Pharmacology of ASL-8052, a novel beta-adrenergic receptor antagonist with an ultrashort duration of action

ASL-8052, a novel beta-adrenergic receptor antagonist, was studied in isolated guinea pig cardiac and tracheal tissues, in isolated frog sciatic nerves, and in anesthetized dogs. The compound was a moderately potent beta-adrenoceptor antagonist in right atria (pA2 6.96) but was much less active in tracheal tissues (pA2 5.33), indicating cardioselective properties. ASL-8052 possessed a small degree of intrinsic sympathomimetic action in isolated guinea pig right atria and caused direct cardiac depression only at concentrations 1,000-fold higher than its cardiac pA2. Significant local anesthetic action in frog sciatic nerve occurred at extremely high concentrations of ASL-8052 (greater than 0.1 M). In anesthetized dogs, ASL-8052 produced steady-state levels of beta-blockade within 10 min during a 3-h intravenous infusion. In contrast, propranolol produced increasing levels of blockade throughout most of the infusion period. Recovery from beta-blockade occurred rapidly following termination of ASL-8052 infusion (80% recovery in approximately 12 min), whereas very little recovery occurred following cessation of propranolol infusion. Intravenous infusion of ASL-8052 produced dose-dependent blockade of cardiac responses to isoproterenol but only minimally decreased hindlimb vascular responses to isoproterenol. The results indicate that ASL-8052 is a novel cardioselective beta-blocker with an ultrashort duration of action.     

Beta-blocking and electrophysiological effects of propafenone in volunteers

Summary The chemical structure of propafenone (P) and certain experimental findings suggest that this antiarrhythmic compound could possess beta-blocking properties. To evaluate the clinical relevance of the latter cardiovascular effects of P during exercise were studied. After oral administration of P 150 and 300 mg insolution, six healthy volunteers were subjected to graded exercise. These doses of P, which are usually effective against arrhythmias, decreased exercise-induced tachycardia, whereas the systolic blood pressure was lowered but only at rest, and the diastolic pressure was slightly raised. However, taking into account dose ratio, and the intensity and duration of the reduction in exercise tachycardia, this effect of P was only about 5|X% at its maximum compared to propranolol and similar active beta-blocking compounds. The reduction in heart rate produced by P was not correlated with the plasma level nor did it show dose dependency, in contrast to beta-blocking agents, and also in contrast to its electrophysiological effects on the PQ interval.     

Antiarrhythmic and hemodynamic effects of prifuroline

The antiarrhythmic activity of 4-(2-benzofuranyl)-2-(dimethylamino)-1-pyrroline (prifuroline) has been evaluated in rats, guinea-pigs and dogs. Prifuroline dose-dependently antagonizes the arrhythmogenic action of aconitine in rats, when administered either intravenously (5, 10 or 20 mg/kg) or intraduodenally (10, 20 or 50 mg/kg); it exhibits effectiveness by the digestive route at doses only twice as greater as the active i.v. doses: its intravenous anti-aconitine activity is comparable to that of disopyramide, and superior to that of quinidine; lidocaine is inactive in this test. Prifuroline also diminishes ventricular susceptibility to electrical stimulation in open-chest rats; its effect is comparable to that of disopyramide and amiodarone at the same dose levels; quinidine and lidocaine are less effective. Only prifuroline and propranolol were able to antagonize ouabain toxicity in guinea-pigs, quinidine showing only borderline activity, and disopyramide, lidocaine and verapamil being ineffective. In a model of arrhythmias induced by anoxic stress in rats, all the tested compounds were found active, with prifuroline and disopyramide providing complete protection at high dose levels. The arrhythmias induced in dogs by coronary artery ligation were markedly antagonized by prifuroline after doses of 5 and 10 mg/kg i.v. or 30 mg/kg intraduodenally; the duration of its antiarrhythmic activity in this model of arrhythmias in conscious dogs was much longer after intraduodenal than after i.v. administration. Prifuroline was also able to restore sinus rhythm in guinea-pigs after intracardiac conduction blockade with acetylcholine, although being devoid of anticholinergic activity. It also diminishes the maximal frequency of guinea-pig atria electrically stimulated in viro (EC25 = 5 X 10(-6) g/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological studies of celiprolol: I. Beta-blocking effect, intrinsic sympathomimetic activity, vasodilating and hypotensive effects

