Effect of anesthesia on reactivity of large coronary arteries in the dog

Epicardial coronary arteries dilate after release of a transient coronary occlusion in awake chronically instrumented dogs but not in anesthetized dogs studied acutely after surgery. To determine whether anesthesia or surgical trauma is responsible for this lack of reactive dilation, we evaluated the effect of anesthesia on reactive coronary dilation in six chronically instrumented dogs. Circumflex coronary diameter was measured with sonomicrometry. Response to release of a 20- or 30-s coronary occlusion was studied before and after sodium pentobarbital (20 +/- 2 mg/kg) and before and after alpha-chloralose (100 mg/kg) plus either morphine or fentanyl and droperidol. Pentobarbital blunted the peak flow response to release of a transient coronary occlusion (114 +/- 15 vs. 128 +/- 16 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before pentobarbital: 3.68 +/- 0.30-3.74 +/- 0.30 mm; after pentobarbital: 3.66 +/- 0.31-3.71 +/- 0.31 mm). alpha-Chloralose blunted the peak flow response to release of a transient coronary occlusion (96 +/- 12 vs. 141 +/- 25 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before chloralose: 4.00 +/- 0.28-4.06 +/- 0.28 mm; after chloralose: 3.91 +/- 0.31-3.98 +/- 0.31 mm). Therefore, each drug blunted the peak flow response to release of a transient coronary occlusion, but dilation of large coronary arteries was not impaired. The lack of reactivity of large coronary arteries in acutely studied dogs is probably due to the trauma of recent surgery and not the anesthesia.     

The effects of pronethalol and propranolol on the coronary circulation of the dog

1. The actions of pronethalol and propranolol have been studied to see if there was any relationship between the reduction in coronary flow and any other cardiovascular action they have.2. The experiments were carried out in anaesthetized open chest dogs. Measurements included central arterial, left and right venous or atrial pressures, heart rate, ventricular size and stroke volume, intra-ventricular pressures, total left coronary flow, arterial and coronary sinus blood pO(2). The pressure-time index (PTI) and maximum rate of isovolumetric contraction (dp/dt) were obtained from these records.3. It was concluded that, in these experiments, the reduction in coronary flow produced by pronethalol and propranolol was not directly related to a decrease in perfusion pressure, a raised venous pressure, the increase in ventricular volume and hence wall tension, the decrease in heart rate, or to the increased duration of systole.4. The PTI and dp/dt were always reduced at the same time as the coronary flow. These findings are discussed.5. Studies of the effects of sympathetic stimulation, of phentolamine, of reduced arterial oxygen tension and electrical pacing of the heart, all after beta-blockade, did not support the suggestion that the reduction in coronary flow after beta-blockade was due to the unmasking of an active vasoconstriction.     

Blood flow in intact and constricted coronary arteries under the influence of ouabain

Summary The effects of ouabain on intact and experimentally constricted coronary arteries were investigated in anaesthetized, thoracotomized dogs. Ouabain decreased the blood flow in the intact artery without changing the flow per beat values and increased flow in the constricted artery. Since ouabain decreased left ventricular enddiastolic pressure, it is proposed that the drug-induced augmentation of flow in the constricted artery is related to an elevation of driving pressure to the endocardial layers of the myocardium which are supplied by the constricted artery.     

The effect of diltiazem on the coronary haemodynamic and cardiac functional effects produced by intracoronary administration of endothelin-1 in the anaesthetized dog.

