Clonidine prevents the sympathetic initiation and aggravation of poststenotic myocardial ischemia

We studied the effects of clonidine (10 micrograms/kg i.v.) on the positive feedback between poststenotic myocardial ischemia and cardiac sympathetic nerve activation and on the initiation of poststenotic myocardial ischemia during bilateral carotid occlusion in 12 anesthetized, open-chest dogs. During 20 min of acute severe coronary stenosis, cardiac sympathetic nerve activity increased by 24 +/- 6%, poststenotic coronary resistance increased from 0.45 +/- 0.05 to 0.61 +/- 0.08 mm Hg . min . 100 g/ml, and the poststenotic myocardial lactate consumption of 25 +/- 6 mumol/min . 100 g at 1 min of stenosis was reversed to a net lactate production of 8 +/- 3 mumol/min . 100 g after 20 min of stenosis. An additional 60-s bilateral carotid occlusion increased cardiac sympathetic nerve activity furthermore to 157 +/- 7% of control, increased poststenotic coronary resistance to 0.84 +/- 0.14 mm Hg . min . 100 g/ml, and increased the net lactate production to 22 +/- 6 mumol/min . 100 g. With heart rate and left ventricular pressure kept constant, clonidine decreased cardiac sympathetic nerve activity to 21 +/- 6% of control and prevented any further sympathetic activation during 20 min of coronary stenosis and bilateral carotid occlusion. Conversely, poststenotic coronary resistance and myocardial lactate consumption remained unchanged. Intracoronary clonidine (100 micrograms) in five of the 12 dogs increased poststenotic coronary resistance from 0.47 +/- 0.04 to 0.61 +/- 0.05 mm Hg . min . 100 g/ml and reversed the myocardial lactate consumption of 36 +/- 4 mumol/min . 100 g to a net lactate production of 7 +/- 5 mumol/min . 100 g. Our results suggest that clonidine can, by a central nervous action, prevent the sympathetic initiation and aggravation of poststenotic myocardial ischemia and may thus be effective in the treatment of exertional angina.     

Enalaprilat effects renin-angiotensin and adrenergic response to induced hypotension in the rabbit.

The effects of enalaprilat on the renin-angiotensin system and sympathetic nervous system during sodium nitroprusside (SNP)-induced hypotension and halothane anesthesia were studied in three groups of New Zealand white rabbits. Two groups of rabbits (E and EH) were treated with an infusion of enalaprilat at 3.5 micrograms/kg/min i.v. One enalaprilat-treated group (EH) and the third, untreated group (H) received SNP to induce hypotension. In these two groups, the mean arterial blood pressure (MAP) was reduced by 40% for 150 min. Group E did not undergo SNP-induced hypotension and served to document the effects of enalaprilat alone during the 150-min study period. Arterial blood samples for norepinephrine (NE), epinephrine (EPI), and plasma renin activity (PRA) were drawn prior to and during hypotension, and during the recovery period. The SNP dose required to maintain the hypotension was continuously recorded. NE, EPI, and PRA all increased in group H, indicating activation of both the renin-angiotensin system and the sympathetic system during hypotension. The amount of SNP required by group H to maintain a 40% reduction in MAP correlated with circulating NE levels (p less than 0.001) and not PRA. In group EH, PRA levels rose sharply and remained elevated. Plasma NE and EPI levels increased slightly with a decline in the SNP dose requirement. Group E demonstrated a rise in PRA levels, accompanied by unchanged NE and EPI levels and MAP during the study period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of histamine H1-receptor stimulation on coronary hemodynamics in man

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H1 and H2-receptors present on human heart and on coronary arteries. We studied the effects of selective H1-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 micrograms/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO2) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103 +/- 5 to 85 +/- 6 mmHg (p less than 0.02) and CVR from 1.00 +/- 0.16 to 0.81 +/- 0.14 mmHg/ml/min (p less than 0.05); CSBF and MVO2 did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D3, reduction in CSBF and an increase in CVR. These results indicate that H1-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.     

