Dilation of epicardial arteries in conscious dogs induced by angiotensin-converting enzyme inhibition with enalaprilat

Vasodilators may provoke myocardial ischemia in patients with coronary heart disease. Therefore, we analyzed in conscious dogs the effect of angiotensin-converting enzyme (ACE) inhibition by enalaprilat on parameters potentially important to provocation of myocardial ischemia, such as sympathetic activity, myocardial oxygen consumption, and vascular tone in coronary conduit and resistance vessels. Under normal sodium intake (2-4 mEq/kg/day), enalaprilat (0.03 and 0.3 mg/kg i.v. during 5-min infusion with 30-min intervals, n = 8) did not modify the norepinephrine release rate into plasma (a parameter of overall sympathetic activity). The higher dosage reduced myocardial oxygen consumption (to 87 +/- 2% of control), mean arterial pressure (MAP) (to 90 +/- 1%) and coronary conduit artery tone (normalized delta diameter: +3.2 +/- 0.7%) without dilating coronary resistance vessels. Following renin-angiotensin activation by sodium deprivation (3 X 1 mg/kg furosemide plus 7 days sodium intake less than 0.2 mEq/day), enalaprilat similarly lowered myocardial oxygen consumption and reduced vascular tone both in coronary conduit (normalized delta diameter: +4.0 +/- 0.9%) and resistance vessels (delta coronary flow: +45 +/- 12%). Although MAP declined to 76 +/- 6%, heart rate and norepinephrine release rate were not modified significantly. We propose that the dilation of epicardial arteries results from a direct intramural action. Enalaprilat seems unlikely to provoke myocardial ischemia even in states with a strongly activated renin-angiotensin system.     

Amlodipine induces a flow and pressure-independent vasoactive effect on the brachial artery in hypertension.

1. The objectives of this study were to study the flow-dependent arterial reactivity and pressure-independent arterial compliance of the calcium antagonist amlodipine in hypertensive men. 2. Twenty-one hypertensive patients were randomized to receive 2 months treatment with placebo (n = 10) or 5-10 mg amlodipine (n = 11) once a day. Non-invasive measurement of brachial artery mean blood pressure, diameter and flow (pulsed Doppler) and compliance (arterial mechanography and logarithmic elastic model) were obtained before and after drug administration. Vasoreactivity was studied by means of response of the brachial artery during exclusion of the hand and hyperaemia post-ischaemia. 3. Compared with placebo, amlodipine reduced mean blood pressure (% change +/- s.e. mean 11 +/- 1% vs 4 +/- 3%, P < 0.05), and increased arterial compliance at prevailing pressure (44 +/- 13%, vs 1 +/- 8%, P < 0.05) and at isobaric pressure (26 +/- 10% vs -3 +/- 6%, P < 0.05). A significant % change increase from baseline in brachial artery diameter between placebo and amlodipine was observed at rest (-2 +/- 3 vs 8 +/- 3%; P < 0.05), after wrist occlusion (-3 +/- 3 vs 6 +/- 2%; P < 0.05) and during reactive hyperaemia (-5 +/- 3 vs 18 +/- 5%; P < 0.05). No significant differences between amlodipine and placebo groups were observed in blood velocity after forearm manoeuvres before and after treatment. 4. No differences were observed between groups in brachial flow-dependent vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

What is the mechanism of flow‐mediated arterial dilatation

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Tissue angiotensin II and endothelin-1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats

In resistance arteries pressure-induced (myogenic) tone (MT) and flow (shear stress)-induced dilation (FD) are potent determinant of vascular resistance. We investigated the role of angiotensin II and endothelin-1 in FD and MT in resistance arteries and their potential change in hypertension. Flow - diameter - pressure relationship was established in situ, under anaesthesia, in two daughter branches of a mesenteric resistance artery (180 microM, n=7 per group) from spontaneously hypertensive (SHR) or normotensive (WKY) rats. One artery was ligated distally, so that it was submitted to pressure only, while the other was submitted to pressure and flow. Drugs were added to the preparation and external diameter, pressure and flow measured continuously. External diameter (with flow) ranged from 150+/-3 to 191+/-7 microM in WKY (n=28) rats and from 168+/-6 to 186+/-6 microM in SHR (n=28). Flow induced a dilation of the non-ligated arteries which was lower in SHR (13+/-5 - 31+/-4 microM vs WKY: 5+/-5 - 44+/-4 microM). In the ligated artery, the diameter did not significantly change, due to MT. In the vessels submitted to flow angiotensin converting enzyme inhibition (perindopril, 10 micromol L(-1)) increased the diameter in SHR (+11+/-2 microM) significantly more than in WKY (+2+/-1 microM). Angiotensin type 1 receptor (AT(1)R) blockade (losartan, 10 micromol L(-1)) increased the diameter in the vessels with flow in SHR only (+6+/-1 microM). Angiotensin type 2 receptor (AT(2)R) blockade (PD 123319, 1 micromol L(-1)) decreased arterial diameter in WKY only (9+/-2). Endothelin-1 type A receptor (ET(A)R) blockade (LU135252, 0.1 micromol L(-1)) increased the diameter only in SHR in the artery submitted to flow (by 6+/-1 microM). Thus FD was counteracted by a flow-dependent AT(1) and ET(A) receptors-activation in SHR whereas in WKY FD AT(2)-dependent dilation is involved.     

EFFECTS OF NEUROPEPTIDE Y ON BAROREFLEX CONTROL OF HEART RATE AND MYOCARDIAL CONTRACTILITY IN CONSCIOUS RABBITS

1. The effects of intravenous (i.v.) neuropeptide Y (NPY, 10 micrograms/kg bolus) on the stimulus-response curves relating changes in heart period (HP) and in peak left ventricular (LV) dP/dt to acute changes in mean arterial pressure (MAP) were determined in conscious, normotensive rabbits. 2. The relationship between increases and decreases in MAP and the subsequent changes in HP were represented by a sigmoid-shaped curve described by a logistic function. Following NPY administration there was a baroreflex-dependent increase in the maximum slope (sensitivity) at the midpoint of this MAP-HP curve from 7.0 +/- 0.5 to 10.6 +/- 1.3 ms/mmHg (P less than 0.05). NPY caused an upward shift in the whole curve which reflected the NPY-induced bradycardia and was independent of baroreflexes. 3. The relationship between increases in MAP and decreases in peak LV dP/dt was determined during fixed-rate atrial pacing to prevent the effects of the accompanying bradycardia. Increases in MAP and the corresponding reductions in peak LV dP/dt were represented by an exponential function. The slope of the curve, measured at its origin 5-15 min after NPY administration, was reduced from -0.9 +/- 0.2 to -0.4 +/- 0.1 units (P less than 0.05). 4. The effects of NPY are consistent with an action on efferent connections of the arterial baroreceptor reflex, mediated through a reduction in cardiac beta-adrenergic tone. They would also be explained through actions on the afferent or central neural connections of the baroreflex.     

Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition

Endothelial damage or removal abolishes the dilation of epicardial coronary arteries induced by increments in flow through these arteries in vitro. Therefore, we tested whether or not the release of a cyclooxygenase product from endothelial cells in vivo is the mechanism of this flow-dependent dilation. In eight conscious dogs, instrumented to register the external diameter of two epicardial branches--anterior descending and circumflex--of the left coronary artery, increments in coronary flow increased and reductions in coronary flow decreased the diameter of the left circumflex epicardial artery by 182 +/- 11 micron/100% change in flow. When mean coronary flow in one epicardial branch was kept constant by a distal, flow-limiting stenosis during the application of flow-augmenting stimuli (temporal coronary occlusion or 80-400 micrograms/kg adenosine i.v.), no dilation of this artery was observed. Cyclooxygenase inhibition (suppressing the bradykinin-induced elevation of plasma 6-keto-PGF1 alpha) by indomethacin (5 mg/kg) or by diclofenac (10 mg/kg) increased smooth muscle tone in both epicardial arteries, but did not modify the flow-diameter relation (181 +/- 10 and 179 +/- 9 microns/100% change in flow, respectively). It is concluded that a tonic, instantaneous influence of coronary flow on the smooth muscle tone of the epicardial coronary arteries exists in vivo. It is unlikely that prostacyclin or another prostanoid is a mediator of this endothelium-mediated influence of flow on smooth muscle tone.     