1. We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary (i.c.) administration of endothelin-1 (ET-1) in anaesthetized dogs. 2. ET-1, 1, 3 and 10 ng kg-1 i.c., produced dose-related increases in coronary blood flow with no cardiac functional or systemic haemodynamic changes. ET-1, 30, 100 and 300 ng kg-1 i.c., produced dose-related reductions in coronary artery blood flow. The reduction in coronary blood flow was accompanied by dose-related falls in cardiac output, mean arterial pressure, +dP/dt and -dP/dt and increases in left ventricular end-diastolic pressure. However, there was no reflex tachycardia in response to the fall in blood pressure and at 300 ng kg-1, ET-1 produced a 22% reduction in heart rate. 3. Following a series of abnormal ECG changes, four out of five dogs died of ventricular fibrillation at 13 +/- 2 min after 300 ng kg-1 ET-1. 4. The administration of diltiazem (15 micrograms kg-1 min-1, i.v.) reduced mean arterial pressure by 10% and heart rate by 15%, and increased coronary blood flow by 39%. Diltiazem did not have any significant effect on the coronary dilator response to low doses of ET-1. Although there was a general trend for diltiazem to inhibit the coronary vasoconstrictor responses to ET-1, diltiazem significantly attenuated only the reduction in coronary blood flow produced by 100 ng kg-1 ET-1 by 60% but not the response to 30 or 300 ng kg-1 ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

INFLUENCE OF NICORANDIL, AN ANTIANGINAL AGENT, ON THE THERAPEUTIC AND TOXIC CARDIOVASCULAR ACTIONS OF OUABAIN IN THE ANAESTHETIZED DOG

The effects of nicorandil were investigated on ouabain-induced cardiovascular actions in pentobarbitone-anaesthetized dogs. Nicorandil (500 micrograms/kg per h) and ouabain (100 micrograms/kg per h), alone and in combination, were infused intravenously to three groups of dogs. Nicorandil gradually decreased systemic blood pressure, pressure-rate product, left ventricular systolic pressure, and coronary vascular resistance, but did not significantly affect heart rate, left ventricular dP/dt max, coronary blood flow, plasma electrolyte concentrations and ECG patterns. The lethal dose of ouabain was 122 micrograms/kg (s.e.m. = 3, n = 6) and the dose required to elicit ventricular premature beats was 63 micrograms/kg (s.e.m. = 3, n = 6). When nicorandil and ouabain were simultaneously infused intravenously, nicorandil did not affect either the lethal dose of ouabain or the dose required to produce ventricular premature beats, but it significantly inhibited the marked increases in coronary vascular resistance and systemic blood pressure induced by ouabain alone. Even in combination with nicorandil, ouabain maintained its own positive inotropic effect. The results indicate that the combination of ouabain with nicorandil may be beneficial in some conditions of angina pectoris.     

Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism

We investigated the cardiovascular profile of nicorandil, an antianginal agent, in humans. Pharmacologically, nicorandil acts as both an adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel opener and a nitrate. We examined which of these mechanistic components has a predominant vasodilatory effect at clinical doses. Fourteen patients underwent cardiac catheterization. The effects of the continuous intravenous infusion of nicorandil (12 mg/45 min) were examined in angiographically normal coronary arteries. Coronary vascular resistance was calculated from coronary artery diameter and coronary blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intracoronary injection of nitroglycerin (250 microg) and papaverine (12 mg). The epicardial coronary arteries responded to nicorandil at the lowest plasma concentration examined (dilation of +14.0 +/- 3.3% at approximately 170 ng/ml), whereas dilation of the coronary resistance arteries (i.e., a decrease in coronary vascular resistance) took place only at higher concentrations (>200 ng/ml). Nitroglycerin caused no further changes in coronary artery diameter or coronary vascular resistance. Papaverine caused no further increase in coronary artery diameter, but markedly decreased coronary vascular resistance (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil significantly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac preload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated epicardial coronary arteries rather than coronary resistance arteries, and had a stronger effect on preload than on afterload. These changes in human coronary hemodynamics suggest that the nitrate actions of nicorandil as a coronary vasodilator predominate over those as a K(ATP) opener.     