EFFECT OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION ON RENAL NOREPINEPHRINE SPILLOVER RATE AND BAROREFLEX RESPONSES IN CONSCIOUS RABBITS

1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension. 2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values. 3. During SNP infusion at 10 μg/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively. 4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P<0.05) than the 97% (s.e.m. = 16) change observed in controls. 5. Enalaprilat treatment resulted in a higher renal to total NE spillover ratio (P<0.05). The ratio fell in parallel in both groups during SNP-induced hypotension. 6. This study indicates that the sympathetic nervous system interacts dynamically with the renin-angiotensin system during hypotensive stimulation but this occurs predominantly at sites other than the kidney.     

Acetylcholine induces constriction of epicardial coronary arteries in anesthetized dogs after removal of endothelium

The acetylcholine-induced relaxation of isolated coronary arteries is reversed to contraction in the absence of endothelium. The importance of endothelium for the regulation of coronary blood flow remains unclear. We thus tested the effects of acetylcholine on epicardial arteries and on coronary resistance vessels in situ in 8 anesthetized dogs. The left circumflex coronary artery was perfused at constant pressure. Epicardial vasomotion was evaluated by sonomicrometry, the vasomotion of coronary resistance vessels by calculated end-diastolic resistance. Acetylcholine (1 microgram/kg/min i.c.) decreased epicardial resistance by 8.6 +/- 1.6% and end-diastolic resistance by 65.8 +/- 6.3%. The epicardial coronary segment was perfused with distilled water for 65 +/- 5 s to denude it of endothelium. After removal of epicardial endothelium, the decrease in end-diastolic resistance caused by acetylcholine was unchanged (59.6 +/- 1.2%); however, epicardial resistance was increased by 7.7 +/- 1.7%. Application of glyceryl trinitrate (5 micrograms/kg/min i.c.) induced a similar decrease of epicardial resistance before and after removal of endothelium:7.9 +/- 1.4 and 6.2 +/- 1.9%, respectively. We conclude that acetylcholine-induced dilation of epicardial coronary arteries is endothelium-dependent in vivo. However, the constriction of epicardial coronary arteries in the absence of endothelium is insufficient to reduce blood flow and to induce myocardial ischemia.     

Cardioprotective effects of amlodipine in animal models of ischemia and reperfusion

The protective effect of amlodipine was studied in isolated blood-perfused cat hearts made globally ischemic for 60 min followed by reperfusion for 60 min. Ischemia-induced alterations of left ventricular developed pressure and compliance were monitored. Amlodipine produced significant decreases in myocardial oxygen consumption (6.2 +/- 0.4 to 4.4 +/- 0.4 ml of oxygen/min/100 g) and coronary vascular resistance, as assessed by changes in perfusion pressure (120 +/- 1 to 100 +/- 4 mm Hg). When administered before the onset of global ischemia, amlodipine decreased the development of ischemic contracture as reflected by a progressive increase in resting left ventricular diastolic pressure. The return of contractile function, 60 min after reperfusion, was improved significantly in amlodipine-treated hearts compared to controls and there was better maintenance of the tissue concentration of Na+, Ca2+, and K+. In a canine model of regional myocardial ischemia (6 h) followed by reperfusion, amlodipine at 150 microg/kg, administered 15 min before reperfusion (90 min), reduced infarct size expressed as a percentage of the area at risk (34.5 +/- 3.8% vs. 45.9 +/- 2.8%, p = 0.027). We conclude that amlodipine reduces myocardial ischemic injury by mechanism(s) that may involve a reduction in myocardial oxygen demand as well as by positively influencing transmembrane Ca2+ fluxes during ischemia and reperfusion.     

Involvement of the renin-angiotensin system in ischemic damage and reperfusion arrhythmias in the isolated perfused rat heart.

