Differential regulation of mesenteric and femoral blood flow in the rat as revealed by computerized data acquisition and evaluation

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Further investigations into the mechanism of the antihypertensive activity of the angiotensin AT1 receptor antagonist, GR138950.

1. The angiotensin AT1 receptor antagonist, GR138950, produces a long-lasting antihypertensive effect in conscious renal artery ligated hypertensive (RALH) rats but this effect does not correlate temporally with its antagonist profile against angiotensin II (AII). In the present experiments we have compared the inhibitory profiles of GR138950 and enalapril, against angiotensin I (AI), with their respective antihypertensive activities. 2. GR138950 (1 mg kg-1, i.a.) and enalapril (3 mg kg-1, i.a.) reduced blood pressure in RALH rats to a similar degree. Maximum reductions in blood pressure occurred approximately 5-24 h and 3-5 h after administration, respectively. The antihypertensive effect of GR138950 lasted for 24-48 h. However, the effect of enalapril lasted for only 5-24 h. 3. In conscious normotensive rats, inhibition of AI-induced pressor responses was maximal 1 h after systemic administration of GR138950 and enalapril. Dose-response curves to AI were displaced to the right, in a parallel manner, 1406 and 102 fold by GR138950 (1 mg kg-1, i.a.) and enalapril (3 mg kg-1 i.a.), respectively. The inhibitory effect of enalapril lasted for < 24 h whereas that of GR138950 lasted for up to 48 h. 4. Contractile responses to AI were extensively inhibited in aortae removed from either RALH rats or normotensive rats, 1 and 5 h after administration of GR138950 (1 mg kg-1, i.a.). Responses were still significantly reduced 24 h after administration but had returned to control levels after 48 h. Enalapril pretreatment (3 mg kg-1, i.a.) did not inhibit contractile responses to AI in aortae isolated from normotensive rats at any time point. 5. These experiments confirm that GR138950 is an effective and long-lasting antihypertensive agent. GR138950 was a more potent and longer lasting antagonist against AI than has previously been found against AII, and the duration of its antihypertensive activity coincides better with its blockade of responses to AI. Blockade of the effects of AII generated locally within the vascular wall might play an important role in the antihypertensive profile of GR138950.     

A comparison of the characteristics of angiotensin receptors in the renal and mesenteric vascular beds of the anesthetized cat.

Experiments were performed in anesthetized cats to compare the characteristics of angiotensin receptors in the renal and mesenteric vascular beds. Injection of either angiotensin II (Ang II; 0.3-30 ng) or angiotensin III (Ang III; 0.3-30 ng) directly into the superior mesenteric or renal artery caused dose-related, reproducible reductions in mesenteric and renal blood flow, respectively. Ang II and Ang III were equipotent as vasoconstrictors in both vascular beds. The peptide angiotensin receptor antagonists saralasin and Ile7-Ang III (1 microgram/kg/min intravenously, i.v.) and the nonpeptide angiotensin receptor antagonist DuP 753 (3 mg/kg plus 20 micrograms/kg/min i.v.) caused a rightward displacement of dose-response curves to Ang II or Ang III in both the mesenteric and renal vasculature. Vasoconstrictor responses to Ang II or Ang III in either vascular bed were blocked to similar extents by each antagonist. In separate cats, the dose of the antagonists required to cause a 10-fold rightward displacement of the Ang II dose-response curve (DR10) in both vascular beds was determined. The DR10 values indicated that the potency of each antagonist was similar in the renal and mesenteric vascular beds. These results provide no evidence to suggest that angiotensin receptors mediating vasoconstriction in the renal and mesenteric vasculature have different characteristics.     

Inhibition of noradrenergic neurotransmission by apomorphine and pergolide in the in situ autoperfused rat renal and superior mesenteric vascular beds