苦碟子注射液对犬心脏功能和血流动力学的影响

目的考察苦碟子注射液对麻醉开胸犬心脏功能和血流动力学的影响。方法采用麻醉开胸犬模型,测量其心率、心输出量、冠脉流量、心肌耗氧量以及血流动力学各参数。结果苦碟子注射液以2.0、4.0 g.kg-1静脉注射给药可显著增加戊巴比妥钠麻醉犬的心输出量和冠脉流量,降低平均动脉压、左心室内压和左心室舒张末期压力,减少左室内压力变化速度和心肌耗氧量(P<0.05,P<0.01)。结论苦碟子注射液能显著改善麻醉开胸犬血流动力学。     

The Effect of Prolonged Pentobarbital Anaesthesia on Cardiac Electrophysiology and Inotropy of the Dog Heart in Situ

Abstract The effect of prolonged pentobarbital anaesthesia was tested on the dog heart in situ by means of His bundle electrography and programmed electrical stimulation, monophasic action potential recordings from the right ventricle and measurements of peak dp/dt obtained by Millar tip transducer in the left ventricle. Sixteen dogs were used. Immediately after catheterization during anaesthesia, a slight decreased heart rate, a reduction in the conduction velocity and an increase in the functional refractory period of the atrioventricular node occurred. From 15 to 30 min. after catheterization we observed no change in cardiac electrophysiology during the 8 hrs observation period. A slight decrease in contractility, however, appeared towards the end of the period. We conclude that dogs anaesthetized with pentobarbital could serve as a suitable model for testing drug effect on cardiac electrophysiology and contractility. The limitations of the model area are discussed.     

Coronary vasodilatation following diazepam (Valium)

1. The effects of diazepam (Valium) on coronary and systemic vascular resistance were studied in anaesthetized dogs on cardiopulmonary bypass under conditions of constant heart rate and aortic pressure.2. Pharmacological doses of diazepam uniformly produced coronary vasodilation lasting 30 min; systemic vascular resistance also decreased, but to lesser degree.3. When coronary blood flow was maintained constant at physiological levels, diazepam produced no changes in left ventricular contractility, as assessed by peak LV isovolumetric pressure, dp/dt max, force-velocity, and length-tension relations, whereas previous experiments had demonstrated a positive inotropic effect in a similar preparation in which coronary blood flow was responsive to alterations in coronary vascular resistance.4. In five dogs, complete separation of the coronary and systemic circulations was accomplished by a double pump-oxygenator system; direct intracoronary administration of diazepam produced coronary vasodilatation, but coronary pressure and flow were not altered by administration of diazepam to the systemic circulation.5. It is concluded that diazepam augments myocardial contractility by increasing coronary blood flow. This relationship is independent of extracardiac humoral mechanisms, and appears to require the delivery of diazepam to the coronary circulation.     

Cardiovascular effects of a new 1,5-benzothiazepine calcium antagonist in anesthetized dogs

Cardiovascular effects of TA-3090 ((+)(2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), a new 1,5-benzothiazepine derivative, were studied in pentobarbital anesthetized dogs. TA-3090 administered intraarterially (i.a.) was 3 times more potent than diltiazem in increasing vertebral and coronary blood flows. In the autoperfused preparation, TA-3090 i.a. exhibited weak negative inotropic effect as compared with its coronary vasodilating effect; negative inotropy was less than 10% at a dose which increased coronary blood flow by 50%. The selectivity of TA-3090 for coronary artery was greater than that of verapamil. Intravenous administration of TA-3090 (0.025-0.2 mg/kg) produced increases in cardiac output and arterial, especially vertebral and coronary blood flow as well as in left ventricular dp/dtmax. The increasing effect in blood flow was most prominent in the vertebral artery. Upon intraduodenal administration of 2 and 5 mg/kg TA-3090, the increases in vertebral and coronary blood flow lasted for more than 2-5 h; the effect of TA-3090 on vertebral blood flow was approximately twice as potent as that of diltiazem. Thus, TA-3090 could be demonstrated to possess potent and long-lasting vasodilating activity with selectivity for vertebral and coronary arteries, exerting however, weak negative inotropic effect.     