We have investigated the contribution of the renin-angiotensin system to the damage caused by 40-min global ischemia in the isolated rat heart. A converting enzyme inhibitor, enalaprilat (70 nM), an angiotensin II receptor antagonist, compound 89 (2 microM), and an inhibitor of rat renin, CGP 44099A (20 nM), given before ischemia reduced the median duration of ventricular fibrillation on reperfusion to a similar extent (5.53, 5.72, and 5.14 min, respectively, compared to 13.98 min in the control group) but had no effect on creatine phosphokinase release (22.2 +/- 2.6, 22.1 +/- 6.8, and 24.1 +/- 3.6, IU/30 min, respectively, compared to 19.9 +/- 1.9 IU/30 min) or recovery or left ventricular developed pressure (67 +/- 6, 73 +/- 7 and 71 +/- 6%, respectively, compared to 66 +/- 3% after 30 min reperfusion). The increase in coronary resistance and left ventricular diastolic pressure on reperfusion was not affected by any of the agents. All three agents also tended to reduce the duration of ventricular fibrillation when given only on reperfusion. We conclude that angiotensinogen is present in the rat heart and it is converted to angiotensin I by a renin or a renin-like aspartic proteinase. The angiotensin I is converted to angiotensin II by converting enzyme. The angiotensin II formed is an important mediator of postreperfusion ventricular fibrillation in the isolated rat heart but does not contribute to the reduction in mechanical function produced by global ischemia in this preparation.     

The KATP channel blocker HMR 1883 does not abolish the benefit of ischemic preconditioning on myocardial infarct mass in anesthetized rabbits

Previous experimental studies showed that the benefit of ischemic preconditioning (IPC) is abolished by K(ATP) channel blockade with glibenclamide. However, the newly discovered K(ATP) channel blocker HMR 1883 (1-[[5-[2-(5-chloro-o-anisamido)ethyl]-methoxyphenyl]sulfonyl]-3-m ethylthiourea) shows marked antifibrillatory activity in the dose range of 3 mg/kg to 10 mg/kg i.v. in various experimental models without affecting blood glucose levels. In order to investigate in a head to head comparison glibenclamide and HMR 1883 with respect to their influence on IPC, experiments were performed in rabbits with ischemia-reperfusion using myocardial infarct mass as final read out. Male New Zealand White rabbits (2.6-3.0 kg) were subjected to 30-min occlusion of a branch of the left descending coronary artery (LAD) followed by 2-h reperfusion. For IPC experiments the LAD was additionally occluded for two periods of 5 min, each followed by 10-min reperfusion, before the long-term ischemia. Infarct mass was evaluated by TTC staining and expressed as a percentage of area at risk. Rabbits (n=7/group) were randomly selected to receive (i.v.) saline vehicle 5 min prior to the 30-min occlusion period in infarct studies without IPC or to receive glibenclamide (0.3 mg/kg) or HMR 1883 (3 mg/kg) in IPC experiments, these substances being given 5 min prior to the first preconditioning or 5 min prior to the long-term ischemia of 30 min. Myocardial risk mass as a percentage of left ventricular mass did not differ between groups. The same was true for the ratio of left ventricular mass to 100 g body weight. Myocardial infarct mass as a percentage of the area at risk in the saline vehicle group without IPC was 41+/-3%. Whereas glibenclamide significantly increased infarct mass (from 41+/-3% to 55+/-4%), HMR 1883 did not affect it. IPC reduced infarct mass from 41+/-3% to 21+/-4% (P<0.05 vs. control without IPC). Glibenclamide given prior to IPC or prior to the long-term ischemia totally abolished the IPC effect (42+/-2% and 55+/-4%, respectively; P<0.05 vs. control). In contrast, HMR 1883 under the same conditions did not affect infarct size when given prior to IPC or prior to the long-term ischemia (21+/-3% and 26+/-2%, respectively). The monophasic action potential duration (MAP50) was reduced from 103+/-3 ms under normoxic conditions to 82+/-2 ms, 5 min after ischemia in the absence of drugs. This ischemia-induced shortening of the MAP was prevented by both HMR 1883 (MAP50 103+/-3 ms) and glibenclamide (MAP50 106+/-3 ms). In conclusion, although both K(ATP) channel blockers prevented ischemia-induced shortening of MAP, HMR 1883 did not abolish the beneficial effects of IPC on myocardial infarct mass in rabbits, whereas glibenclamide totally reversed this cardioprotective effect of IPC. This suggests that the sarcolemmal ATP-sensitive potassium channels are not involved in the mechanism of IPC.     

Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. II. Studies with dopamine and ouabain in the barbiturate-anesthetized dog

To test the hypothesis that selective increases in inotropic state without concomitant acceleration of heart rate would not augment acute ischemic injury in the non-failing heart of the anesthetized dog, we carried out studies in 16 dogs subjected to serial 10-min occlusions of the left anterior descending coronary artery. The severity of ischemic injury was determined by mass spectrometric measurement of the rise in intramural carbon dioxide tension (delta PmCO2) in the ischemic zone, and inotropic stimulation was provided by either dopamine or ouabain. In Group I dogs (n = 9), dopamine [4 +/- 1 (SD) micrograms/kg/min] was infused before the final occlusion to increase left ventricular (LV) dP/dt without changing heart rate; delta PmCO2 was not significantly different between control (64 +/- 21 mm Hg) and postdopamine (67 +/- 22 mm Hg) occlusions. In Group II dogs (n = 7), ouabain (0.03 mg/kg) was administered 15 min before the final occlusion, resulting in a significant increase in LV dP/dt and a slight decrease in heart rate (average 13 beats/min); delta PmCO2 was slightly decreased in the occlusion after ouabain (60 +/- 12 mm Hg) compared with the preceding occlusion without inotropic stimulation (67 +/- 13 mm Hg), p less than 0.05. Throughout the studies in both groups, there were no significant changes in collateral blood flow to the central ischemic zone, or in heart rate-systolic arterial pressure product, an estimate of myocardial oxygen consumption. Analyses of individual responses revealed that when LV dP/dt increased by 50% or more after dopamine or ouabain, ischemia was more likely to intensify.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute limb ischemia does not facilitate but inhibits norepinephrine release from muscle sympathetic nerve endings in anesthetized rabbit

Although myocardial ischemia is associated with regional cardiac sympathetic nerve deterioration, it remains unknown whether acute hindlimb ischemia impairs muscle sympathetic nerve function. In the study presented here we implanted dialysis probes in the adductor muscle of anesthetized rabbits and measured dialysate norepinephrine levels as an index of muscle sympathetic nerve activity. Acute hindlimb ischemia was induced by injection of microspheres and occlusion of the common iliac artery. Dialysate norepinephrine levels decreased from 19.3 +/- 3.5 pg/ml at control to 9.4 +/- 3.7 pg/ml at 30 min of ischemia and further to 1.7 +/- 0.2 pg/ml at 75 min of ischemia. During acute hindlimb ischemia, baroreflex (bilateral carotid occlusion) and high potassium level-induced norepinephrine response was inhibited, but tyramine-induced norepinephrine response was preserved. In conclusion, acute hindlimb ischemia caused decreases in dialysate norepinephrine levels. This reduction may be mediated by an impairment of axonal conduction and/or of norepinephrine releasing function at skeletal muscle sympathetic nerve endings.     

Effects of glucagon on systemic circulation, coronary blood flow and myocardial oxygen consumption in the anesthetized dog (author's transl)]

The systemic and coronary hemodynamic effects of 10, 20, 40 and 80 mug/kg glucagon have been studied in 9 anesthetized normoventilated closed-chest dogs. Intravenous administration of this agent produced a dose-related increase in the average coronary blood flow between 19% (10 mug/kg) and 49% (80 mug/kg). Coronary vascular resistance decreased by between 16% (10 mug/kg) and 39% (80 mug/kg). A--V O2 difference 1 min after the administration of glucagon no changes in myocardial oxygen extraction were observed after 5, 10 and 20 min. The calculated myocardial oxygen consumption rose up to 50% after 80 mug/kg glucagon. We conclude that the increase in coronary blood flow and the decrease in coronary resistance are mainly secondary to the metabolic effects of the increased myocardial contractility and heart rate, and that there is only an initial direct vasodilating effect on the coronary vessels.     