ETA receptors mediate vasoconstriction of large conduit arteries during reduced flow in humans

Vascular tone is regulated by endothelium-derived vasodilating and constricting substances, mainly nitric oxide and endothelin (ET)-1. These 2 mediators, which antagonize the actions of each other, are released in response to shear-stress produced by blood flow. The aim of this study was to delineate the contribution of endogenous ET-1 on vascular tone of a large conduit artery during reduced and hyperemic flow. Radial artery diameter was continuously measured with a high-resolution ultrasonic echo-tracking device in 8 healthy subjects. After establishing stable baseline conditions, a wrist cuff was inflated to suprasystolic pressure for 5 minutes. In another 5 subjects, measurements were obtained during intraarterial infusion of saline or an ETA receptor antagonist (BQ-123, 1 nmol/min) in a dosage not affecting basal radial diameter. Wrist occlusion caused a progressive vasoconstriction of the radial artery (P = 0.0001). Vasoconstriction of the radial artery during wrist occlusion was significantly attenuated by ETA receptor antagonism (-2.7% +/- 0.6% versus -6.8% +/- 0.6% during saline, P = 0.007). Flow-mediated vasodilation was not influenced by BQ-123 (7.5% +/- 0.8% versus 7.8% +/- 1.1%, P = NS). This study demonstrates active vasoconstriction of large conduit arteries during conditions of reduced blood flow via ETA receptoractivation. This may play an important role in disease states with reduced systemic or local blood flow and indicates the therapeutic potential of ETA receptor antagonism.     

Restoration of flow-dependent coronary dilation by ACE inhibition improves papaverine-induced maximal coronary blood flow in hypertensive patients: demonstration that large epicardial coronary arteries are more than conductance vessels

Restoration of flow-dependent coronary artery dilation by angiotensin-converting enzyme inhibition (ACEI) has been demonstrated in patients with hypertension. The aim of the present study was to evaluate whether dilation of conductance coronary arteries may alter maximal coronary blood flow (CBFmax) and minimal coronary resistance (CRmin) in hypertensive patients with reversible impairment of flow-dependent coronary artery dilation. Thirteen hypertensive patients with angiographically normal coronary arteries and no other risk factors were studied. Cross-sectional areas (CSAs) of proximal and distal left anterior descending (LAD) coronary arteries were determined by quantitative angiography. Coronary flow velocity was recorded in the distal LAD with an intracoronary Doppler catheter. Estimates of coronary blood flow and resistance were calculated at rest and during maximal increase in blood flow induced by papaverine injected in the midportion of the LAD, both before and after ACEI. Flow-dependent dilation of the proximal LAD, abolished before ACEI, was restored after (26.7 +/- 11.2%; p < 0.001). The increase in CSA of the distal LAD exposed to papaverine was significantly higher after ACEI than before (from 33.4 +/- 20.5% to 51.5 +/- 23.4%; p < 0.001). After restoration of proximal LAD flow-dependent dilation, CBFmax was increased by +21.0 +/- 10.3% (p < 0.001), and CRmin was reduced by 19.3 +/- 9.5% (p < 0.001). Thus, dilation of epicardial coronary arteries participates substantially in the coronary resistance in hypertensive patients. Restoration of flow-dependent coronary artery dilation by ACEI may improve the ability of coronary circulation to deliver its maximal myocardial blood flow in hypertensive patients.     

Comparative effects of captopril and isosorbide dinitrate on the arterial wall of hypertensive human brachial arteries

Blood pressure, diameter, volume distensibility, and compliance of brachial artery were measured noninvasively in patients with sustained essential hypertension before and after Captopril in 11 patients and before and after isosorbide dinitrate (ISDN) in 11 other patients. Both drugs caused a similar significant decrease in mean arterial pressure (MAP) (p less than 0.001) and increase in arterial compliance (p less than 0.001), defined as the product of arterial volume by distensibility. ISDN increased arterial compliance through a dominant increase in arterial diameter (0.524 +/- 0.029 vs. 0.455 +/- 0.022 cm; p less than 0.001) and hence volume, whereas Captopril increased compliance through an increase in volume distensibility (0.20 +/- 0.02 vs. 0.12 +/- 0.02% change volume/mm Hg; p less than 0.001) with minimal changes in arterial diameter. The study provided evidence that of the two vasodilating drugs, ISDN and Captopril, only Captopril caused a predominant pharmacological relaxing effect on the wall of hypertensive human brachial arteries studied in situ.     