Haemodynamic and coronary effects of quazodine in cats with developing myocardial infarcts

Acute ligation of the descending branch of the left coronary artery in anaesthetized cats resulted, within 1–2 h, in a 30% decrease in local blood flow in the region mainly supplied by the ligated vessel, a fall in systemic blood pressure, in cardiac output, and in left ventricular dP/dt max (LVdP/dt). There was electrocardiographic evidence of myocardial ischaemia (pronounced ST elevation). In these animals with developing myocardial infarcts, intravenous infusions of quazodine (MJ1988; 6,7-dimethoxy-4-ethyl-quinazoline) markedly increased myocardial contractility and local myocardial blood flow in the developing infarct, and decreased systemic arterial pressure, peripheral vascular resistance and left ventricular end-diastolic pressure, effects similar to those observed in normal cats. The increase in cardiac contractility (cardiac output and LVdP/dt) occurred without a concomitant increase in myocardial metabolic heat production. This ‘oxygen sparing effect’ probably results from a decrease in left ventricular wall tension. It is suggested that quazodine warrants further investigation as a cardiac stimulant in power failure following myocardial infarction in man.     

The effect of urocortin II administration on the coronary circulation and cardiac function in the anaesthetized pig is nitric-oxide-dependent

We planned to determine the primary effects and mechanisms of urocortin II, a member of the corticotrophin-releasing factor (CRF) family highly expressed in the cardiovascular system, on coronary blood flow and myocardial function in vivo. Urocortin II was infused into the left anterior descending coronary artery in 25 anaesthetized pigs whilst measuring haemodynamic variables, coronary blood flow, ventricular dP/dt(max) cardiac output and percentage of segmental shortening. This infusion was repeated after blockade of the autonomic nervous system, nitric-oxide synthase (NOS) or subtype 2 of the CRF receptors. In all experiments changes in heart rate and aortic blood pressure were prevented. Intra-coronary urocortin II increased, within 60 s, coronary blood flow (15+/-3.2%, P<0.05), dP/dt(max) (12.7+/-2.6%, P<0.05), cardiac output (16+/-2.3%, P<0.05) and percentage of segmental shortening (19.8+/-3.8%, P<0.05). Blockade of NOS abolished only the coronary effects whereas blockade of subtype 2 of the CRF receptors abolished all cardiac and coronary effects. It was shown for the first time that urocortin II administration primarily increases coronary blood flow and myocardial function through the release of nitric oxide and activation of subtype 2 of the CRF receptors in the anaesthetized pig. This provides a mechanism through which a local increase of urocortin II levels can help improve a compromised cardiovascular function.     

Myocardial and haemodynamic effects of phentolamine

1. In cats anaesthetized with pentobarbitone, intravenous infusions of phentolamine ((10-50 mug/kg)/min for 5 min) increased heart rate, left ventricular dp/dt max (without increasing end-diastolic pressure), aortic dp/dt, cardiac output, myocardial blood flow and metabolic heat production.2. Phentolamine-induced increases in myocardial contractility occurred irrespective of the direction or magnitude of the blood pressure change and were maintained well beyond the actual infusion period.3. In cats treated with alprenolol, bretylium or reserpine there was no evidence of increased cardiac contractility following phentolamine administration.4. It is concluded that phentolamine, in doses less than those required to produce significant alpha-adrenoceptor blockade, increased myocardial contractility through an effect on the sympathetic nervous system.     

The effect of prolonged pentobarbital anaesthesia on cardiac electrophysiology and inotropy of the dog heart in situ.

The effect of prolonged pentobarbital anaesthesia was tested on the dog heart in situ by means of His bundle electrography and programmed electrical stimulation, monophasic action potential recordings from the right ventricle and measurements of peak dp/dt obtained by Millar tip transducer in the left ventricle. Sixteen dogs were used. Immediately after catheterization during anaesthesia, a slight decreased heart rate, a reduction in the conduction velocity and an increase in the functional refractory period of the atrioventricular node occurred. From 15 to 30 min. after catheterization we observed no change in cardiac electrophysiology during the 8 hrs observation period. A slight decrease in contractility, however, appeared towards the end of the period. We conclude that dogs anaesthetized with pentobarbital could serve as a suitable model for testing drug effect on cardiac electrophysiology and contractility. The limitations of the model area are discussed.     

