Adrenoceptor blocking and cardiovascular effects of the optical isomers of amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor blocking agent, and the corresponding desoxy derivative (YM-11133) in rats

The pharmacological activities of the enantiomers of amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor antagonist, and the corresponding desoxy derivative (YM-11133) were investigated in the cardiovascular system of rats. The optical isomers of amosulalol and YM-11133 antagonized the vasopressor effect of phenylephrine and the positive chronotropic effect of isoproterenol in normotensive pithed rats. Based on DR2 values (micrograms/kg, i.v.) obtained from Schild plots, (+)-amosulalol and YM-11133 (DR2 = 30) were approximately 10 times more potent than (-)-amosulalol (DR2 = 324) in blocking alpha 1-adrenoceptors. For beta 1-adrenoceptors, in contrast, (-)-amosulalol (DR2 = 107) was approximately 60 times more potent than (+)-amosulalol (DR2 = 6460), which was almost equipotent with YM-11133 (DR2 = 3250). The results indicate that the optical isomers of amosulalol interact differently with alpha 1- and beta 1-adrenoceptors. The effects of these phenethylamines on blood pressure and heart rate were studied in urethane-anesthetized rats (i.v.). The rank order of hypotensive potency in anesthetized rats [+)- = desoxy greater than (-)-form) was consistent with the rank order of alpha 1-adrenoceptor antagonism in pithed rats. In contrast, (-)-amosulalol having a more potent beta 1-adrenoceptor antagonist activity than (+)-amosulalol and YM-11133 only produced dose-dependent bradycardia at the hypotensive doses. The results indicate that the vascular alpha 1- and cardiac beta 1-adrenoceptor blocking activities of the optical isomers of amosulalol contribute to their hypotensive and bradycardia, respectively. Thus, the racemate of amosulalol appears to exert an overall activity reflecting the activities of the individual isomers.     

Cardiovascular effects of a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent, YM-16151-4, in anesthetized and conscious dogs.

Cardiovascular effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in dogs. In anesthetized dogs, YM-16151-4 (0.01-1 mg/kg intravenously, i.v.) dose-dependently increased coronary blood flow (CBF) and decreased mean blood pressure (MBP), total peripheral resistance (TPR), dP/dtmax, double product, and left ventricular (LV) work without increasing heart rate (HR) and cardiac output (CO). YM-16151-4 increased vertebral blood flow as well as CBF, but had no effect on carotid, mesenteric, renal, and femoral blood flow. Coronary vasodilating activity of YM-16151-4 was also observed after intracoronary artery injection (i.a.). In anesthetized and vagotomized dogs, YM-16151-4 dose-dependently inhibited isoproterenol (0.2 micrograms/kg i.v.)-induced tachycardia and decrease in diastolic BP (DBP), with ED50 values of 0.039 and 0.52 mg/kg i.v., respectively. In conscious dogs, YM-16151-4 (0.1-1 mg/kg i.v.) produced a dose-dependent hypotensive effect with no effect on HR or PQ-interval. The hypotensive effect of YM-16151-4 (0.3 and 1 mg/kg i.v.) reached its maximum approximately 1-2 h after each dosing and lasted 6-8 h. These results suggest that YM-16151-4 actually behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and that this compound could be a novel long-acting antianginal and antihypertensive agent.     

Autonomic and antihypertensive activity of oral amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor blocking agent in conscious rats

The autonomic and antihypertensive activities of amosulalol (YM-09538) were studied in conscious rats. Single oral administration of amosulalol antagonized the phenylephrine-induced pressor and isoproterenol-induced positive chronotropic responses with DR10 values of 11.5 and 13.6 mg/kg in pithed rats, respectively, indicating that the compound inhibits both alpha 1- and beta 1-adrenoceptors to almost the same extent in agreement with previously reported results in vitro. Amosulalol was approximately 50 times less potent than prazosin and 12 times more potent than labetalol at alpha 1-adrenoceptors, and it was approximately as effective as labetalol and 2 times more potent than propranolol at beta 1-adrenoceptors. In spontaneously hypertensive rats (SHR), renal hypertensive rats and DOCA/salt hypertensive rats, a single oral administration of amosulalol (3-30 mg/kg) lowered acutely systolic blood pressure with a duration of over 6 hr and was found to be approximately 50 times less potent than prazosin and 3 times more potent than labetalol in lowering blood pressure. Propranolol did not cause such an immediate hypotensive effect. Amosulalol and labetalol did not increase heart rate, whereas prazosin induced a tachycardia in the hypertensive rats. Repeated oral administrations of amosulalol and labetalol (50 mg/kg/day, b.i.d., for 12 weeks) produced not only an antihypertensive effect without evidence of tolerance, but also reductions in plasma renin activity (PRA) and heart rate in SHR with established hypertension. We conclude that alpha-adrenoceptor blockade by amosulalol might account for its antihypertensive activity and that its beta-adrenoceptor blockade might inhibit reflexogenic increases in heart rate and PRA due to the reduction in blood pressure.     