Summary In vitro studies have provided evidence that presynaptic dopamine receptors are present in the rat renal and superior mesenteric vascular beds. To confirm this in vivo, the effects of locally administered apomorphine and pergolide were studied in the in situ autoperfused renal and superior mesenteric vascular beds.Local infusion of apomorphine (1 g · kg^–1 · min^–1 for 5 min) or pergolide (1 g · kg^–1 · min^–1 for 5 min) into either the renal or the superior mesenteric artery had no effect on perfusion pressure per se. In the renal vascular bed, the pressure response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) was reduced to 49.8±4.8% by apomorphine and to 54.8±2.7% by pergolide; in the mesenteric vascular bed, apomorphine reduced the pressure response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) to 53.8±2.9, pergolide to 52.0±1.8%. Increases of perfusion pressure in the renal and in the mesenteric vascular bed induced by locally administered noradrenaline were not modified by apomorphine or pergolide.In both vascular beds, the inhibition of the stimulation-evoked pressure responses by apomorphine or pergolide was completely antagonized by local administration of the dopamine receptor antagonist haloperidol in a dose (1 g · kg^–1) which did not influence the inhibitory effect of the ₂-adrenoceptor agonist UK-14,304; the ₂-adrenoceptor antagonist rauwolscine, in a dose (100 g · kg^–1) which completely antagonized the inhibitory effect of UK-14,304, did not antagonize the inhibitory effects of apomorphine and pergolide.Local administration of rauwolscine per se increased the pressure response to stimulation at 4 Hz in both vascular beds. In contrast, local administration of haloperidol did not influence the stimulation-evoked pressure response.These results provide evidence for the presence of presynaptic, inhibitory dopamine receptors on sympathetic nerves in the rat renal and mesenteric vascular beds; these receptors could be involved in the blood pressure lowering effects of dopamine receptor agonists, such as apomorphine and pergolide.Research Associate of the National Fund for Scientific Research (Belgium)     

The role of angiotensin II AT1 receptor in the maintenance of hemodynamics in a canine model of coronary microembolization-induced heart failure

The purpose of this study was to determine whether Angiotensin II (Ang II) contributes to the regulation of resting hemodynamics via Ang II type 1 (AT1) receptors in awake dogs with coronary microembolization-induced heart failure. Six dogs were surgically instrumented for measurement of systemic hemodynamics and for coronary microembolization. The acute hemodynamic effects of a selective AT1-receptor antagonist, GR138950 (1 mg/kg, i.v.), were determined before and after congestive heart failure (CHF). GR138950 had no effects on hemodynamics before CHF Daily coronary microembolizations (through the previously implanted coronary catheter) resulted in CHF, as documented by hemodynamic measurements, a slight but significant increased Ang II plasma level (17.4 +/- 1.6 vs. 23 +/- 1.0 pg/ml; p < 0.05), and characteristic clinical signs of CHF. After CHF, GR138950 significantly increased left ventricular dP/dt(max) (LVdP/dt(max)) from 1,754 +/- 68 to 2,347 +/- 114 mm Hg/s and decreased LV systolic pressure (LVSP) from 118 +/- 5 to 101 +/- 7 mm Hg; meanwhile, heart rate (from 132 +/- 4 to 102 +/- 6 beats/min) and LV end-diastolic pressure (LVEDP; from 17 +/- 3 to 9 +/- 1.5 mm Hg) were significantly decreased. Mean arterial pressure (MAP) was not affected. The peak effects occurred 90 min after administration. Thus Ang II contributes significantly to resting hemodynamics via AT1 receptors in this CHF model; that is, the specific AT1 blocker inhibits the negative inotropic actions of Ang II in the CHF state.     

强心扩血管药羟苯氨酮对大鼠,猫和狗心脏血流动力学的影响

为了解强心扩血管新药羟苯氨酮( oxyphenamone,9003 )对在体心血管系统的效应,用多导生理仪与电磁流量计测定大鼠,猫与狗的心脏血流动力学参数。结果表明,静注羟苯氨酮引起血压与血管阻力中度下降,心输出量,心肌收缩力与收缩力变化速度,冠状动脉和股动脉血流量明显增加。羟苯氨酮对心率与左室压的影响呈现种系差别,它增加狗的左室收缩压与压力变化速度,降低左室舒张末期压力,小剂量羟苯氨酮(1或3mg·kg^-1)引起狗的心率轻度降低,剂量增到6mg·kg^-1,心率中度加快。羟苯氨酮不影响猫的心率与左室压。大鼠静注羟苯氨酮后引起心率,左室收缩压与压力变化速度降低,左室舒张末期压力无变化。羟苯氨酮对心脏血流动力学的影响有待用病理模型作进一步观察。     