The effect of catecholamine infusions on myocardial blood flow, metabolic heat production and on general haemodynamics, before and after alprenolol (H56/28), in anaesthetized cats

1. In cats anaesthetized with pentobarbitone sodium, infusions of adrenaline, noradrenaline (0.5 mug/kg per min) and isoprenaline (0.25 mug/kg per min) increased myocardial blood flow, myocardial heat production, left ventricular systolic and end-diastolic pressures, left ventricular +ve and -ve dp/dt max, and calculated cardiac output, effort and oxygen consumption. These effects (apart from the effect of noradrenaline on left ventricular systolic pressure) were markedly reduced by previous administration of alprenolol (0.5 or 1.0 mg/kg).2. Infusions of adrenaline and noradrenaline increased arterial diastolic blood pressure and isoprenaline reduced it. After alprenolol the effects of adrenaline and noradrenaline were potentiated and that of isoprenaline abolished; in some experiments isoprenaline increased arterial diastolic pressure after alprenolol. Alprenolol did not influence the increases in arterial systolic pressure which followed the administration of adrenaline and noradrenaline.3. Isoprenaline-induced tachycardia was markedly reduced and adrenaline tachycardia was converted to bradycardia after alprenolol. The bradycardia which occurred during noradrenaline infusions was unaffected.4. After blockade by alprenolol, recovery of the effects of isoprenaline on left ventricular dp/dt and on heart rate occurred more quickly than recovery of the effects on arterial diastolic pressure. This suggests that alprenolol has a greater affinity for beta(2)- than for beta(1)-adrenoceptors.5. Intravenous administration of acetylcholine decreased arterial blood pressure, left ventricular pressure and +ve and -ve dp/dt max. During recovery from these effects there was a marked increase in +ve dp/dt max. which was absent after the administration of alprenolol (0.5 mg/kg). Because this dose of alprenolol is thus able to block the effects of reflex sympathetic cardiac nerve stimulation but does not completely antagonize the effects of exogenous adrenaline on dp/dt, it is suggested that alprenolol may have some adrenergic neurone blocking activity.6. Increases in liver and myocardial blood flow and heat production produced by noradrenaline, adrenaline and isoprenaline were reduced after alprenolol.7. Isoprenaline reduced air-way resistance and this effect was abolished by alprenolol; increases in air-way resistance produced by adrenaline and nor-adrenaline were augmented. All three amines inhibited intestinal smooth muscle contractions in vivo. Only the effect of isoprenaline was reduced by alprenolol.     

alpha- and beta-receptor blockade of isoproterenol- and norepinephrine-induced effects on regional blood flow and blood flow acceleration.

The effects of the beta-receptor blocking agent propranolol (100 microgram/kg i.v.) and of the alpha-receptor blocking agent dihydroergotamine (50 microgram/kg i.v.) on hemodynamic responses to isoproterenol and norepinephrine (both 1--1024 ng/kg) were investigated in anesthetized dogs. The effects studied were: (1) flow in the ascending aorta and the coronary, common hepatic, gastroduodenal, splenic, cranial mesenteric, renal and femoral arteries: (2) maximal flow acceleration in the splenic, cranial mesenteric and femoral arteries; (3) maximal rate of change of left ventricular pressure (LV dP/dt max). Propranolol shifted the dose-response curves for the isoproterenol-induced flow increases in the common hepatic, gastro-duodenal, and cranial mesenteric arteries to the right. It did not influence the flow responses to isoproterenol in the ascending aorta or the coronary, splenic, renal and femoral arteries. Propranolol prevented the decrease of arterial pressure evoked by isoproterenol. Propranolol shifted the isoproterenol-induced increase of LV dP/dt max and maximal blood flow to the same extent. Propranolol blocked the flow to the liver and gastrointestinal tract to a greater extent than the LV dP/dt max and maximal flow acceleration. Propranolol had no effect on the norepinephrine-induced increases in flow in the splenic, femoral and coronary arteries, but blocked the norepinephrine-evoked increases of flow accelerations and LV dP/dt max to the same extent. Dihydroergotamine inhibited the norepinephrine-induced increase in flow in the femoral artery and the decreases in flow in the hepatic, splenic, cranial mesenteric and renal arteries, and reversed the reduction of flow in the gastroduodenal artery. It is argued that dihydroergotamine may inhibit the increase in femoral flow through two mechanisms: (1) blocking the flow reduction to norepinephrine in the abdomen, and thereby passively shunting blood from the abdomen in preference to the femoral bed; (2) attenuating the norepinephrine-evoked reflexogenic femoral vasodilatation. It is concluded that: (1) propranolol is a beta-receptor blocking agent with a preference for blockade of isoproterenol-induced vascular effects; (2) norepinephrine-induced flow increases are not direct actions on vascular beta-receptors; (3) the increase of maximal blood flow accelerations after isoproterenol and norepinephrine is mediated by stimulation of cardiac beta-receptors; (4) dihydroergotamine is an alpha-receptor blocking agent particularly in the splanchnic vascular region.     