Effect of pinacidil on myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle.

This study examined the effect of pinacidil on the transmural distribution of myocardial blood flow in the chronically pressure overloaded hypertrophied left ventricle. Studies were performed in six dogs in which banding of the ascending aorta had resulted in an 88% increase in left ventricular mass, as well as in six normal control animals. Two doses of pinacidil were administered to decrease mean arterial pressure by approximately 10 mm Hg (low dose) and 20 mm Hg (high dose). Animals with hypertrophy required significantly smaller drug doses to achieve the desired reductions in arterial pressure. During control conditions mean myocardial blood flow was significantly higher in animals with hypertrophy (1.90 +/- 0.21 ml/min/g) than in normal animals (1.12 +/- 0.08 ml/min/g; p less than 0.05). Subendocardial flow (endo) exceeded subepicardial flow (epi) in normal dogs during control conditions (endo/epi = 1.41 +/- 0.13), but not in animals with hypertrophy (endo/epi = 1.06 +/- 0.06; p less than 0.05). Pinacidil caused coronary vasodilation with similar relative increases in blood flow in both normal and hypertrophied hearts, so that after pinacidil, absolute blood flow rates remained higher than normal in animals with hypertrophy. Pinacidil caused a redistribution of blood flow away from the subendocardium in normal hearts (endo/epi = 0.90 +/- 0.11 during high-dose pinacidil) and in hearts with hypertrophy (endo/epi = 0.81 +/- 0.13 during high-dose pinacidil). The endo/epi ratios during high-dose pinacidil were not significantly different between the two groups. This study demonstrates that pinacidil is a potent coronary vasodilator in both normal and hypertrophied hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dilazep on coronary and systemic circulations

In order to assess the effects of dilazep on central hemodynamics and regional flows, 0.2 mg/kg of the drug were administered intravenously to 6 open-chest anesthetized dogs. Hemodynamic and flow measurements were performed under control conditions, and approximately 5, 10 and 25 min after treatment. Dilazep caused a marked and sustained reduction of coronary resistance and increased coronary blood flow. Flow increased uniformly in the subendocardial and subepicardial layers of the left ventricle so that no significant change occurred in the endo/epi flow ratio. Dilazep caused a significant reduction of total systemic resistance and aortic pressure, however flow to the liver, kidney and spleen was not reduced. We conclude that dilazep exerts a dilating action on the coronary and systemic arterial beds and increases uniformly regional myocardial blood flow. Dilazep does not alter the transmural distribution of coronary blood flow and does not impair kidney, liver and spleen perfusion.     

The slow-channel calcium blocking agent, nitrendipine, and coronary collateral blood flow

The effects of a new dihydropyridine slow-channel calcium blocking agent, nitrendipine, on hemodynamics and myocardial blood flow in normal and ischemic areas distal to either an acute or chronic coronary artery occlusion were studied in anesthetized dogs. Nitrendipine produced significant and dose-related decreases in mean aortic blood pressure and increases in flow through the nonobstructed coronary artery. In acute coronary artery occlusion experiments, only small changes in perfusion of the ischemic zone were observed following nitrendipine. On the other hand, in dogs with a chronic coronary artery occlusion and well-developed collateral circulation, nitrendipine produced significant and dose-related increases in subepicardial perfusion within the central ischemic zone. No change in subendocardial blood flow during drug-induced hypotension was observed, but when aortic pressure was held constant, there was an increase in subepicardial, subendocardial, and overall transmural myocardial perfusion. The data demonstrate that nitrendipine improves oxygen supply to collateral-dependent myocardium via an increase in coronary collateral blood flow in a model of chronic coronary occlusion.     