AT1 RECEPTOR ANTAGONIST, TCV 116, DOES NOT PREVENT CARDIAC HYPERTROPHY IN SALT-LOADED DAHL SALT-SENSITIVE RATS

1. We investigated the effects of direct blockade of angiotensin II (AngII) by a potent, non-peptide angiotensin II type 1 (AT₁) receptor antagonist, TCV 116, on the development of cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats.
2. Six week old male Dahl salt-sensitive rats ( n = 44) were fed a 4% salt diet and were simultaneously given various doses of TCV 116 orally for 7 weeks. Each control group received vehicle alone.
3. Dietary high salt intake elevated blood pressure continuously and caused left ventricular hypertrophy in rats treated with vehicle. TCV 116 had a minor effect on the rise in blood pressure. Left ventricular mass (left ventricular weight/body-weight) decreased slightly but not significantly, in rats treated with 3mg/kg per day of TCV 116 ( n = 8). Higher doses of TCV 116 (6 and 10 mg/kg per day; n = 8 each) did not show a decrease in left ventricular mass compared with the vehicle control.
4. These results suggest that AngII blockade has only minor effects on hypertension and on cardiac hypertrophy in salt-loaded Dahl salt-sensitive rats and that the renin-angiotensin system may not contribute to the development of cardiac hypertrophy in Dahl salt-sensitive rats on a moderately high-salt diet.     

Influence of intravenous infusion of ethanol on regional blood flow in conscious rats

Abstract— The effects of intravenous infusions of ethanol and saline (0·9% NaCl) on mean arterial pressure (MAP), heart rate (HR), total peripheral resistance (TPR), cardiac contractility (dP/dt_max) and systemic haemodynamics were studied in conscious, unrestrained rats by the radioactive microsphere technique. Saline (0·03 and 0·06 mL min^?1 kg^?1 for 12 min each dose) in the time-control group did not affect MAP, HR, TPR, dP/dt_max or vascular conductances in any organs or beds. While the low dose ethanol (2·4 mg min^?1 kg^?1) did not alter MAP, HR, TPR, systemic haemodynamics or dP/dt_max, the high dose (4·8 mg min^?1 kg^?1) slightly reduced MAP and TPR but did not affect HR, cardiac output or dP/dt_max. Both doses of ethanol vasodilated the intestine and spleen, but vasoconstricted the skin. The high dose caused additional vasodilatation in the heart and testes and the low dose also constricted the skeletal muscle bed. Our results show that ethanol, at non-hypotensive or slightly hypotensive doses, has marked vasodilator effects in the heart, intestine, spleen and testes.     

Comparison of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition in pregnant sheep during late gestation.

1. The effects of antagonism of the maternal renin-angiotensin system (RAS) with either an angiotensin II type 1-(AT1) specific receptor blocker (GR138950) or an angiotensin-converting enzyme (ACE) inhibitor (captopril) were compared in chronically-catheterised ewes and their foetuses during late gestation. 2. Daily from 127 +/- 1 days of gestation until parturition at 145 +/- 2 days, each ewe received i.v. either GR138950 (3 mg kg-1; n = 10), captopril (3 mg kg-1; n = 6) or an equivalent volume of vehicle solution (0.9% w/v saline; n = 10). 3. Within 2 h of drug administration, GR138950 abolished the maternal, but not the foetal, pressor responses to angiotensin II (AII; 100-188 ng kg-1, i.v.; P < 0.05), whereas captopril abolished both the maternal and foetal pressor responses to angiotensin I (AI; 400-750 ng kg-1, i.v.; P < 0.05). 4. On the first day of treatment, maternal blood pressure decreased in all GR138950-treated (-21 +/- 4 mmHg; P < 0.05) and captopril-treated (-13 +/- 5 mmHg; P > 0.05) ewes at 2 h after drug administration. Captopril also significantly decreased foetal blood pressure by 5 +/- 1 mmHg (P < 0.05). However, foetal blood pressure in the GR138950-treated animals remained unchanged. Maternal and foetal heart rates were unaffected by any treatment. Uterine blood flow was significantly reduced within 2 h of both GR138950 (-130 +/- 20 ml min-1; P < 0.05) and captopril (-72 +/- 16 ml min-1; P < 0.05) administration. 5. On the first day of treatment, maternal arterial haemoglobin (Hb) concentration and oxygen (O2) content increased at 2 h in all GR138950-treated and captopril-treated ewes. Foetal arterial pH and oxygenation (O2 content, O2 saturation and Pao2) were reduced by a similar extent in both groups of drug-treated ewes. 6. After one week of daily GR138950 administration, maternal blood pressure decreased from a pretreatment value of 96 +/- 5 mmHg on day 1 to 79 +/- 2 mmHg by day 7 (P < 0.05). Captopril treatment had no long-term effect on maternal blood pressure. Although foetal blood pressure increased by 3 +/- 1 mmHg over a week of vehicle treatment (P < 0.05), no significant differences were observed between the long-term changes in foetal blood pressure in all three groups of animals. 7. There were no long-term effects of drug administration on maternal Hb concentration or oxygenation, or on the foetal haematological parameters. However, changes in maternal PaCo2 observed in the GR138950-treated (+1.4 +/- 0.5 mmHg; P < 0.05) and captopril-treated (+3.3 +/- 1.1 mmHg; P > 0.05) ewes were significantly different from those seen in the vehicle-treated animals (P < 0.05). 8. There were no apparent adverse effects of maternal GR138950 or captopril treatment on foetal viability. 9. The present study demonstrated that administration of either GR138950 or captopril to pregnant ewes effectively blocked the maternal RAS, and caused hypotension and a decrease in uterine blood flow. However, only captopril appeared to cross the placenta to influence directly the RAS of the sheep foetus. This suggests that the fall in foetal oxygenation observed after AT1-specific receptor blockade and ACE inhibition originates primarily from changes in the maternal and/or placental vasculature. Despite these changes, neither GR138950 nor captopril were detrimental to the outcome of pregnancy when foetal blood loss was kept to a minimum.     