ROLE OF NITRIC OXIDE AND ENDOTHELIUM IN THE FLOW-INDUCED DILATION OF RAT CORONARY ARTERIES UNDER TWO PRECONSTRICTION CONDITIONS

1. Pressure-induced tone and flow-induced dilations were studied in a rat perfused epicardial coronary artery mounted in an arteriograph. Spontaneous tone was assessed in arteries submitted either to 60 or 90 mmHg intraluminal pressure either under control conditions, after incubation with NG-nitro-L-arginine methyl ester (L-NAME; 100 mumol/L) or after endothelial denudation. Flow-induced dilation was quantified under these conditions in preparations either submitted to 60 mmHg and preconstricted with 10 mumol/L 5-hydroxytryptamine (5-HT) or exhibiting spontaneous tone at 90 mmHg. 2. Spontaneous tone was greater at 90 mmHg compared with tone obtained at 60 mmHg (21 +/- 2 vs 10 +/- 2% reduction of the fully dilated diameter after sodium nitroprusside incubation, respectively). Incubation with L-NAME or removal of the endothelium significantly increased spontaneous tone at both pressures compared with control. 3. In arteries submitted to 60 mmHg and preconstricted with 10 mumol/L 5-HT, flow (0-800 microL/min) induced a continuous dilation (maximal value 63 +/- 4%). As a function of flow, shear stress first increased and then plateaued at values of approximately 76 +/- 6 dyn/cm2. After L-NAME incubation or endothelial denudation, the flow-induced dilation was reduced to the same extent and was obtained for higher values of shear stress (172 +/- 14 and 150 +/- 14 dyn/cm2, respectively). 4. In arteries exhibiting spontaneous tone, starting flow led, first, to a constriction followed by a dilation up to 76 +/- 4% of the initial tone. Incubation with L-NAME greatly altered flow-induced dilation. Endothelium removal further reduced the dilation obtained for very high values of shear stress (up to 300 dyn/cm2). 5. The present study shows that different patterns of vasodilation induced by flow can be observed, depending on the initial vasoconstrictor stimulus. In 5-HT-preconstricted arteries, flow-induced dilation appears to be fully dependent on the synthesis and release of nitric oxide. In arteries with spontaneous tone, a vasoconstrictor substance could be released for low values of flow. Nitric oxide is mainly, but not exclusively, responsible for the vasodilation. For both experimental conditions, removal of the endothelium greatly reduced the response, but a dilation was still observed.     

莫索尼定对麻醉大鼠颈动脉窦压力感受器反射的影响

观察莫索尼对颈动脉窦压力感受器反射的影响。方法：利用灌流左颈动脉窦方法，观察莫索尼定对麻醉大鼠压力反射机能参数的影响。恒流灌流股动脉，记录灌流压变化，确定莫索尼定对血管阻力的影响。结果；莫索尼定３２．１００μｍｏｌ．Ｌ＾－１使颈动脉窦压力反射机能曲线向右上移位，曲线最大斜率和反射性平均动脉压下降幅度均减小，提示莫索尼定对压力感受器反射有抑制作用。     

In vivo manipulation and continuous measurement of muscle blood flow with venous effluent sampling