Cardiovascular studies of 5-(3-tert-butylamino-2-hydroxy) propoxy-3,4-dihydrocarbostyril hydrochloride (OPC-1085), a new potent beta-adrenergic blocking agent

The beta-adrenergic blocking and hemodynamic properties of 5-(3-tert-butyl-amino-2-hydroxy) propoxy-3,4-dihydrocarbostyril hydrochloride (OPC-1085) were investigated and compared with those of propranolol and pindolol on myocardial contractile force, heart rate and arterial blood pressure in pentobarbital anesthetized dogs. OPC-1085 showed almost the same beta-adrenergic blocking potency as pindolol, but was approximately 30 and 20 times stronger than propranolol against isoproterenol and cardiac nerve stimulation, respectively. Slight negative inotropic and chronotropic responses were observed with OPC-1085 in effective blocking doses from 1 to 10 mug/kg but were converted to positive ones in doses from 30 to 3000 mug/kg in non-reserpinized dogs. In reserpinized dogs, both OPC-1085 and pindolol induced only positive responses. These responses were more evident with OPC-1085.     

New sulfamoylphenethylamines, potent alpha 1-adrenoceptor antagonists

The (+)-isomer of amosulalol, a combined alpha- and beta-adrenoceptor antagonist, was one log unit order more potent and less potent than the (-)-isomer in blocking alpha 1- and beta 1-adrenoceptors, respectively, in anaesthetized rats. Nine newly synthesized desoxy compounds derived from amosulalol and its analogues were found to possess potent alpha 1-adrenoceptor blocking activity and to be practically devoid of beta 1-adrenoceptor blocking activity. Among the desoxy derivatives, YM-12617 was more potent than prazosin in blocking alpha 1-adrenoceptors in anaesthetized rats and in reducing blood pressure, total peripheral resistance and left ventricular work in anaesthetized dogs.     

Coronary effects of a combined beta adrenoceptor blocking and calcium antagonist therapy in running dogs.

The effects of YM-16151 (1 mg/kg, i.v.), a combined beta 1-adrenoceptor blocking and calcium antagonist drug, on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs at rest and during treadmill exercise. These effects were compared to those in the same animals of nicardipine (0.1 mg/kg, i.v.), atenolol (1 mg/kg, i.v.) and their combination (at the same doses). Circumflex artery diameter (CxAD) and coronary blood flow increased and coronary vascular resistance (CVR) decreased during control exercise under saline. YM-16151 and the nicardipine-atenolol combination similarly dilated large and small coronary arteries at rest, but dilation of large conductance vessels was abolished during exercise, while CVR decreased further. Both YM-16151 and the nicardipine-atenolol combination only slightly increased the rate-pressure product at rest, but strongly opposed its exercise-induced rise. Nicardipine maximally increased CxAD, decreased CVR, and enhanced the rate-pressure product at rest and during exercise. Conversely, atenolol decreased CxAD and the rate-pressure product and increased CVR at rest, but large coronary arteries remained constricted during exercise despite the concomitant dilation of small resistance vessels. Thus, in the coronary vascular bed of conscious dogs, YM-16151 really behaves as a hybrid drug, combining beta 1-adrenoceptor blocking and calcium antagonist properties, both at rest and during exercise. As a result, YM-16151 increases oxygen supply at rest and decreases oxygen demand during exercise. Finally, this study emphasizes the major role of beta 1-adrenoceptors in the mediation of exercise-induced dilation of large coronary arteries.     

Adrenoceptor-blocking activity and cardiohemodynamic effects of carvedilol in animals.