The beta-blocking effect, intrinsic sympathomimetic activity (ISA), and vasodilating and hypotensive effects of celiprolol were tested. 1. Celiprolol competitively antagonized the isoproterenol-induced positive chronotropic and inotropic effects in guinea pig right atrial and papillary muscles and isoproterenol-induced guinea pig tracheal relaxation with pA2 values of 8.03, 7.98 and 6.43, respectively. 2. In dogs, isoproterenol-induced increases in cardiac contractility and heart rate were markedly inhibited by celiprolol (83.1 and 84.8%, respectively), while isoproterenol-induced hypotension was suppressed only by 16.8%. 3. Celiprolol increased the beating rate of the right atrium and relaxed the trachea isolated from normal and reserpinized guinea pigs. Celiprolol also potentiated the contractility of the left atrium isolated from reserpinized animals. These effects of celiprolol were antagonized by propranolol. 4. Celiprolol concentration-dependently relaxed rat femoral arteries contracted by methoxamine. The concentration-relaxation curve was shifted to the right by pretreatment with propranolol. 5. Orally administered celiprolol produced long lasting hypotension in conscious SHR without any heart rate change. 6. These results indicate that celiprolol is a highly cardioselective beta-blocker with a significant ISA, which contributes to its vasodilatory and hypotensive effects.     

Electrophysiologic and hemodynamic effects of apomorphine in dogs.

Apomorphine is a dopamine receptor agonist used as an emetic, for Parkinson's disease, and for treating erectile dysfunction. This study was conducted to monitor cardiovascular function in dogs given the standard emetic dose (0.05 mg/kg) or 10 times that. Measurements were made during baseline and at 1, 5, 15, 30, 45, and 60 min after iv administration. There were no changes produced by the 0.05 mg/kg dose of apomorphine except for a decrease in mean systemic arterial pressure (AoPm) at the 1 through 15 min recordings. For the 0.5 mg/kg dose, there were reductions in systemic vascular resistance at the 1 and 5 min recordings and in AoPm at the 1 through 60 min recordings. Although not significant, when AoPm fell, heart rate, stroke volume, and cardiac output tended to increase. Action potentials were recorded from superfused Purkinje and endocardial ventricular fibers while exposed to 10(-9) to 10(-5) M apomorphine (10(-10) M is considered therapeutic and 10(-7) M is considered lethal). There were no changes in action potential characteristics of Purkinje fibers, but action potential duration at 90% repolarization prolonged approximately 10-12% in endocardium at concentrations of 10(-6) M and greater. At the usual emetic dose (0.05 mg/kg) apomorphine resulted in no signs of cardiovascular toxicity and, at 0.5 mg/kg, cardiovascular changes were minimal. The emetic dose is higher than that for Parkinson's disease or erectile dysfunction; thus apomorphine appears to be a safe compound for clinical use in dogs and by extrapolation to man.     

Antiadrenergic and hemodynamic effects of ranolazine in conscious dogs

Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.2, 3.6, and 6 mg/kg, intravenous) alone caused transient (<1 minute) and reversible hemodynamic changes. PE (0.3-10 μg/kg) caused a dose-dependent increase in blood pressure and decrease in HR. ISO (0.01-0.3 μg/kg) caused a dose-dependent decrease in blood pressure and an increase in HR. Ranolazine at high (11-13 mM), but not at moderate (4-5 mM) concentrations partially attenuated changes in mean arterial blood pressure and HR caused by either PE or ISO in normal conscious dogs. However, in dogs treated with hexamethonium (20 mg/kg) to cause autonomic blockade, ranolazine (both 4-5 and 11-13 μM) significantly attenuated both the PE- and ISO-induced changes in mean arterial blood pressure. The results suggest that a potential antiadrenergic effect of ranolazine was masked by autonomic control mechanisms in conscious dogs but could be observed when these mechanisms were inhibited (eg, in the hexamethonium-treated dog). Ranolazine, at plasma concentrations <10 μM and in conscious dogs with intact autonomic regulation, had minimal antiadrenergic (α and β) effects.     

体外冲击波对犬血流动力学影响的实验研究

目的：探讨体外冲击波（ESW）冲击犬心脏对血流动力学的影响。方法：以杂种犬的右室心尖部作为ESW的冲击靶点,右侧股动脉插管监测股动脉血压;采用Swan-Gans导管监测右房压、右室压、肺动脉压;热稀释法测定犬的心输出量。结果：ESW冲击犬心脏后,股动脉收缩压和右室收缩压下降（P〈0.05）,右室舒张压和肺动脉的收缩压、舒张压和平均压均升高（P〈0.05）;心输出量无明显改变（P〉0.05）。结论：ESW冲击犬心脏可导致血流动力学紊乱。     