1. An acute in vivo hindlimb skeletal muscle preparation was developed in anaesthetized sheep in order to facilitate studies of the effects of altered blood flow states on drug kinetics in skeletal muscle. 2. A continuous index of blood flow was recorded via ultrasonic Doppler probes on the femoral artery and vein. Skeletal muscle effluent blood was sampled via a catheter in the femoral vein proximal to the probe. Low- and high-blood flow states were achieved by direct femoral artery infusion of adrenaline (0.002-0.006 mg/min) or magnesium (0.4-1 mmol/min), which produced mean (+/-SD) stable flow states of 25+/-12 and 185+/-56% (both n = 5) of baseline, respectively. The correlation coefficients between arterial and venous Doppler frequency shifts in five sheep during and after adrenaline infusion were 0.96 (indicating these vessels probably supplied and drained common tissue). 3. The venous Doppler frequency shifts were calibrated against timed collections of the femoral vein outflow to provide estimates of the low and normal blood flow states (mean flows of 2.8+/-1.7 and 9.3+/-5.7mL/100 g per min; both n = 3) and against an indirect Kety-Schmidt method during low- and high-blood flow states (mean flows of 2.2+/-1.3 and 18.2+/-7.0 mL/100 g per min; both n = 5). There was a generally good agreement between the two methods. 4. The tissue was neither hypoxic nor acidotic in the low- or high-flow states and altering the flow produced no change in muscle oxygen consumption, suggesting the flow changes were largely due to changes in resistance vessel tone. 5. Postmortem femoral artery dye injection and dissection of stained tissues showed the artery supplied 657+/-96 g (n = 5) of skeletal muscle and 42+/-20 g (n = 5) of other tissues. 6. It is concluded that the method is suitable for sampling predominantly muscle effluent blood at low- or high-blood flow states according to experimental requirements.     

Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice

Vasopressin ([Arg(8)]vasopressin)-induced contraction was characterized using receptor agonists and antagonists for vasopressin and channel blockers in the rat basilar artery ring preparations. Vasopressin induced rhythmic contractions superimposed on a contraction in endothelium-intact preparations but not in denuded ones. Endothelium removal shifted the concentration-response curve for vasopressin leftward and upward. In endothelium-denuded preparations, vasopressin V(1) receptor antagonist shifted the concentration-response curve for vasopressin downward and rightward. Vasopressin V(1) receptor agonist caused contraction but V(2) receptor agonist did not. The contractile response to vasopressin was partly inhibited by nifedipine, SK&F 96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole) and niflumic acid. In the absence of extracellular Ca(2+), vasopressin produced a transient contraction. Charybdotoxin produced an upward and leftward shift of the concentration-response curve for vasopressin. These results suggest that vasopressin elicits contraction due to Ca(2+) influx through voltage-dependent and receptor-operated Ca(2+) channels and to Ca(2+) release from Ca(2+) stores by activating vasopressin V(1) receptors in the rat basilar artery.     

Vasoactive intestinal peptide in bovine pulmonary artery: localisation, function and receptor autoradiography.

The role of vasoactive intestinal peptide (VIP) in the control of pulmonary vascular tone was investigated by functional response, immunocytochemical localisation and receptor autoradiography in bovine pulmonary arteries. VIP-immunoreactive nerve fibres were present at the adventitial-medial junction and in the media of the vessels. Exposure of precontracted bovine pulmonary artery segments to VIP in vitro resulted in almost complete (86 +/- 3%; mean +/- s.e.mean) relaxation, the concentration needed for 50% relaxation being 4.47 +/- 0.37 X 10(-9)M. VIP effects did not depend on the presence of intact endothelial cells. The distribution of VIP receptors was studied by autoradiography using [125I]-VIP. A high density of VIP receptors was found in arterial vascular smooth muscle, with a gradient of density from adventitia to luminal surface. There were no receptors on endothelial cells. These data show that VIP is a potent vasodilator of bovine pulmonary arteries, via direct activation of VIP receptors in vascular smooth muscle. VIP-immunoreactive nerves may influence pulmonary vascular tone directly and could, therefore, be important in regulating pulmonary blood flow.     

Effect of pinacidil on myocardial blood flow in the presence of a coronary artery stenosis.