The beta-blocking activities of a new beta-adrenoceptor blocking drug, carvedilol, evaluated in isolated atria and trachea of the guinea pig were 2.0 (beta 1) and 3.2 times (beta 2), respectively, as potent as those of propranolol. Carvedilol exhibited the alpha-blocking activities in the aorta of guinea pigs and rats. Carvedilol was 2 and 50 times less potent in guinea pigs and rats, respectively, than prazosin as an alpha-blocker. Thus, the alpha-blocking activities were twice as potent as the beta-blocking activity in the rat and one-fifth that of the beta-blocking activity in the guinea pig. In anesthetized open-chest dogs, the beta-blocking activity of carvedilol was 1.5 times more potent than that of propranolol and had 3.8 times the alpha-blocking activity. Thus, carvedilol is a nonselective beta-blocking drug with a potent alpha-blocking activity. Carvedilol and propranolol showed dose-dependent and significant decreases in the blood pressure, total cardiac output, left ventricular pressure, dp/dt, heart rate, coronary flow, and oxygen consumption in anesthetized open-chest dogs. Carvedilol decreased the total peripheral resistance significantly (the decrease was not proportional to the decreases in the blood pressure at high doses), while propranolol increased it significantly and dose-dependently. These results indicate the importance of alpha-adrenoceptor blocking activity in the decrease in blood pressure produced by carvedilol.     

Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist

The pharmacological profile of nebivolol (N), a chemically novel beta-adrenergic antagonist, was assessed in investigations on isolated tissues, awake spontaneously hypertensive rats (SHR), closed-chest anesthetized dogs, and humans. In vitro, N was found to be a potent antagonist of beta 1-adrenergic receptors (A2 value, 5.8 X 10(-9) M) and only a weak beta 2-adrenergic antagonist (A2 value, 1.7 X 10(-6) M). The selectivity for the beta 1-adrenergic receptor was higher for N than for any of the reference compounds. In dogs--similarly with atenolol--N was more potent in blocking the isoprenaline (I)-induced increases in left ventricular performance than the I-induced decrease in arterial pressure. In dogs, as compared with propranolol, N (0.025 and 0.01 mg.kg-1 i.v.) increased cardiac output and stroke volume, lowered systemic vascular resistance, and had no significant effect on the variables related to left ventricular contraction. In contrast to other beta-adrenergic antagonists, N acutely lowered arterial blood pressure in SHR (1.25 mg.kg-1 i.p.) and in hypertensive patients (1 oral dose of 5 mg) for several hours. In healthy volunteers N (5 mg) lowered systemic vascular resistance during daily oral treatment and did not negatively affect left ventricular function. In conclusion, N is a potent and selective beta 1-adrenergic blocking agent with an interesting hemodynamic profile. In hypertensive subjects and SHR, a single dose lowers arterial blood pressure for substantial periods of time.     

The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium.

beta-Adrenoceptor agonists increase myocardial ischemic injury, mainly by elevating myocardial oxygen consumption. Moreover, it has been shown that isoprenaline may "steal" regional myocardial blood flow (RMBF) from ischemic to non ischemic areas and from epicardium to endocardium. The mechanisms of these two isoprenaline-induced redistributions of RMBF have been investigated by the use of radioactive microspheres in an experimental model of canine myocardial ischemia with simultaneous measurement of ST-segment elevation. Isoprenaline increased RMBF in both epi- and endocardial non ischemic areas and in epicardial ischemic areas, leading to a significant decrease in the endo/epi ratio. After atenolol, isoprenaline still increased RMBF but to a lesser extent and the endo/epi ratio was still decreased. Salbutamol, in doses inducing no significant changes in cardiac parameters or myocardial oxygen consumption, produced effects similar to those of isoprenaline. These results indicate a non-homogeneous beta2-stimulation-induced vasodilation in endo- and epicardium, which might be due either to the higher epicardial coronary vasocilatory reserve or to a heterogeneous distribution of transmural beta2-adrenoceptors. Isoprenaline also decreased the ischemic/non ischemic total blood flow ratio (I/NI) and caused further increases in ST-segment elevation. These effects were abolished by atenolol pretreatment, indicating the deleterious effects of isoprenaline-induced tachycardia in this I/NI decrease and in the ischemic injury.     