VASOCONSTRICTOR RESPONSES TO COMPONENTS OF THE RENIN-ANGIOTENSIN SYSTEM IN CYCLOSPORIN-INDUCED HYPERTENSION IN THE RAT

1. Since plasma renin activity is increased in cyclosporin A (CsA)-induced hypertension in the rat, the role of the vascular renin-angiotensin system (RAS) in CsA-induced hypertension was investigated in rat mesenteric resistance vessels. 2. Female Wistar rats received CsA (10 mg/kg per day, s.c.) or vehicle for 30 days. CsA treatment increased tail-cuff systolic blood pressure (CsA treated 135 ± 3 mmHg vs control 125 ± 1 mmHg, P<0.0001). 3. Mesenteric resistance arteries (200–300 μm) were isolated and mounted in a microvessel myograph. Concentration-response curves to tetradecapeptide renin substrate (10-¹¹-10^?6 mol/L), angiotensin I (10-^l1-10^?6 mol/L) and angiotensin II (10-¹²-10^?6 mol/L) showed no differences between CsA-treated and control groups. 4. Mesenteric vascular angiotensin-converting enzyme (ACE) characteristics were determined by radioligand binding. There were no differences in the content or affinity of ACE between CsA-treated and control rats. 5. These results suggest that the mesenteric vascular RAS does not play a major role in CsA-induced hypertension in the rat.     

Comparative Cardiovascular Effects of the Angiotensin II Type 1 Receptor Antagonists ZD 7155 and Losartan in the Rat

Binding experiments show that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. In this study this novel substance was studied in normotensive and hypertensive rats. The relative potency and duration of the antihypertensive effects of ZD 7155 were compared with those of the reference substance, losartan. The inhibitory effects of both compounds on angiotensin II-induced pressor actions were studied in the conscious normotensive Sprague-Dawley (SD) rat and in the conscious, spontaneously hypertensive rat (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intraarterial recording. Angiotensin II infusion was administered intravenously in the dose range 53.3 ng—12.8 μg kg^?1 min^?1 to the conscious rats. ZD 7155 was administered in a bolus dose of 1.082 μmol kg^?1 (0.51 mg kg^?1) and losartan in bolus doses of 2.165 and 6.495 μmol kg^?1 (1.0 and 3.0 mg kg^?1). In conscious SD rats, ZD 7155 and losartan behaved as competitive antagonists and the pressor response curve to angiotensin II was shifted to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response (240 ng kg^?1; 10 min infusion). In addition, experiments with conscious rats demonstrated that ZD 7155 could suppress the angiotensin II-induced pressor response for approximately 24 h when ZD 7155 was administered intravenously in a 1.082 μmol kg^?1 bolus dose and angiotensin II was given at 240 ng kg^?1 (in a 10?min infusion). Experiments in conscious SHRs using ZD 7155 (1.082 μmol kg^?1) and losartan (6.495 μmol kg^?1) as intravenous boluses indicated that both ZD 7155 and the reference compound losartan exhibited a significant antihypertensive effect. These results demonstrate that ZD 7155 is a potent angiotensin II-type 1 antagonist which is approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response. Furthermore, ZD 7155 may suppress the angiotensin II-induced pressor response for 24 h and in the SHR ZD 7155 induces a pronounced and persistent antihypertensive effect.     