Direct coronary vasodilation induced by intracoronary vasoactive intestinal peptide.

Vasoactive intestinal peptide (VIP) is a neurotransmitter that has been identified in epicardial coronary arteries. To evaluate the direct effect of VIP on coronary hemodynamics and blood flow, graded doses of VIP (0.01, 0.03, 0.10, and 0.30 micrograms/min) were infused into the left coronary artery of 7 patients at the time of diagnostic cardiac catheterization for chest pain syndromes. None of the patients had coronary stenoses greater than 50% during subsequent angiography. Coronary sinus VIP concentrations increased during each infusion (22 +/- 28 pg/ml at baseline to 109 +/- 22 pg/ml at 0.30 micrograms/min; p less than 0.05), but arterial VIP was elevated (39 +/- 29 pg/ml) only at the maximal dose of 0.30 micrograms/min. During all dosages of VIP, heart rate, right atrial and left ventricular end-diastolic pressure, and the heart rate x blood pressure product did not change. Moreover, neither mean aortic pressure nor left ventricular peak + dP/dt changed significantly at doses less than 0.30 micrograms/min; at 0.30 micrograms/min, mean aortic pressure decreased (97 +/- 15 to 90 +/- 15 mm Hg; p less than 0.05) and LV peak + dP/dt increased (1,621 +/- 230 to 1,801 +/- 226 mm Hg/s; p less than 0.05). Compared to baseline, the arterial-coronary sinus O2 content difference and myocardial O2 extraction diminished progressively at the 0.03, 0.10, and 0.30 micrograms/min doses of VIP (118 +/- 12 ml O2/L vs. 94 +/- 15, 70 +/- 9, and 61 +/- 26 ml O2/L, respectively, and 0.64 +/- 0.05 vs. 0.53 +/- 0.10, 0.38 +/- 0.06, and 0.34 +/- 0.15, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of blood pressure changes on the catecholamine release in the locus coeruleus of cats anaesthetized with pentobarbital or chloralose

Summary Effects of carotid occlusion and drugs applied intravenously on the release of endogenous catecholamines in the locus coeruleus of cats anaesthetized with pentobarbital or chloralose were investigated. The locus coeruleus was superfused bilaterally with artificial cerebrospinal fluid through push-pull cannulae inserted stereotaxically. Dopamine, noradrenaline and in some experiments also adrenaline were determined radioenzymatically in the superfusate.Under pentobarbital anaesthesia, a bilateral carotid occlusion increased the release rate of noradrenaline in the locus coeruleus, while the release of dopamine was decreased. These changes were due to the fall of blood pressure in the carotid sinus caused by the occlusion. Loading of baroreceptors by elevating blood pressure with phenylephrine (10 g·kg^–1·min^–1, i.v. infusion) was accompanied by a decreased release of noradrenaline in the locus coeruleus. This decrease in noradrenaline release was not detected in the caudal aspect of the locus coeruleus. Under chloralose anaesthesia, phenylephrine diminished the release rate of noradrenaline to about the same extent as under pentobarbital anaesthesia. The release rate of adrenaline was also decreased. A prolonged infusion of phenylephrine led to a prolonged pressor response associated with a sustained decrease in the noradrenaline release rate. Intravenous injection of chlorisondamine (3 mg·kg^–1) did not change the release of noradrenaline, while dopamine release was reduced.It is concluded that the release of catecholamines in the locus coeruleus is influenced by signals originating from peripheral baroreceptors. The influences are similar under pentobarbital and chloralose anaesthesia. Noradrenergic neurons responding to haemodynamic signals are not uniformly distributed within the locus coeruleus. It is suggested that noradrenergic and possibly dopaminergic and adrenergic neurons of the locus coeruleus are involved in the baroreceptor reflex, thus contributing to central homeostasis of blood pressure.     