Pharmacologic inhomogeneity between the reactivity of intramural coronary arteries and arterioles

We hypothesized that because of their size, anatomic location, and hemodynamic function, coronary arteries and arterioles would respond differently to vasoactive substances. Intramural arteries (281.7 +/- 23.1 microm) and arterioles (77.3 +/- 6.6 microm) of the left anterior descending coronary of rats were isolated and cannulated. Spontaneous tone was lower in arteries than in arterioles (81.1 +/- 5.7 vs. 53.0 +/- 3.9% of passive diameter, p < 0.05 at 60 mm Hg intraluminal pressure). Arterial tone was adjusted by the thromboxane receptor agonist U46619 (5 x 10(-8) M ) to reach an active tone close to that of arterioles. Bradykinin elicited dilations in both types of vessels. Acetylcholine (10(-6) - 10(-5) M ) dilated arteries (by 42.6 +/- 11.5 microm) but constricted arterioles (by 16.4 +/- 9.3 microm). Sodium nitroprusside and adenosine elicited significantly greater dilations in arterioles than in arteries (by 7.9 and 11.9%, respectively, p < 0.05), whereas dilations to norepinephrine were similar. Inhibition of nitric oxide synthesis caused a significantly smaller constriction in arteries (10.2 +/- 3.31%) than in arterioles (31.6 +/- 6.9%) and completely blocked bradykinin-and acetylcholine-induced dilations, whereas it did not affect dilations to sodium nitroprusside, adenosine, and norepinephrine. Compared with arteries, arterioles have a greater spontaneous tone and enhanced nitric oxide modulation of basal tone and exhibit greater responsiveness to nitric oxide and adenosine. In addition, nitric oxide synthase is activated differently by pharmacologic stimuli in these segments. The qualitative and quantitative differences among vasoactive responses of coronary arteries and arterioles demonstrated in this study suggest segment-specific roles for endothelial and metabolic factors in regulation of coronary vascular resistance.     

Inhibition of rho-kinase by hydroxyfasudil prevents vasopressin-induced myocardial ischemia in Donryu rats by attenuating coronary vasoconstriction

BACKGROUND: Inhibition of rho-kinase has been shown to attenuate vasopressin (AVP)-induced myocardial ischemia measured as S-wave depression in Donryu rats. This has been attributed to a direct inhibitory effect on AVP-induced coronary vasoconstriction. However, since AVP also increased mean arterial blood pressure (MAP) which was attenuated by the rho-kinase inhibitors used, the prevention of myocardial ischemia could have been due to effects on afterload. RESULTS: The purpose of this study was to determine if rho-kinase inhibition prevents S-wave depression independent of the effects on blood pressure. In anesthetized Donryu rats (200-340 g), infusion of AVP (0.1 IU/kg) resulted in a sustained increase in MAP (DeltaMAP=46+/-7 mm Hg) and a transient S-wave depression (-90+/-20 microV). Infusion of phenylephrine titrated to achieve a comparable pressor response (DeltaMAP=52+/-2 mm Hg) resulted in a significantly smaller S-wave depression (-30+/-20 microV). Pretreatment with the rho-kinase inhibitor, hydroxyfasudil (3 mg/kg), decreased MAP by -28+/-2 mm Hg and significantly attenuated AVP-induced S-wave depression (-10+/-10 microV) compared to AVP. When rats were pretreated with phenylephrine titrated to maintain MAP, hydroxyfasudil still significantly attenuated AVP-induced S-wave depression (-14+/-12 microV). Hydralazine (1 mg/kg), which lowered MAP by -36+/-5 mm Hg, had no significant effect on AVP-induced S-wave depression (-105+/-32 microV). CONCLUSION:These data indicate that inhibition of rho-kinase with hydroxyfasudil attenuates AVP-induced myocardial ischemia independent of changes in MAP and are consistent with an inhibitory effect on coronary vasoconstriction.     

Effect of a new alpha 2-adrenoceptor antagonist on poststenotic coronary resistance and myocardial function

The effect of the alpha 2-adrenoceptor antagonist 4-fluoro-2-(imidazoline-2-ylamino)-isoindoline maleate (BDF 8933) on poststenotic end-diastolic distal coronary resistance and poststenotic myocardial function (sonomicrometry) was investigated under control conditions and during cardiac sympathetic nerve stimulation (CSNS = electrical stimulation of the left ventrolateral cervical cardiac nerve). In 7 vagotomized, open-chest dogs end-diastolic distal coronary resistance was determined. This variable was essentially unchanged after administration of the agent. In additional 6 dogs regional myocardial function was measured as systolic wall thickening (SWT). CSNS increased SWT of the posterior circumflex-perfused myocardium from 12.7 +/- 4.6% to 21.9 +/- 8.4% (p less than 0.05) under control conditions. With a severe stenosis on the left circumflex coronary artery, SWT was reduced to 5.4 +/- 4.0% and further decreased to 2.1 +/- 5.1% (p less than 0.05) during CSNS. After i.v. injection of 150 micrograms/kg BDF 8933, poststenotic myocardial function at rest was 4.2 +/- 4.2%, and 5.6 +/- 3.6% during CSNS. Regarding to the systemic effects BDF 8933 significantly increased peak left ventricular pressure in all 13 dogs. Thus, the new alpha 2-adrenoceptor antagonist BDF 8933 at the chosen dosage prevents sympathetically induced myocardial ischemia, but increases left ventricular afterload resistance.     