Pharmacodynamics of ZM 241385, a Potent A2a Adenosine Receptor Antagonist,after Enteric Administration in Rat,Cat and Dog

4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A_2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1–10 mg kg^?1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg^?1 min^?1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg^?1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6–10 mg kg^?1, i.v.) by 94% after 10 mg kg^?1 (p.o.) and by up to 74% after 0.3 mg kg^?1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg^?1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1–10 mg kg^?1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg^?1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg^?1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A_2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A_2a receptors in the action of adenosine in-vivo.     

Effects of the neuropeptide Y Y1 receptor antagonist SR 120107A on sympathetic vascular control in pigs in vivo

The possible involvement of neuropeptide Y in sympathetic vasoconstriction in various vascular beds in anesthetized pigs in vivo was studied using the neuropeptide Y Y₁ receptor antagonist SR 120107A. Single impulse sympathetic nerve stimulation evoked rapid vasoconstrictor responses in hind limb and nasal mucosa which were not affected by SR 120107A (1.5 mg kg^–1). Vascular responses to high frequency stimulation was measured in kidney, spleen (three I s bursts at 20 Hz or 300 impulses at 10 Hz), hind limb and nasal mucosa (three 1 s bursts at 20 Hz). High frequency stimulation evoked rapid vasoconstriction in all vascular beds studied. This was followed by a long-lasting phase of reduced blood flow in hind limb and nasal mucosa. SR 120107A (1.5 mg kg^–1) attenuated the vasoconstriction evoked by the 20 Hz stimulation in the kidney, whereas a higher dose (a total of 6.0 mg kg^–1) was required to reduce the vascular response in kidney to the 10 Hz stimulation. SR 120107A (1.5 mg kg^–1) did not inhibit the vascular responses in spleen, hind limb or nasal mucosa to the 20 Hz stimulation or the vasoconstriction in spleen to the 10 Hz stimulation (a total of 6 mg kg-1). Subsequent addition of the adrenoceptor antagonists phenoxybenzamine (5 mg kg-1) plus timolol (2 mg kg-1) strongly reduced the vascular responses to single impulse stimulation and high frequency stimulation (20 Hz series) in all vascular beds. We conclude that endogenous neuropeptide Y acting on the neuropeptide Y Y₁ receptor, as revealed by SR 120107A, is likely to account for part of the sympathetic vasoconstriction upon high frequency stimulation in the kidney.     

Pharmacokinetics and tissue distribution of a new carbapenem,DA-1131, after intravenous administration to mice,rats, rabbits and dogs

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA-1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After iv administration to mice (20, 50, 100, and 200 mg kg⁻¹), rats (50, 100, 200, and 500 mg kg⁻¹), rabbits (20, 50, 100, and 200 mg kg⁻¹), and dogs (10, 20, 50, 100, and 200 mg kg⁻¹), the pharmacokinetic parameters of DA-1131 seemed to be independent of DA-1131 doses studied in all four animal species. However, the renal clearance and percentage of iv dose of DA-1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg⁻¹) and dogs (from 100 mg kg⁻¹) due to reduced kidney function induced by DA-1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg⁻¹ compared with that in the control rabbits (0.466 versus 4.31 mL min⁻¹ kg⁻¹). Renal active secretion of DA-1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA-1131 was observed in dogs. Although DA-1131 was widely distributed in all tissues studied in mice (20–200 mg kg⁻¹), rats (200 mg kg⁻¹), rabbits (50 mg kg⁻¹), and dogs (50 mg kg⁻¹), affinity of DA-1131 for tissues was low: the tissue-to-plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA-1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147–187 mL kg⁻¹), rabbits (91.7–148 mL kg⁻¹), and dogs (243–298 mL kg⁻¹). The contribution of biliary excretion of unchanged DA-1131 to nonrenal clearance of DA-1131 seemed to be minor in rats (200 mg kg⁻¹) and dogs (50 mg kg⁻¹); the percentages of iv dose excreted in 8 h bile as unchanged DA-1131 were 1.76 and 2.71% after iv administration of the drug to rats and dogs, respectively. © 1998 John Wiley & Sons, Ltd.     