Impact of captopril on hemodynamic and hormonal effects of nitroprusside

The impact of oral captopril, 2 mg . kg-1, on the dose and on the hemodynamic and hormonal effects of nitroprusside was studied in seven patients (Group II). A comparable group (Group I, n = 7) received nitroprusside alone. In both groups, nitroprusside produced comparable decreases in mean arterial pressure, systemic vascular resistance, and right atrial pressure; cardiac output increased because of a significant change in heart rate. Although plasma renin activity increased significantly (compared with control values) in both groups, it was greater (p = 0.01) through the operative period in patients pretreated with captopril. Plasma aldosterone concentration increased in Group I (p = 0.01) but decreased in Group II (p = 0.01). Plasma catecholamine concentrations increased (p = 0.01) with nitroprusside alone but were unchanged in captopril-treated patients. Plasma converting enzyme activity was markedly inhibited (p = 0.001) by captopril. Following cessation of nitroprusside infusion in Group I, rebound hypertension occurred in conjunction with a significant (p = 0.01) increase in systemic vascular resistance; it was associated with elevated plasma renin activity, catecholamines, and aldosterone concentrations. In contrast, captopril-treated patients showed no rebound hemodynamic changes. Nitroprusside dose was less (p = 0.01) with captopril pretreatment (2.1 +/- 0.3 vs. 4.8 +/- 0.9 microgram . kg-1 . min-1). Thus, captopril is a useful adjunct to nitroprusside-induced hypotension.     

Acute hemodynamic effects of labetalol in severe hypertension

Intravenous injection of labetalol induced an immediate fall (-22.4%) in blood pressure (BP) in 11 patients with severe hypertension. Hypotensive episodes were avoided by repeated injections of 0.2-0.8 mg/kg. The pressure reduction was associated with a mean fall in total peripheral resistance of 13.6%. Cardiac output fell 10.1% owing to a fall in heart rate of 10.8%, while stroke volume remained virtually unchanged. Despite excellent acute control of BP by intravenous injection, oral labetalol alone or in combination with hydrochlorothiazide was not effective in long-term treatment of these patients with severe hypertension. After 1 week, mean arterial pressure was still 10.4% below the pretreatment level, but after 4 months BP was back to pretreatment level in all except one patient whose BP is still well controlled after more than 2 years on labetalol.     

Antihypertensive therapy with ketanserin: metabolic and hemodynamic effects

Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 h), blood pressures measured 12 h after dosing were not significantly different from those obtained during the placebo period. However, 2 h after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (p less than 0.01) and 6 +/- 5 mm Hg (p less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. At the time of peak antihypertensive activity, plasma renin activity, aldosterone, growth hormone, and prolactin levels were unchanged. Prolactin levels decreased slightly (4.1 +/- 3.0 vs. 3.7 +/- 2.9 ng/ml, p less than 0.05) during ketanserin therapy when measured 12 h after dosing. Other pituitary hormones, serum testosterone, plasma catecholamines, and plasma lipids showed no changes. Heart rate was also unchanged. Stroke volume, measured 2 h after dosing, increased (70 +/- 22 vs. 85 +/- 31 ml, p less than 0.05) with ketanserin therapy, but cardiac output did not change significantly. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24-h antihypertensive activity.     

Acute hemodynamic effects of tetramethylpyrazine and tetrandrine on cirrhotic rats

The hemodynamic effects of tetramethylpyrazine (TMP) and tetrandrine (TET), both alkaloids isolated from Chinese herbs Ligusticum wallichii Franch and Stephania tetrandra S. Moore, respectively, were assessed in anesthetized cirrhotic rats. TMP induced dose-dependent decreases of portal venous pressure (P.V.P.) and mean arterial pressure (M.A.P.) after intravenous infusion. The maximum percentage reduction of P.V.P. after TMP was 3.6 +/- 0.8%, 6.8 +/- 0.5%, and 17.8 +/- 0.6% of baseline, respectively, for the dosages given (3.0, 9.9 and 30.0 mg/kg). Similarly, TET induced dose-dependent decreases of P.V.P. and M.A.P. The maximum percentage reduction of P.V.P. after TET was 5.4 +/- 1.0%, 9.2 +/- 0.8%, and 23.7 +/- 1.2% of baseline, respectively, for the dosages given (2.0, 6.6 and 20.0 mg/kg). Total peripheral resistance was also reduced by TMP as well as TET. Our results showed that TMP and TET induced P.V.P. reduction in cirrhotic rats, together with reduction in M.A.P. and total peripheral resistance.     