水杉总黄酮对麻醉犬实验性心肌梗死的保护作用

目的　观察水杉总黄酮对麻醉犬急性心肌梗死的保护作用。方法　采用结扎犬冠状动脉左前降支的方法造成急性心肌梗死模型 ,十二指肠给药 ,测定犬冠脉循环及心肌耗氧量参数 ,心肌缺血程度和缺血范围 ,梗死面积 ,血清CK、LDH活性及FFA含量。结果　水杉总黄酮能降低冠脉阻力 ,增加冠脉流量 ,减少心肌耗氧量 ,减轻心肌缺血程度和缺血范围 ,缩小心肌梗死面积 ,降低血清CK、LDH活性及FFA含量。结论　水杉总黄酮能改善冠脉循环 ,减少心肌耗氧量 ,纠正心肌缺血时FFA代谢紊乱 ,对缺血心肌具有明显保护作用。     

Effects of three beta adrenergic receptor blockers on myocardial oxygen consumption in the dog

The effects of cardiac sympathetic nerve stimulation on heart rate, cardiac contractile force, cardiac output, arterial and left atrial blood pressure, coronary blood flow and myocardial oxygen consumption were studied before and after intravenous administration of alprenolol (0.3 mg/kg), propranolol (0.3 mg/kg) or practolol (1.2 mg/kg). The three β-blockers were equally effective inhibitors of cardiac stimulation, coronary vasodilatation and increase of myocardial oxygen consumption elicited by sympathetic nerve stimulation. A transient coronary vasoconstriction seen immediately after the start of sympathetic nerve stimulation tended to be slightly potentiated by all three blockers.     

地奥心血康对犬心肌缺血及血流动力学的影响

本文研究地奥心血康对结扎冠状动脉所造成的犬急性心肌缺血及心脏血流动力学的影响。地奥心血康１００ｍｇ／ｋｇ，ｉｖ，能明显减少心肌缺血范围，减轻缺血损伤程度；可使心率明显减慢，血压、心输出量、左室内压、左室作功、心肌耗氧量、冠状动脉阻力和总外周阻力下降，冠状动脉血流量增加。提示该药有抗心肌缺血作用，并能改善心脏血流动力学。     

Adrenoceptor subtypes involved in the baroreceptor reflex constriction of large coronary arteries in the anaesthetized dog

The baroreceptor reflex was invoked by bilateral occlusion of the carotid arteries in anaesthetized dogs. The effect of bilateral carotid occlusion on the diameter of the left circumflex coronary artery and late diastolic coronary resistance was examined after bilateral vagotomy and antagonism of beta-adrenoceptors and then compared to responses after selective antagonism of alpha 1- and alpha 2-adrenoceptors. In the absence of any change in heart rate, bilateral carotid occlusion decreased coronary artery diameter (-8 +/- 1%) and increased coronary resistance (59 +/- 14%). Prazosin (0.01 mg/kg i.a.), a selective antagonist of alpha 1-adrenoceptors, significantly attenuated the bilateral carotid occlusion-induced changes in coronary artery diameter (-2 +/- 2%) and late diastolic coronary resistance (20 +/- 11%). Selective antagonism of alpha 2-adrenoceptors by the intra-coronary injection of idazoxan (0.05 mg/kg) significantly reduced the bilateral carotid occlusion-induced increase in coronary resistance (14 +/- 12%) but did not affect the large artery constriction (-8 +/- 4%). When injected into the coronary circulation the alpha 1-adrenoceptor agonist phenylephrine constricted both the large artery and the resistance vessels. In contrast B-HT 920, a selective alpha 2-adrenoceptor agonist, constricted the resistance vessels but did not affect large coronary artery tone. The responses to phenylephrine and B-HT 920 were selectively antagonised by prazosin and idazoxan respectively. Reflex activation of the sympathetic nervous system results in constriction of both large coronary arteries and coronary resistance vessels when there is no change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute cardiovascular effects of the alpha2-adrenoceptor antagonist, idazoxan, in rats: influence of the basal sympathetic tone