This study examined the effect of pinacidil on transmural distribution of myocardial blood flow during normal conditions and in the presence of a coronary artery stenosis. Studies were performed in 11 awake dogs; blood flow was measured with radioactive microspheres. Two doses of pinacidil were administered to decrease mean arterial pressure (MAP) by approximately 10 mm Hg (low dose, 0.18 +/- 0.02 mg/kg) and 20 mm Hg (high dose, 0.32 +/- 0.03 mg/kg). Measurements were performed during unimpeded arterial inflow and with two levels of coronary stenosis that limited blood flow to approximately 60% above (moderate stenosis) and approximately 30% above basal flow (severe stenosis). With no stenosis, coronary flow increased 227 +/- 17% after low-dose and 321 +/- 31% after high-dose pinacidil (each p less than 0.01). During control conditions, subendocardial (endo) flow exceeded subepicardial (epi) flow (endo/epi ratio = 1.33). This ratio was not changed by low-dose pinacidil but decreased to 0.93 after high-dose pinacidil (p less than 0.05). During high-dose pinacidil, a coronary stenosis caused uniform reduction of blood flow across the left ventricular wall, with no further significant change in the ratio of endo/epi flow. With low-dose pinacidil, both moderate and severe degrees of stenosis caused redistribution of flow away from the subendocardium similar to that observed with high-dose pinacidil. Although a stenosis that limited the increase in mean coronary flow after pinacidil administration to 162% of the predrug control value had a 95% probability of not causing a decrease in absolute subendocardial flow, the data suggest that pinacidil could have potential for aggravating subendocardial ischemia in severe occlusive coronary artery disease.     

Blockade of endothelium-derived relaxing factor synthesis with NG-nitro-L-arginine methyl ester leads to enhanced venous reactivity in vivo.

This study was performed to examine whether endothelium-derived relaxing factor (EDRF) influences venous tone and reactivity in vivo. The inferior vena cava and abdominal aorta were studied simultaneously under continuous haemodynamic monitoring in anaesthetised rabbits. In addition, a 20-MHz intravascular ultrasound catheter was placed in the vena cava for on-line two-dimensional imaging of vessel cross-sectional area and calculation of wall stress (T(ension) = P(mean) * r(adius)/2). This approach enabled simultaneous visualisation of both venous (CA(ven)) and aortic (CA(art)) cross-sectional area with continuous recording of vessel dimensions. Measurements were made before and after administration of NG-nitro-l-arginine methyl ester (L-NAME; 10 mg.kg i.v.), a specific inhibitor of EDRF biosynthesis. After L-NAME there was a significant increase in central venous pressure and a decrease in CA(ven). On the arterial side, L-NAME caused a significant increase in mean pressure and CA(art), resulting in a significantly augmented arterial wall stress. The venodilatation elicited by increasing doses of glyceryltrinitrate was markedly enhanced after L-NAME. Norepinephrine caused a parallel shift of the dose-response curve for CA(ven) in the presence of a lower baseline value. These results suggest that EDRF contributes substantially to the control of large capacitance veins in vivo and that L-NAME increases venous reactivity to both norepinephrine and glyceryltrinitrate.     

Effects of nicorandil on large epicardial coronary artery in conscious dogs

The effect of 2-nicotinamidoethyl nitrate (nicorandil, SG-75, Sigmart) on coronary circulation was studied in conscious dogs, instrumented previously under sterile condition with sonomicrometers for the external coronary diameter measurement, and an electromagnetic flow plobe on the left circumflex coronary artery and a catheter into the thoracic aorta. Intravenous administration of nicorandil in doses of 10, 30, 100 and 300 micrograms/kg increased coronary blood flow dose-relatedly by 13 +/- 2, 24 +/- 3, 144 +/- 18 and 309 +/- 36%, respectively. Nicorandil also increased the diameter of the large epicardial coronary artery by 38 +/- 6, 71 +/- 11, 150 +/- 24 and 173 +/- 26 microns in doses of 10, 30, 100 and 300 micrograms/kg, respectively. To eliminate flow-dependent dilation of the coronary artery, the external diameter of the large epicardial coronary artery was measured during fixing the amount of coronary blood flow constant by a cuff occluder after intravenous administration of nicorandil, however, the degree of coronary diameter increase was not attenuated. Thus, nicorandil dilates both large and small coronary arteries in conscious dogs, the former dilation being independent from changes in coronary blood flow.     

The antiarrhythmic effects of the nucleoside transporter inhibitor,R75231, in anaesthetized pigs.

