Stanley H. Taylor

Effect of intravenous propranolol on the systemic circulatory response to sustained handgrip

Abstract The changes in the systemic circulation in response to sustained handgrip have been compared before and after the intravenous administration of 10 mg. of propranolol. Similar increases in the mean aortic pressure were seen both before and after administration of the drug, but the cardiac output response was reduced and this reduction was compensated by increased systemic vascular resistance. The percentage increase in heart rate during grip was greater after propranolol was given. The possible mechanisms of thse changes have been discussed.

Influence of nicardipine on the blood pressure at rest and on the pressor responses to cold, isometric exertion, and dynamic exercise in hypertensive patients.

Summary The dose-response effects of a new slow-calcium-channel blocker, nicardipine, on the resting blood pressure and on the pressor responses induced by skin cold, isometric exertion, and dynamic exercise were examined in a single-blind placebo-controlled study in six male patients with stable uncomplicated essential hypertension. Nicardipine was administered orally in doses of 5 mg, 10 mg, 20 mg, and 20 mg each given three times daily consecutively for I week. At the end of each dose period the effects on blood pressure and heart rate at rest and during the three pressor stimuli were measured. There was a significant dose-related reduction in the resting diastolic blood pressure without change in pulse pressure, accompanied by an increase in heart rate. No postural effects on blood pressure were observed. There was a small reduction in the pressor response to hand cold, which was statistically significant at the higher doses. There was no attenuation of the increases in pressure and heart rate induced by handgrip contraction or submaximal treadmill walking at any dose of nicardipine. These results are compatible with a direct relaxing effect of the drug on the smooth muscle of the arteriolar resistance vessels without substantial impairment of the sympathetic influences responsible for postural control of the systemic blood pressure or those involved in the pressor responses to the three stimuli tested.

Intrinsic sympathomimetic activity: Clinical fact or fiction?

The therapeutic importance of the ancillary pharmacologic property of partial agonist activity, or intrinsic sympathomimetic activity (ISA), of a beta-adrenoceptor antagonist is controversial. Its pharmacologic definition and accepted physiologic potential are now joined by convincing evidence that ISA may have important therapeutic implications. The ability to support basal cardiac functions while preventing the potential hazards of random sympathetic stimulation is an important attribute of this property, particularly in the damaged heart. The beneficial effects of ISA on peripheral blood flow, systemic vascular resistance and left ventricular afterload are established. Although all beta-blocking drugs are contraindicated in patients with asthma, ISA appears to be at least as important as cardioselectivity in offsetting some of the increase in airway resistance that results from beta blockade alone both at rest and during exertion. These pharmacodynamic consequences of ISA may explain the lesser reduction in exercise tolerance afforded by beta-blocking drugs with ISA than by those without. ISA may also enhance the primary oxygen-sparing effects of beta blockade in the ischemic myocardium by reducing coronary resistance, enhancing coronary blood flow, and reducing anaerobic metabolism. The adverse effects of beta-blocking drugs on blood lipids and carbohydrate metabolism also appear to be largely negated in drugs with ISA. The risks of rebound effects from abrupt withdrawal are significantly less in drugs with ISA than in those without.

First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function

A prospective randomised trial compared the immediate haemodynamic effects of intravenous diuretic (frusemide), venodilator (isosorbide dinitrate). arteriolar dilator (hydralazine), and positive inotropie stimulation (prenalterol) as first-line therapy for acute left ventricular (LV) failure following myocardial infarction. Forty-eight patients with transmural myocardial infarction and a pulmonary artery occluded pressure (PAOP) of >20 mm Hg were studied within 18 h of admission to a coronary care unit. Both frusemide (-4 mm Hg: p < 0.01) and isosorbide dinitrate (-6 mm Hg: p < 0.01) reduced LV filling pressure without change in cardiac index and heart rate. Although both hydralazine and prenalterol increased cardiac index (p < 0.01), the reduction in LV filling pressure (-2 mm Hg: p < 0.05) was less than with frusemide and isosorbide dinitrate. and was associated with an increased heart rate (+8 and + 13 beats min−1: p < 0.01). These data suggest that in acute heart failure following myocardial infarction the four treatment modalities could be ranked in descending order of potential benefit as follows: (a) venodilatation (isosorbide dinitrate) — decrease of LV pressure/work: (b) diuretic therapy (frusemide)— decrease of LV pressure/work offset by a transient pressor effect: (c) arteriolar dilatation (hydralazine) —decrease of LV pressure/work and of PAOP. but offset by tachycardia: and (d) positive inotropic therapy (β1-agonist prenalterol) — tachycardia and augmented LV afterload. Combination of the former and latter agents, because of their differing modes of action, should offer haemodynamic advantages over monotherapy and deserves further evaluation.