Antagonism of vasopressin-induced coronary artery constriction by the vasopressin antagonist d(CH2)5Tyr(Me)-AVP

d(CH2)5Tyr(Me)-AVP is a potent inhibitor of the systemic vasoconstrictor action of vasopressin (AVP). In order to examine the effectiveness of this agent in blocking AVP-induced coronary vasoconstriction, 11 pentobarbital-anesthetized mongrel dogs were instrumented for the measurement of left circumflex (LCX) coronary blood flow, systemic arterial blood pressure, heart rate, lead II electrocardiogram, left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular +/- dP/dt. Direct injection of AVP (0.01-1 microgram) into the LCX produced a dose-dependent decrease in coronary artery blood flow (maximum reduction: 60.5 +/- 8.1% after 1 microgram), - dP/dt (maximum reduction: 41.8 +/- 5.3% after 1 microgram), and +dP/dt (maximum reduction: 14.6 +/- 5.3%), whereas a dose-dependent increase in left ventricular end-diastolic pressure was observed (maximum increase: 62.6 +/- 20.2%). No significant changes occurred in heart rate, mean blood pressure, or left ventricular developed pressure. Intravenous administration of d(CH2)5Tyr(Me)-AVP reduced (1 microgram/kg) or abolished (5 micrograms/kg) the effects of AVP on coronary blood flow +/-dP/dt and left ventricular end-diastolic pressure. In addition, doses of 1,2, and 5 micrograms/kg of d(CH2)5Tyr(Me)-AVP alone produced increases of LCX blood flow of 5.1 +/- 1.5, 2.0 +/- 0.7, and 6.8 +/- 1.7 ml/min, respectively (p less than 0.05). We conclude that d(CH2)5Tyr(Me)-AVP is effective in preventing the coronary artery constriction and hemodynamic sequelae of intracoronary administered AVP.     

The effect of heart rate on indices of myocardial contractility in the dog

1. Changes in heart rate were evoked by atrial pacing in anaesthetized dogs with no pretreatment and in dogs given reserpine or guanethidine for 72 h. The effect of alterations in heart rate were related to two indices of myocardial contractility: the maximal rate of change of left ventricular pressure (dp/dt), and an index which was independent of initial fibre length (dp/dt)/IIT, where IIT is integrated isometric tension. 2. An increase in heart rate in control dogs was accompanied by a rise in both dp/dt and (dp/dt)/IIT confirming that the Bowditch staircase does exist in the intact ventricle. The regression line relating heart rate to (dp/dt)/IIT was significantly steeper than that relating heart rate to dp/dt because the reduction in left ventricular preload at high heart rate tends to attenuate the rise in dp/dt. 3. Reserpine, but not guanethidine pretreatment was accompanied by either a slight decrease or no change in (dp/dt)/IIT during pacing. 4. Acute elevation of (dp/dt)/IIT by either calcium or isoprenaline infusion in reserpine pretreated dogs did not restore the Bowditch effect. 5. Acute depression of (dp/dt)/IIT by propranolol and pentobarbitone was accompanied by a greater rise in (dp/dt)/IIT with pacing in control dogs and a rise rather than a fall in reserpine-pretreated dogs.