5–25 mg kg⁻¹, i.p., 30 min before carrageenan, 2% w/v) of animals with L-N6-iminoethyllysine (L-NIL, selective inhibitor of iNOS) (5–25 mg kg⁻¹) failed to affect the early phase hindpaw oedema response but did produce a dose-related inhibition of the late phase oedema. L-NIL pretreatment also inhibited the carrageenan-induced increase in both hindpaw iNOS and cNOS activity as well as the rise in hindpaw cyclic GMP concentration.
5. The present experiments demonstrate an anti-inflammatory effect of 7-NI as evidenced by inhibition of carrageenan-induced hindpaw oedema in the rat. Inhibition of nNOS (early phase) and iNOS (late phase) at the site of inflammation most probably accounts for the anti-inflammatory activity observed. These data suggest a role for nitric oxide synthesized by the nNOS isoform (most probably within sensory nerves) in this model of inflammation.

     

T-type and L-type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats

1. This study aimed to investigate and to compare the effects of pharmacological T-type calcium channel and of L-type calcium channel blockade on the renin system. To this end, male healthy Sprague-Dawley rats were treated with the T-channel blocker mibefradil or with the L-channel blocker amlodipine at doses of 5 mg kg⁻¹, 15 mg kg⁻¹ and 45 mg kg⁻¹ per day for four days and their effects on plasma renin activity (PRA) and kidney renin mRNA levels were determined.
2. Whilst amlodipine lowered basal systolic blood pressure at 5 mg kg⁻¹, mibefradil had no effect on basal blood pressure in the whole dose range examined. Amlodipine dose-dependently induced up to 7 fold elevation of PRA and renin mRNA levels. Mibefradil significantly lowered PRA and renin mRNA levels at 5 mg kg⁻¹ and moderately increased both parameters at a dose of 45 mg kg⁻¹, when PRA and renin mRNA levels were increased by 100% and 30%, respectively. In primary cultures of renal juxtaglomerular cells neither amlodipine nor mibefradil (0.1–10 μM) changed renin secretion.
3. In rats unilateral renal artery clips (2K-1C) mibefradil and amlodipine at doses of 15 mg kg⁻¹ day⁻¹ were equally effective in lowering blood pressure. In contrast mibefradil (5 mg kg⁻¹ and 15 mg  kg⁻¹ day⁻¹) significantly attenuated the rise of PRA and renin mRNA levels, whilst amlodipine (15 mg kg⁻¹) additionally elevated the rise of PRA and renin mRNA levels in response to renal artery clipping.
4. These findings suggest that T-type calcium channel blockers can inhibit renin secretion and renin gene expression in vivo, whilst L-type calcium channel blockers act as stimulators of the renin system. Since the inhibitory effect of T-type antagonists is apparent in vivo but not in vitro, one may infer that the effect on the renin system is indirect rather than directly mediated at the level of renal juxtaglomerular cells.

     

The influence of tumour necrosis factor-α on the cardiovascular system of anaesthetized rats

The effects of two vasoactive agents (adenosine A2A agonist, CGS 21680, and adrenoceptor agonist, noradrenaline) were examined on cardiac output (CO), heart rate (HR), blood pressure (BP), mean circulatory filling pressure (Pmcf), resistance to venous return, arterial resistance, dP/dt, plasma levels of NO2-/NO3-, and inducible nitric oxide synthase (iNOS) activity in lungs ex vivo, following treatment with tumour necrosis factor-alpha (TNF-alpha; 30 microg/kg) in anaesthetized rats. Treatment with TNF-alpha produced significant reduction in CO (41+/-2%), dP/dt (26+/-3%), BP (26+/-2%) and Pmcf (27+/-4%; n=6; mean+/-SEM), but increased arterial resistance. There were no significant changes in the plasma levels of NO2-/NO3-levels over time following treatment with TNF-alpha, but there was a significant increase (approximately twofold) in the activity of the iNOS in the lungs of animals treated with TNF-alpha. Administration of CGS 21680 (1.0 microg/kg per min) significantly increased CO (44+/-6%), HR (12+/-2%), Pmcf (24+/-4%) and dP/dt (24+/-5%) in TNF-alpha-treated rats. CGS 21680 also significantly reduced arterial resistance (33+/-2%) without altering resistance to venous return in TNF-alpha-treated rats. While noradrenaline (1.0 microg/kg per min) infusion did not significantly increase CO, it did significantly increase HR (12+/-1%), BP (55+/-9%), Pmcf (47+/-5%), dP/dt (65+/-7%), resistance to venous return (64+/-20%), and arterial resistance (41+/-16%) in TNF-alpha-treated animals. The reduction in BP due to administration of TNF-alpha is the result of significant reduction in CO. Consequently, the decline in CO can be attributed to a combination of a negative inotropic effect as well as a reduction in Pmcf. It is evident that infusion with CGS 21680 could reverse the negative impact of TNF-alpha on CO by increasing dP/dt, Pmcf and HR as well as a reduction in arterial resistance. The fact that noradrenaline did not significantly increase CO in TNF-alpha-treated rats can be attributed to increased arterial resistance as well increase in resistance to venous return.     

Comparative effects of the dual metallopeptidase inhibitor,MDL 100,240 and of enalaprilat on regional and on cardiac haemodynamics in conscious,hypertensive, transgenic ((mRen-2)27) rats

1. Heterozygous, male, hypertensive, transgenic ((mRen-2)27) rats (350–450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin-converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg⁻¹, 3 mg kg⁻¹ h⁻¹; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B₂)-receptor antagonist, Hoe 140 (1 mg kg⁻¹, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin.
2. Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (−54 ± 9 mmHg) was greater than that of enalaprilat (−38 ± 4 mmHg), because the former caused a significantly greater reduction in cardiac index.
3. Between 8–24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds.
4. There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug.
5. These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen-2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.