Intravenous amrinone in left ventricular failure complicated by acute myocardial infarction

Hemodynamic dose-response effects of intravenous amrinone were studied in 22 male patients aged 38 to 62 years with left ventricular failure occurring within 18 hours of acute myocardial infarction. After hemodynamic confirmation of a raised left-sided cardiac filling pressure--pulmonary artery occluded pressure greater than 20 mm Hg--patients were randomized to either low-dose infusion of amrinone (200 micrograms/kg/hr for 30 minutes, 400 micrograms/kg/hr for 30 minutes and then 800 micrograms/kg/hr for 30 minutes) or high-dose infusion of the drug (800, 1,600 and 3,200 micrograms/kg/hr sequentially, each for 30 minutes). Hemodynamic measurements were obtained at 1 hour before amrinone and at the end of each infusion step. Low-dose infusion of amrinone resulted in a progressive increase in cardiac output (p less than 0.05) and stroke volume (p less than 0.05) and progressive reductions in pulmonary artery occluded pressure (p less than 0.01) and systemic vascular resistance (p less than 0.05). Systemic blood pressure and heart rate were unchanged. High-dose infusion resulted in a similar increase in cardiac output (p less than 0.05) but no change in stroke volume owing to associated tachycardia (p less than 0.01). There was a significantly greater decrease in pulmonary artery occluded pressure compared with the low-dose infusion (p less than 0.05), and systemic arterial diastolic and mean pressures were also decreased (p less than 0.05). The decrease in systemic vascular resistance was of a similar order to that induced by the low-dose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of amlodipine for angina pectoris.

Calcium antagonists are effective antianginal agents in the treatment of patients with stable exercise-induced angina pectoris. A series of randomized, double-blind, placebo-controlled studies with the novel, once-daily calcium antagonist amlodipine have been completed in a large number of patients with stable exercise-induced angina pectoris. Compared with placebo, once-daily amlodipine demonstrated a significant dose-related extension in exercise duration and workload accomplished, and reduction in number of anginal attacks and associated glyceryl trinitrate consumption. The clinical antianginal attributes of amlodipine were accompanied by significant reductions in electrocardiographic evidence of myocardial ischemia. In comparison with other antianginal drugs, once-daily amlodipine at a dosage range of 5-10 mg demonstrated antianginal activity comparable to thrice-daily diltiazem and once-daily nadolol. Amlodipine administered once daily achieves symptomatic and electrocardiographic amelioration of myocardial ischemic episodes induced by exercise in the majority of patients with stable angina pectoris. Amlodipine does not depress left ventricular pumping activity, and its side-effect profile does not differ substantially from that of placebo.

The efficacy of amlodipine in myocardial ischemia.

Calcium antagonists are among the most potent and efficacious drugs used in the treatment of angina pectoris. Amlodipine, a new member of this family of dihydropyridines, has a unique pharmacokinetic profile with high bioavailability and an extended period of pharmacodynamic activity. In formal randomized, double-blind, placebo-controlled trials with exercise tests carried out 24 hours after administration, amlodipine was significantly more effective than the placebo and comparable in efficacy with the calcium antagonist diltiazem and the beta-blocking drug nadolol. In addition to extending exercise capacity in patients with angina pectoris, amlodipine significantly reduces ECG evidence of myocardial ischemia. Amlodipine has also been found to be effective in reducing the anginal attack rate in patients with vasospastic angina. From the evidence available, it is concluded that once-daily treatment with amlodipine in the dose range of 5 to 10 mg is effective in improving exercise capacity and reducing anginal attack rate in patients with chronic stable angina pectoris and also those with vasospastic angina.

Diuretics in cardiovascular therapy: the new clinicopharmacological bases that matter.