Intravenous administration of the alpha2-adrenoceptor antagonist, idazoxan, elicits variable cardiovascular effects, depending on experimental conditions. In this study, the effects of idazoxan were investigated in rats with high, low, or no basal sympathetic tone. In a group of conscious Sprague-Dawley rats (n = 9), mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nervous activity (RSNA) were recorded. Idazoxan (250 microg/kg, i.v.) induced a transient decrease in MAP (-12+/-3 mm Hg) that was accompanied by increases in HR (49+/-14 beats/min) and RSNA (53+/-14%). In six of nine rats, a light pentobarbitone anesthesia was given. Basal RSNA was decreased (6.0+/-1.3 microV from 12.8+/-4.1 microV; p<0.05), and the depressor effect of idazoxan was reversed to a pressor effect (21+/-6 mm Hg) associated with bradycardia (-16+/-8 beats/min) and sympathoinhibition (-56+/-15%). In eight conscious intact rats, idazoxan (250 microg/kg, i.v.) attenuated by approximately 40% the pressor response to the selective alpha1-adrenoceptor agonist, cirazoline (0.5 microg/kg, i.v.). In three groups of six to seven ganglion-blocked (chlorisondamine, 2.5 mg/kg, i.v.) conscious rats, idazoxan dose-dependently increased mean arterial pressure (MAP: 39+/-2, 55+/-3, and 69+/-4 mm Hg at 125, 250, and 500 microg/kg, i.v., respectively) with minimal changes in HR. In contrast, the noradrenaline-releasing agent, tyramine (62.5, 125, and 250 microg/kg, i.v.), dose-dependently increased both MAP and HR. The alpha1-adrenoceptor antagonist, prazosin (1 mg/kg, i.v.; n = 8) blunted by approximately 70% (p<0.01) the pressor effect of 250 microg/kg idazoxan. It is concluded that in rats with high sympathetic tone, idazoxan has depressor effects, most likely related to its peripheral alpha-adrenoceptor antagonist properties. In rats with low or no sympathetic tone, idazoxan induced pressor responses mainly secondary to its partial agonist activity at vascular postjunctional alpha1-adrenoceptors.     

Intravenous adrenomedullin in myocardial function and energy metabolism in patients after myocardial infarction

This study investigated the effects of adrenomedullin on left ventricular myocardial contraction and relaxation, coronary blood flow, and myocardial oxygen consumption in comparison with those of atrial natriuretic peptide (ANP). Fourteen patients who had had myocardial infarctions were randomly assigned to receive IV infusion of adrenomedullin (0.05 microg/kg/min) or ANP (0.05 microg/kg/min). Both adrenomedullin and ANP significantly decreased left ventricular systolic pressure (-17 mm Hg, -13 mm Hg, respectively, both p < 0.05). The increase in cardiac index by adrenomedullin (+31%) was significantly greater than that by ANP (+16%). Adrenomedullin significantly increased an index of myocardial contractility, Emax (2.5 +/- 0.3 mm Hg-3.7 +/- 0.3 mm Hg/ml, p < 0.05) and shortened an index of myocardial relaxation, Tau (52 +/- 5 ms-48 +/- 4 ms, p < 0.05). In contrast, ANP did not significantly alter either parameter. In addition, adrenomedullin, but not ANP, significantly increased coronary sinus blood flow (73 +/- 10 ml/min-86 +/- 10 ml/min, p < 0.05). Adrenomedullin did not increase myocardial oxygen consumption. Unlike ANP, IV administration of adrenomedullin enhanced left ventricular myocardial contraction and improved left ventricular relaxation without increasing myocardial oxygen consumption in patients who had had a myocardial infarction.