Pharmacological properties of (+/-)-4-[2-hydroxy-3-(3-(2-methoxyphenoxy)-2-propylamino)propoxy]-1(2H) -isoquinolinone (N-1518), a new combined alpha- and beta-adrenoceptor blocking drug

The alpha, beta-adrenergic blocking, antihypertensive and vasodilating properties of N-1518 were compared with those of labetalol. N-1518 blocked alpha- and beta-adrenoceptors competitively as indicated by parallel rightward displacement of the dose-response curve of each agonist in isolated organs and in anesthetized dogs. As judged by pA2 values and DR10 values, N-1518 was as potent as labetalol in blocking alpha- and beta-adrenoceptors. The beta 1/alpha 1 ratio of N-1518 was 8.3 for pA2 values in isolated organs and 13.6 for DR10 values in anesthetized dogs, respectively. N-1518 inhibited dose-dependently the pressor response to intravenous administration of noradrenaline, but labetalol did not depress the response to noradrenaline in anesthetized dogs. N-1518 is composed of four optical isomers. The SR-isomer was the most potent in blocking beta-receptors, and the RR-isomer was the most potent in blocking alpha-receptors. N-1518 has no intrinsic sympathomimetic activity in reserpinized rats and has no local anesthetic activity in guinea pigs. Single oral administration of N-1518 produced a fall in blood pressure in conscious SHR and renal hypertensive dogs without causing tachycardia. Intra-arterially administered N-1518 in the dog hindlimb resulted in vasodilation as indicated by the increase in blood flow. The magnitude of the responses was approximately 3 times more potent than that of labetalol.     

Effects of propranolol on regional myocardial blood flow and function during severe coronary stenosis in dogs

The effects of propranolol alone or associated with atrial pacing were studied on regional myocardial blood flows (RMBF) and regional contractility (sonocardiometry) in non-ischemic, moderately and severely ischemic areas of the canine myocardium. In non-ischemic areas, propranolol reduced both epicardial and endocardial flows, increased the endo/epi ratio and decreased regional contractility. The reductions in subendocardial flow and function were correlated. In moderately and severely ischemic areas, propranolol increased subendocardial flow, reduced subepicardial flow, increased the endo/epi ratio and preserved or even slightly improved regional contractility. There was a good correlation between the propranolol-induced protective effects on regional contractility and the drug-induced increase in subendocardial flow since under atrial pacing subendocardial flow no longer increased and regional function dropped dramatically.     

Cardiac and systemic hemodynamic actions of the slow channel calcium blocking agent, KB-944

The effects of KB-944 (10-400 micrograms/kg/min, i.v.), a new slow channel calcium blocking agent, on myocardial oxygen utilization, regional myocardial perfusion and hemodynamics were measured in anesthetized dogs. KB-944 produced significant dose-related increases in coronary blood flow and decreases in heart rate, left ventricular systolic pressure, aortic blood pressure and peripheral vascular resistance. At high doses, peak positive and negative dP/dt were both reduced and left ventricular end diastolic pressure increased. KB-944 reduced arterial-venous oxygen content difference across the heart while significantly increasing coronary blood flow. The pressure rate product, an index of myocardial oxygen consumption, was also reduced. KB-944 produced a uniform and dose-related increase in transmural tissue flow within the left ventricular free wall. These results indicate that KB-944, a new slow channel calcium blocking agent, is a potent peripheral and coronary vasodilator with negative inotropic and chronotropic properties and may be potentially useful in coronary artery disease or hypertension.     

Pharmacology of AH 5158; a drug which blocks both α- and β-adrenoceptors

1. AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both alpha- and beta-adrenoceptors.2. AH 5158 is 5-18 times less potent than propranolol in blocking beta-adrenoceptors. It resembles propranolol in its non-selective blockade of beta(1)-cardiac and beta(2)-vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity.3. AH 5158 is 2-7 times less potent than phentolamine in blocking alpha-adrenoceptors. AH 5158 itself is more active on beta- than alpha-adrenoceptors.4. Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose-dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. ;Self-limiting' blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of ;self-limiting' blockade is discussed.5. In doses higher than those required for either alpha- or beta-adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane-stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea-pig left atrial strips, as a negative chronotropic action in syrosingopine pre-treated dogs, and as an increase in the effective refractory period of guinea-pig left atrial strips. AH 5158 was 3-11 times less potent than propranolol in these tests.6. In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to beta-adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent beta-adrenoceptor blocking doses. These differences are attributable to the alpha-adrenoceptor blocking actions of AH 5158.7. In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine and ouabain-induced arrhythmias. Orally administered AH 5158 lowered systolic arterial pressure in conscious renal hypertensive dogs.8. These results show AH 5158 to possess a novel profile of activity. Possible uses of the drug in cardiovascular disorders such as hypertension, angina pectoris and cardiac arrhythmias are discussed.     