Diuretics in current use include early distal tubular (i.e., thiazide-type), loop (i.e., furosemide-type), and potassium-and-hydrogen-retaining substances.Available oral formulations of diuretics differ in terms of their renal excretory potency in man, as formally assessed through the effect of a single dose on 24-hour natriuresis in healthy subjects. The 2.5 mg formulation of the loop diuretic torasemide does not increase mean 24-hour natriuresis, and it is therefore considered a very-low-dose formulation. Amiloride 5 mg and torasemide 5 mg and 10 mg, which increase mean 24-hour natriuresis by less than 40%, are considered low-dose or low-potency diuretic formulations of diuretic substances. Hydrochlorothiazide 25 and 50 mg, furosemide 40 and 80 mg, and torasemide 20 mg, which increase mean 24-hour natriuresis by more than 40%, are considered high-dose or high-potency formulations. A rebound in natriuresis follows the early-after-dosing increase in this variables caused by loop diuretics; hence many oral formulations of loop substances are less potent natriuretics than most oral formulations of thiazide-type diuretics. Hydrochlorothiazide 25 mg and furosemide 80 mg have similar natriuretic potencies.During once-daily administration of diuretic formulations of diuretics to subjects without edema and normal renal function, the increases in 24-hour natriuresis and diuresis that follow the first dose disappear or attenuate markedly. This is due to neuroendocrine reactions to diuretic-induced sodium loss and its attendant hemodynamic shifts. Some of these reactions, e.g. the increase in plasma aldosterone that takes place, account for an elevation in kaliuresis that occurs during once-daily treatment with a high-dose formulation of a thiazide-type diuretic. Common fixed-dose combinations of a thiazide-type or a loop diuretic and a potassium-and-hydrogen-retaining subtance generally do not change kaliuresis, but they increase natriuresis strikingly.Thiazide-type and loop diuretics decrease and increase calciuresis respectively; none of these actions wanes during prolonged administration.Plasma renin activity and aldosterone do not rise in response to very-low-dose formulations of loop diuretics taken once daily.Glomerular filtration rate tends to fall in the course of once-daily administration of high-dose formulations of diuretics, but not during prolonged once-daily treatment with very-low-dose formulations of loop diuretics.

Hemodynamic effects of nifedipine during upright exercise in stable angina pectoris and either normal or severely impaired left ventricular function

The immediate effects of sublingual nifedipine (20 mg) were evaluated in 18 men with stable, exercise-related angina pectoris and angiographically confirmed coronary artery obstructions, stratified at the time of left ventricular (LV) angiography according to the degree of LV dysfunction supine at rest (Group 1: n = 9, left ventricular end-diastolic pressure [LVEDP] less than 20 mm Hg; Group 2: n = 9, LVEDP greater than 20 mm Hg). At rest, in the upright posture in both groups, nifedipine reduced the systemic vascular resistance (p less than 0.01). The systemic arterial mean (p less than 0.05) and diastolic (p less than 0.01) pressures were reduced despite an increase in the cardiac output (p less than 0.05). Heart rate was increased only in Group 1 (p less than 0.05). Pulmonary artery occluded pressure was unchanged in both groups. During upright bicycle exercise in all patients, compared to control measurements, systemic arterial pressure (p less than 0.01) and vascular resistance (p less than 0.05) were similarly reduced, while exercise cardiac output response and LV filling pressure did not change after nifedipine. Heart rate was increased in Group 1 (p less than 0.05) and decreased in Group 2 (p less than 0.05). Stroke volume during exercise after nifedipine decreased 1 ml/m2 in Group 1 (p greater than 0.05) and increased 2 ml/m2 in Group 2 (p greater than 0.05) compared to control measurements; the between-group difference in the exercise heart rate and stroke volume responses after nifedipine were significant at the 5% level.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of intravenous guanethidine on the systemic and pulmonary circulations in man

Abstract The effects of the intravenous injection of guanethidine on the systemic and pulmonary circulations have been studied in 4 normal subjects and 12 hypertensive patients at rest and during graded leg exercise in the supine position. The drug caused a fall in the resting systemic arterial blood pressure and systemic vascular resistance in all subjects; there was a marked quantitative difference in the response of the normal subjects as compared to that of the hypertensive patients, the latter patients exhibiting much greater falls in blood pressure and systemic vascular resistance after a given dose of the drug. Supine leg exercise was not associated with any further fall in systemic blood pressure. Neither the resting nor the exercising cardiac outputs were affected by the drug in either normal or hypertensive subjects. Although the resting heart rate was unchanged after the drug, there was a relative bradycardia during exercise in both the normal subjects and hypertensive patients after the drug, as compared to the control study. There was a small but definite reduction in the pulmonary vascular resistance without change in the pulmonary wedged pressure in both normal subjects and hypertensive patients. These findings are discussed particularly in comparison with the circulatory effects of bretylium tosylate studied under similar conditions.