The effect of Bitis gabonica (Gaboon viper) snake venom on external iliac and mesenteric arterial circulation in the dog

The effects of Gaboon viper (Bitis gabonica) venom on external iliac and mesenteric arterial blood flow and resistance were investigated in eight anaesthetized, close-chest dogs. Venom doses in the range 0.125 – 0.5 mg/kg produced a profound fall in external iliac and mesenteric arterial resistance, which recovered to control values after 30 min. After a third dose of venom, the mean arterial blood pressure failed to recover and the animals died after a period of severe hypotension. External iliac arterial blood flow rose concomitantly with the fall in external iliac resistance and decreased to a value significantly below control after 30 min. Paradoxically, mesenteric blood flow fell during the period of vasodilation. The results suggest that widespread vasodilation of muscle vascular beds (of which the external iliac circulation is representative) leads to shunting of blood away from the less-dilated mesenteric circulation. Venom-induced peritoneal haemorrhage caused a fall in blood volume and increase in viscosity. These undoubtedly contributed to the severe haemodynamic deterioration of the preparations after the third injection of the venom.     

Dilator effect of the angiotensin II antagonist telmisartan on the gastric,but not femoral,arterial bed of the rat

In the present study the effects were examined of the non-peptide angiotensin 11 AT₁ receptor antagonist, telmisartan, and of-angiotensin II on the vascular conductance in the left gastric and the femoral arterial bed of anaesthetized rats. Blood flow was recorded with the ultrasonic transit time shift technique and vascular conductance was calculated as blood flow divided by mean arterial blood pressure. I.v. injection of angiotensin II (1 nmol kg^–1)led to a transient fall of gastric arterial conductance, while femoral arterial conductance was not altered. Telmisartan (1 mg kg^–1, i.v.) increased vascular conductance in the left gastric, but not femoral, arterial bed and inhibited the constrictor response of the left gastric artery to angiotensin II. The ability of arginine-vasopressin (0.3 nmolkg-1, i.v.) to cause hypertension and to constrict the left gastric and the femoral artery was not influenced by telmisartan. These data indicate that the angiotensin II antagonist telmisartan dilates the gastric, but not femoral, arterial bed of the rat and point to a constrictor role of endogenous angiotensin II in the gastric vasculature.     

Cardiovascular effects of GR117289, a novel angiotensin AT1 receptor antagonist.

1. The effect of GR117289, an angiotensin AT1 receptor antagonist, on diastolic blood pressure (DBP) was determined in angiotensin-dependent and angiotensin-independent models of hypertension in rats. In addition, the antagonist profile of GR117289 at angiotensin AT1 receptors was determined in conscious renal hypertensive rats and conscious normotensive rats, dogs and marmosets. 2. Intra-arterial and oral administration of GR117289 (0.3-3 mg kg-1, i.a.; 1-10 mg kg-1, p.o.) to 6-day left renal artery ligated hypertensive (RALH) rats (DBP > 140 mmHg) produced significant, dose-related reductions in DBP with little apparent effect on heart rate (< 15%). The antihypertensive effect of GR117289 developed progressively over several hours and with some doses persisted for 24-48 h after administration. 3. Administration of GR117289 (1 mg kg-1, i.a.) on 5 consecutive days to RALH rats reduced DBP on each day. The antihypertensive effect of GR117289 was not cumulative as DBP had almost returned to base-line values, 24 h after administration of each dose. 4. A dose of GR117289 (3 mg kg-1, i.a.), which produced a substantial reduction in DBP (about 70 mmHg) in RALH rats, was administered to rats in which blood pressure was elevated either by unilateral renal artery clipping, sustained infusion of angiotensin II (AII), DOCA-salt administration or genetic inbreeding. GR117289 reduced DBP in rats in which the renin-angiotensin system was activated by renal artery clipping or AII infusion but had little effect in normotensive rats, DOCA-salt rats and SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

A STUDY OF ANGIOTENSIN II RECEPTORS AFTER CHRONIC INHIBITION OF NITRIC OXIDE SYNTHASE IN THE SPONTANEOUSLY HYPERTENSIVE RAT

1. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors to the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with N^G-nitro-l -arginine-methyl ester (l -NAME). 2. Two groups of 13 week old female SHR were housed four to a box. Group I rats received l -NAME for 7 days (2.5 mg/kg per day) in their drinking water. Group II rats received water only. Blood pressure was monitored daily by tail-cuff plethysmography. Plasma AngII was measured by radioimmunoassay. Aortic and uterine receptor binding was determined by saturation analysis using [¹²⁵I]-Sar⁸, Ile¹)AngII. Data was analysed using the computer program ligand. 3. Mean systolic blood pressure was significantly elevated in rats treated with l -NAME compared with the control group. Plasma AngII concentration was slightly decreased in rats treated with l -NAME compared with control. Densities of both aortic and uterine AngII receptors increased significantly following NO synthase inhibition. Receptor affinity in the aorta decreased in the l -NAME group compared with control. However, uterine AngII receptor affinity was unchanged. 4. We conclude that the increased blood pressure and enhanced pressor responsiveness that occurs with chronic inhibition of NO synthesis may result partly from increased vascular AngII receptor expression.     

Effects of the novel selective endothelin ET(A) receptor antagonist, SB 234551, on the cardiovascular responses to endotoxaemia in conscious rats

1. In conscious, freely moving, male, Long Evans rats, regional haemodynamic responses to exogenous endothelin-1 (ET-1; 25, 50 and 250 pmol kg(-1) i.v.) were assessed in the presence of vehicle, or the selective ET(A)-receptor antagonist, SB 234551. On the following day, the effects of SB 234551 on the haemodynamic responses to lipopolysaccharide (LPS) infusion (150 microg kg(-1) h(-1), i.v.) were determined. 2. When SB 234551 was given i.v. by primed infusion at a dose of 0.3 mg kg(-1) bolus, 0.3 mg kg(-1) h(-1) infusion, it caused selective inhibition of the vasoconstrictor effects of exogenous endothelin-1, whereas at a dose of 1 mg kg(-1), 1 mg kg(-1) h(-1), SB 234551 also inhibited some of the vasodilator effects of endothelin-1. 3. Infusion of LPS, in the presence of vehicle, caused a short-lived (1 - 2 h) hypotension, tachycardia, and vasodilatation in renal, superior mesenteric and hindquarters vascular beds. Thereafter, blood pressure, heart rate and mesenteric vascular conductance returned to baseline values, but renal vasodilatation persisted, and there was vasoconstriction in the hindquarters. 4. In the presence of SB 234551 (0.3 mg kg(-1), 0.3 mg kg(-1) h(-1)), the early (1 - 2 h) cardiovascular responses to LPS infusion were unaffected, but the subsequent recovery of mean arterial blood pressure was impaired, due to developing vasodilatation in the mesenteric and, to a lesser extent, hindquarters, vascular beds. SB 234551 had no effect on the renal haemodynamic responses to LPS infusion. 5. The results confirm an important, regionally-selective, vasoconstrictor role for endogenous endothelin in this model of endotoxaemia.     

Influence of α‐Adrenoceptor Agonists and Antagonists on Imipramine‐Induced Hypothermia in Mice

Abstract: Effects of adrenoceptor agonists and antagonists on imipramine‐induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10–40 mg kg^?1), α₂‐adrenoceptor agonist clonidine (0.05–0.1 mg kg^?1), α₁‐adrenoceptor agonist phenylephrine (6 mg kg^?1) and α₁‐adrenoceptor antagonist prazosin (1–4 mg kg^?1) but not α₂‐adrenoceptor antagonist yohimbine (1–4 mg kg^?1) induced significant hypothermia. The hypothermic response induced by imipramine (10–30 mg kg^?1) was not altered by clonidine (0.05–0.1 mg kg^?1) or phenylephrine (2–6 mg kg^?1). The response of imipramine (10–30 mg kg^?1) was reduced significantly by yohimbine (2 mg kg^?1) and was potentiated by prazosin (1 mg kg^?1). The hypothermic effect of clonidine (0.1 mg kg^?1) and imipramine (20 mg kg^?1) were also decreased significantly by different doses of yohimbine (1–4 mg kg^?1). The hypothermia induced by different doses of prazosin (1–4 mg kg^?1) was not altered by yohimbine (2 mg kg^?1) or by low dose of imipramine (10 mg kg^?1). It is concluded that α₂‐adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.