Coronary and systemic hemodynamic effects of tetramethylpyrazine in the dog

The hemodynamic effects of tetramethylpyrazine were examined in 27 anesthetized open chest dogs with electromagnetic flowmeter probes on the left circumflex coronary artery and ascending aorta. Tetramethylpyrazine, 2-15 mg/kg i.v., caused prominent systemic and coronary vasodilation, with a maximum reduction of mean aortic pressure from 92 +/- 5 mm Hg during control conditions to 62 +/- 7 mm Hg (p less than 0.01), a peak increase in cardiac output from 3.0 +/- 0.4 to 4.1 +/- 0.7 L/min (p less than 0.05), and a peak reduction of systemic vascular resistance from 2,450 +/- 400 to 1,210 +/- 329 dyne X s X cm-5 (p less than 0.01). Simultaneously, heart rate increased from 143 +/- 9 to 174 +/- 8 beats/min (p less than 0.01), and maximum left ventricular dP/dt increased from 2,410 +/- 120 to 4,020 +/- 60 mm Hg/s (p less than 0.01). Dose-related increases of coronary blood flow occurred from 37.3 +/- 3.7 to a maximum of 74.1 +/- 6.6 ml/min (p less than 0.01), while mean coronary vascular resistance decreased from 1,770 +/- 240 to 700 +/- 260 dyne X s X cm-3 (p less than 0.01). Myocardial oxygen consumption increased in proportion to the increase in coronary blood flow. Following beta-adrenergic blockade with propranolol (1 mg/kg, i.v.), ganglionic blockade with hexamethonium, or catecholamine depletion with reserpine (1.0 mg/kg, i.p.), the systemic and coronary vasodilator effects of tetramethylpyrazine persisted, but the increases in heart rate, maximum left ventricular dP/dt, and myocardial oxygen consumption were markedly attenuated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kinetic disposition and hemodynamic effects of tetrandrine in anesthetized dogs

The kinetic disposition and hemodynamic effects ot tetrandrine, l3 mg/kg i.v., over 30 s were studied in five anesthetized dogs during continuous monitoring of the ECG and systemic arterial pressure. Repeated determinations of cardiac output (CO) and pulmonary capillary wedge pressure (PCWP) were made via a flow-directed thermodilution catheter in the pulmonary artery. Blood samples were drawn at intervals for determination of plasma tetrandrine or erythrocyte binding of the drug. Maximal reductions in mean and diastolic arterial pressures of 23 +/- 4% were observed within 5 min of the drug infusion without a change in systolic pressure. CO was increased maximally 52% and systemic resistance reduced 5l% at l0 min, gradually returning to baseline values in l-2 h. PCWP was increased transiently at 5-l0 min. The PR interval was prolonged slightly without alteration in the R-R interval, QRS, or QTc. Changes in MAP and PR interval were correlated significantly with plasma tetrandrine concentrations over time, which followed a two-compartment kinetic model with a distribution t1/2 of 7 min and an elimination tl/2 of 88 min. The apparent volume of distribution at steady state was 57 L/kg. Plasma tetrandrine was greater than 90% bound to plasma proteins, and approximately 44% of whole blood tetrandrine was associated with erythrocytes. Tetrandrine is a potent arteriolar vasodilator drug with slight effects on AV conduction, but without significant negative inotropic effects in anesthetized dogs.     

Acute cardiac and hemodynamic effects of sildenafil on resistant hypertension

Purpose

Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)—inhibiting cGMP breakdown—reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses.

Methods

Subjects (n?=?26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined.

Results

Mean arterial pressure and total peripheral resistance decreased in all patients (84.17?±?21.04 to 75?±?17.21 mmHg; 1149?±?459.7 to 1037?±?340 dyn.s/cm^?5, respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25?±?5.8 to 20?±?4.4; IVRT: 104?±?19.33 to 88?±?15.22; E/e’ septal: 9.7?±?3.8 to 7.9?±?2.9; E/e’ lateral: 7.7?±?3.4 to 6.4?±?3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i.

Conclusion

Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.     

Beta-blocking effect and pharmacokinetics of pindolol in young and elderly hypertensive patients

Summary The pharmacokinetics and beta-blocking effect of pindolol has been compared in 20 patients with essential hypertension (WHO Stage I), 10 below 25 years of age and 10 older than 60 years. Each patient received pindolol 10 mg p.o. once a day for 5 days.The area under the curve (AUC) of pindolol was larger in the old than in the young patients both on the first (p<0.05) and the fifth (p<0.01) days. The AUC of pindolol was 14% higher on the fifth day compared to the first day in the elderly group, indicating minor accumulation at steady-state. There was no change in AUC in the young patients. Endogenous creatinine clearance was lower in the old (80±9 ml/min) than in the young patients (150±45 ml/min). The beta-blocking effect did not differ between the groups at 2h after administration of pindolol on Days 1 or 5. However, 24 h after the first and fifth doses approximately 60% of the beta-blockade persisted in the old group whereas 17 and 19% of the beta-blockade, respectively, persisted in the young group; the difference between the groups was statistically significant (p<0.01). The most probable explanation for the more sustained beta-blocking effect in the elderly is the physiologically decrease in renal function, which results in a more sustained plasma level of pindolol in those patients.     