Actions of two new bradycardic agents, AQ-AH 208 and UL-FS 49, on ischemic myocardial perfusion and function

The effects of continuous infusions (30 min) of two new bradycardic agents, AQ-AH 208 (3,4-dihydro-6,7-dimethoxy-2-(3-((2-(3,4 dimethoxyphenyl) ethyl)-amino methyl) propyl)-1(2H)-isochinolinon) (10 and 25 micrograms/kg/min) and UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3(3((2-(3,4-dimethoxyphenyl) ethyl) methylimino) propyl)-2H-3-benzazepin-2 on) (1.0 and 2.5 micrograms/kg/min) on ischemic myocardial perfusion and function were studied in anesthetized open chest dogs. Coronary stenosis was induced by narrowing an extracorporeal shunt between the carotid and left anterior descending coronary artery. Regional perfusion was measured by use of radioactive microspheres and regional myocardial function (% segment shortening) was assessed by sonomicrometry. AQ-AH 208 and UL-FS 49 produced dose-dependent reductions in heart rate of 13 to 55 beats/min without prominent effects on left ventricular dP/dt, aortic blood pressure, and % segment shortening of the normally perfused area. In nonischemic myocardium, AQ-AH 208 did not change transmural blood flow in spite of the bradycardia, whereas UL-FS 49 decreased flow. At the high infusion rate, ischemic subendocardial perfusion increased from 0.43 to 0.58 ml/min/g following UL-FS 49 and from 0.57 to 0.84 ml/min/g after treatment with AQ-AH 208. Consequently, endo/epi rose from 0.52 to 0.80 and 0.62 to 0.96, respectively. Atrial pacing abolished the effects of UL-FS 49 on ischemic myocardium whereas the effects of AQ-AH 208 were only partially reduced. Ischemic myocardial function deteriorated less during treatment with UL-FS 49 and was significantly improved following AQ-AH 208 as compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

牡荆素对麻醉犬血流动力学及心肌耗氧量的影响

目的研究牡荆素对麻醉犬血流动力学及心肌耗氧量的影响。方法杂种犬30只,人工呼吸下开胸,给药后观察其心率（HR）、血压（MAP）、心输出量（CO）、冠脉血流量（CBF）、左室压（LVP）及血氧含量。计算冠脉阻力（CVR）和体循环总外周阻力（TPR）等血流动力学指标。采用多普勒超声血流仪测定麻醉犬冠脉流量和心输出量,用血气分析仪测定血氧含量。结果牡荆素可减慢心率和左心室内压,并显著增加麻醉犬冠脉血流量和心输出量,降低总外周血管阻力和冠脉阻力,提高心搏出量、心搏指数及心脏指数。结论牡荆素可显著改善麻醉犬血流动力学参数。     

The effect of “selective” β-adrenoceptor blocking drugs on the myocardial circulation

1. A comparison has been made of the effects of a relatively specific beta(1)-adrenoceptor blocking drug (practolol) and a relatively specific beta(2)-adrenoceptor blocking drug (butoxamine) on myocardial and general haemodynamics in anaesthetized cats.2. Practolol, in a dose (10 mg/kg, intravenously) which had little effect on arterial pressure, heart rate, myocardial blood flow or myocardial vascular resistance, markedly reduced the effects of isoprenaline infusions on heart rate, aortic dp/dt, myocardial blood flow, vascular resistance and metabolic heat production, and the cardiac effort index. Isoprenaline induced vasodepression was unaffected.3. Butoxamine (5 mg/kg, intravenously) decreased heart rate, aortic dp/dt, the cardiac effort index and myocardial blood flow and increased myocardial vascular resistance. This is taken as further evidence for the existence of beta(2)-adrenoceptors in the myocardial microcirculation.4. After butoxamine, the effects of isoprenaline on myocardial blood flow, myocardial vascular resistance and heart rate were unaffected but the peripheral vasodilator effect was abolished. The effects on aortic dp/dt and the cardiac effort index were potentiated.5. It is concluded that the effect of isoprenaline in increasing myocardial blood flow is due predominantly to increased cardiac work and oxygen consumption and that practolol, since it has little direct effect on myocardial blood flow yet abolishes the cardiac stimulant and oxygen wasting effects of released catecholamines, has properties which indicate that it should be an effective and safe anti-anginal drug.