1. The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs. 2. In closed chest pigs (n = 4), R75231 exerted a moderate dose-dependent decrease in mean arterial blood pressure (from 97 +/- 4 mmHg to 95 +/- 4, 90 +/- 1 and 83 +/- 2 mmHg at 25, 50 and 100 micrograms kg-1 respectively) and produced a dose-related shift to the left of the blood pressure dose-response curve to intravenous bolus doses of adenosine. The degree of inhibition of adenosine uptake by R75231, assessed ex vivo in erythrocyte suspensions, was 43 +/- 5%, 64 +/- 13 and 114 +/- 15% at doses of 25, 50 and 100 micrograms kg-1 respectively. 3. In open chest pigs, intravenous injection of R75231 (50 micrograms kg-1; n = 6 and 100 micrograms kg-1; n = 10) induced a dose-related decrease in both systolic and diastolic arterial blood pressure which was more marked than in closed-chest pigs (mean pressure 86 +/- 4 to 70 +/- 2 mmHg and 88 +/- 6 to 60 +/- 6 mmHg with 50 and 100 micrograms kg-1 respectively), without affecting heart rate or myocardial contractility. Coronary artery occlusion in these pigs caused a secondary decrease in blood pressure. This was not observed in controls (n = 10). The lower dose of R75231 did not exert any antifibrillatory effects, whereas the higher dose significantly reduced the incidence of ventricular fibrillation, from 80% in control pigs to 30%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different role of nitric oxide and endothelium-derived hyperpolarizing factor in endothelium-dependent hyperpolarization and relaxation in porcine coronary arterial and venous system

OBJECTIVE: We compared the basal and bradykinin (BK)-induced NO release and endothelium-derived hyperpolarizing factor-mediated function between coronary arteries and cardiac veins. METHODS AND RESULTS: Isolated coronary vessels (large arteries, cardiac veins as well as microvessels) were studied. An NO-specific electrode and a conventional intracellular glass microelectrode were used to directly measure NO released from endothelial cells and hyperpolarization of smooth muscle cells in conduit coronary vessels. The basal and BK-induced release of NO was 14.2 +/- 2.0 nmol/L and 237.1 +/- 27.2 nmol/L (n = 8) in the artery, significantly greater than in veins (8.0 +/- 1.1 nmol/L and 135.6 +/- 14.5 nmol/L, n = 8, P < 0.01). The BK-induced hyperpolarization was significantly reduced by N-nitro-L-arginine, indomethacin, and hemoglobin in both arteries and veins and was greater in the arteries. The EDHF-mediated relaxation was significantly higher in the arteries than in veins, greater in microveins than in large veins, and almost abolished by charybdotoxin and apamin. CONCLUSIONS: Both NO and EDHF are involved in the regulation of the vascular tone in the coronary arterial and venous systems but the amount of NO release and the EDHF-mediated relaxation and associated hyperpolarization are less significant in the vein than in the artery in the coronary system.     

The in vivo effect of adrenomedullin on rat dural and pial arteries

Adrenomedullin is related to the calcitonin gene-related peptide (CGRP) family and is present in cerebral blood vessels. It may be involved in migraine mechanisms. We measured the change in dural and pial artery diameter, mean arterial blood pressure and local cerebral blood flow flux (LCBF(Flux)) after intravenous (i.v.) infusion of adrenomedullin. The study was performed in the presence or absence of the CGRP1 (calcitonin-receptor-like-receptor (CALCRL)/receptor activity-modifying protein-1 (RAMP1)) receptor antagonists BIBN4096BS, CGRP-(8-37) and the adrenomedullin receptor antagonist adrenomedullin-(22-52). I.v. infusion of 15 mug kg(-1) adrenomedullin (n=8) induced dilatation of dural (32+/-7.5%) and pial (18+/-5.5%) arteries, a reduction in mean arterial blood pressure (19+/-3%) and an increase in LCBF(Flux) (16+/-8.4%). The duration of the responses was 25 min for the dural artery, while the response of the pial artery lasted for 15 min. The CGRP1-receptor antagonists BIBN4096BS and CGRP-(8-37) and the adrenomedullin receptor antagonist adrenomedullin-(22-52) significantly inhibited the effect of adrenomedullin (n=7, P<0.05 for both arteries) on dural and pial artery diameter and mean arterial blood pressure. No significant inhibition of LCBF(Flux) was found. The antagonist alone had no effect on mean arterial blood pressure or LCBF(Flux). In conclusion, we suggest that adrenomedullin in the rat cranial circulation dilates dural and pial arteries, reduces mean arterial blood pressure and increases LCBF(Flux), probably via a CGRP1-receptor.