The hemodynamic effects of isradipine and nifedipine in hypertension]

Hemodynamic Effects of Isradipine and Nifedipine in Hypertension Myocardial wall tension is an important determinant of the oxygen demand, the function and the degree of hypertrophy of the left ventricle. Myocardial wall tension should be influenced more favourably by a non-cardiodepressive antihypertensive than by a potentially cardiodepressive one. Therefore, we investigated the effects of an intravenous infusion of the calcium antagonists isradipine (I; 0.4 mg; 3,5-pyridinecarboxylic acid, 4-[benzofurazanyl]-1,4-dihydro-2,6-dimethyl-,methyl-ethylester+ ++ [9CI]; CAS75695-93-1) and nifedipine (N; 2.0 mg) resp., on hemodynamics and myocardial wall tension in 12 hypertensives by an intraindividual comparison. The adrenergic reflex activation induced by vasodilation was limited by pre-medication with 0.1 mg propranolol/kg body weight (i.v.) before application of I and N. Baseline blood pressure of the patients and its changes in response to both calcium antagonists were statistically comparable, as were the left ventricular end-diastolic volumes. The end-systolic volumes, however, decreased significantly on I but not on N: before I: 69 +/- 7.0 (mean +/- standard error), after I: 61 +/- 6.1 ml, 2p less than 0,001; before N: 62 +/- 6.1, after N: 64 +/- 7.0 ml, n.s. (difference to I: 2 p less than 0.05). Stroke volume increased only on I (before I: 62 +/- 4.1, after I: 69 +/- 4.1 ml, 2p less than 0.001; before N: 64 +/- 3.5, after N: 65 +/- 3.8 ml, n.s. (difference to I: 2p less than 0.05)).(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol

The beta-adrenoreceptor antagonist properties of ASL-8123, the primary metabolite of esmolol, were determined in vitro and in vivo. ASL-8123 demonstrated weak competitive beta-adrenoreceptor blocking activity in isolated guinea pig right atria with a pA2 of 3.73 +/- 0.07; no agonist-like activity was observed in this tissue at concentrations of ASL-8123 from 3 X 10(-5) to 1 X 10(-2) M. In anesthetized dogs, ASL-8123 was infused at increasing dosages from 0.2-25.6 mg/kg/min, each dose rate maintained for 20 min. The compound produced a slight decrease in heart rate of 15-22 beats/min at cumulative doses of 508-1,020 mg/kg and decreased diastolic blood pressure by 14-47 mm Hg at cumulative doses of 252-1,020 mg/kg. ASL-8123 dose-dependently inhibited the heart rate and diastolic blood pressure responses to isoproterenol (0.5 micrograms/kg i.v.). Blood levels of ASL-8123 were linearly correlated with inhibition of the heart rate response to isoproterenol (r = 0.95-0.99 for each dog, n = 6). The blood level of ASL-8123 that produced a 50% inhibition of isoproterenol-induced tachycardia averaged 293 +/- 65 micrograms/ml. Recovery from beta-adrenoreceptor blockade after terminating the infusion of ASL-8123 occurred slowly, decreasing from 81% at the end of the infusion to 55% 60 min later, and was paralleled by a slow decrease in blood levels of ASL-8123. Thus, ASL-8123 is a weak beta-adrenoreceptor antagonist which is approximately 1,600-1,900 times less potent than its parent, esmolol.     

Comparison of hemodynamic effects of furosemide and piretanide in normovolemic patients

The effects of furosemide and piretanide (Hoe 118) on the pulmonary hemodynamics in 20 patients recovering from uncomplicated myocardial infarctions were compared in a double-blind study. The diuretic effects and half-lives of the two drugs were not significantly different, so that their hemodynamic actions could be compared directly. Both drugs progressively reduced cardiac output and pressures in the pulmonary circulation, whereas systemic vascular resistance increased significantly. Both drugs slightly increased pulmonary blood volume but not significantly. Total blood volume decreased less rapidly than cardiac output, so that the ratio of cardiac output to total blood volume decreased with time. We conclude that both drugs increase venous compliance in normovolemic subjects and probably increase the compliance of pulmonary vessels.