O. J. Hartling

Immediate haemodynamic effects of propranolol, practolol, pindolol, atenolol and ICI 89,406 in healthy volunteers

SummaryChanges in cardiac output, heart rate and arterial blood pressure were determined in 31 healthy volunteers after i. v. administration of equipotent doses of five different adrenergic betareceptor blocking drugs. Propranolol was given to seven subjects, atenolol to five, practolol to seven, pindolol to five, and (a new drug) ICI 89,406 to seven. Each drug was given in six logarithmically spaced doses. Propranolol is non-cardioselective and lacks intrinsic sympathomimetic activity. Atenolol, practolol, and ICI 89,406 are cardioselective. Practolol, pindolol, and ICI 89,406 have intrinsic sympathomimetic activity. Cardiac output was determined by impedance cardiography at supine rest. The dose-response curves for cardiac output and heart rate were of three different types: one obtained after administration of drugs without intrinsic activity, represented by propranolol and atenolol, both of which caused a maximal decrease in cardiac output of about 27%, and in heart rate of about 21%. A second type, obtained after drugs with moderate intrinsic sympathomimetic activity, represented by practolol, showed small but significant decreases in cardiac output of 12%, and in heart rate of 11 per cent. A third type, after drugs with marked intrinsic sympathomimetic activity, was represented by pindolol and ICI 89,406, which did not significantly reduce cardiac output or heart rate. The blood pressure was essentially unchanged in all subjects, even after the largest dose of any of the drugs. It was concluded that the degree of intrinsic sympathomimetic activity possessed by an adrenergic betareceptor blocking agent is responsible for acute changes in heart rate and cardiac output, and cardioselectivity is of no importance in this respect.

Adrenergic beta receptor blockade: Hemodynamic importance of intrinsic sympathomimetic activity at rest

Dose‐response curves for heart rate, cardiac output, arterial blood pressure, and pulmonary artery pressure were obtained in 37 patients with ischemic heart disease after intravenous administration of six increasing doses of propranolol, atenolol, practolol, pindolol, CPEP (1 ‐[2‐cyanophenoxy]‐3β‐[3‐phenylureido]‐ethylamino‐2‐propanol), and BMMP (1‐t‐butylamino‐3‐[2‐N‐methylcarbamoyl‐methoxyphenoxy]propan‐2‐ol‐hydrochloride). The doses were equipotent, as indicated by reduction in exercise‐induced tachycardia. The dose‐response curves for cardiac output and heart rate can be divided into three groups according to the degree of intrinsic sympathomimetic activity. One group without intrinsic sympathomimetic activity included propranolol and atenolol, which reduced cardiac output (about 26% to 28%) and heart rate (about 15% to 17%). A second group with moderate intrinsic sympathomimetic activity, represented by practolol and BMMP, induced less reduction in cardiac output (about 12% to 17%) and heart rate (about 7% to 10%). A third group with pronounced intrinsic sympathomimetic activity, represented by pindolol and CPEP, did not reduce cardiac output and heart rate. Mean systemic blood pressure was essentially unchanged even after the largest dose of any of the drugs. Mean pulmonary artery pressure rose after atenolol, propranolol, and BMMP but not after pindolol, CPEP, and practolol. Atenolol, BMMP, and practolol are beta‐1–selective drugs, it is concluded that the acute hemodynamic response to adrenergic beta receptor blocking drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta‐1 selectivity did not modify the central hemodynamic responses to beta adrenoceptor blockade.

Immediate haemodynamic effects of prenalterol, a new adrenergic beta-1-receptor agonist, in healthy volunteers

SummaryThe acute haemodynamic effects of prenalterol, a selective adrenergic beta-1-receptor agonist, were studied in eight healthy male volunteers. Prenalterol was administered i.v. in five increasing doses to a cumulative dose of 5.55 mg. After the last dose of prenalterol, three doses of the selective adrenergic beta-1-receptor antagonist metoprolol were administered i.v. to a cumulative dose of 17.5 mg. After each dose, cardiac output (CO), stroke volume (SV), blood pressure (BP), heart rate (HR), systolic time intervals (STI) and forearm blood flow (FBF) were determined.Prenalterol had the following effects: CO was significantly increased by 21.0% after the fourth dose, but the fifth dose did not further change CO. SV was unchanged after the first four doses, but after the fifth dose a significant decrease in SV of 7.0% was seen. Mean BP was increased significantly by 7.7%, but diastolic BP remained unchanged. HR was increased by 28.4%. Total peripheral resistance was reduced by 8.8%. STI were reduced significantly after the second dose, which indicates that prenalterol has a positive inotropic action. FBF was increased significantly after the fourth dose. After the third dose of metoprolol, the CO, SV, mean BP, HR, STI and FBF had returned to their control values. It is concluded that prenalterol has positive inotropic and chronotropic effects on the myocardium, and that metoprolol is a specific antidote.

Acute and long-term effects of labetalol on systemic and pulmonary haemodynamics in hypertensive patients.

SummaryThe effects of the combined adrenergic alpha- and beta-receptor blocking compound labetalol on the systemic and pulmonary circulation were studied after its acute and long-term administration to patients with essential hypertension (WHO grade I–II). Nine men and one woman (mean age 46 years) participated in the acute study. Cardiac index, systemic blood pressure, pulmonary artery pressure and heart rate were measured at rest in the supine and upright positions, and during supine exercise at two work loads (50 and 100 watt), before and after intravenous administration of labetalol 50 mg. Eight of the men were re-examined after three months oral treatment with labetalol 600–900 mg daily. In the acute study cardiac index was unchanged by labetalol, except at the work load of 100 watt, when it decreased by 18.7%. The mean blood pressure decreased under all conditions; 11.6 mm Hg at supine rest, 22.3 mm Hg in the upright position, and by 15.9 mm Hg and 16.9 mm Hg at the two work loads. Heart rate was unchanged at supine rest, but was reduced in the upright position 9,0% and during exercise — at 50 watt by 9.3%, and at 100 watt by 10.3%. Systemic vascular resistance decreased at rest in the supine and upright positions, but not during exercise. The pulmonary artery pressure remained unchanged both at rest and during exercise. In the long-term study cardiac index was unchanged except at the heavy work load, when it decreased by 11.4%. Mean blood pressure was reduced significantly under all circumstances, by 14.6 mm Hg at supine rest, 16.8 mm Hg in the upright positions, and by 13.9 mm and 13.4 mm, respectively, at the two work loads. Heart rate was reduced both at rest 13.6% and during exercise at the two work loads 9.6% and 12.4%. Systemic vascular resistance decreased at rest, but not during exercise. The pulmonary artery pressure were unchanged. Thus, the haemodynamic patterns after acute and long-term administration of labetalol were essentially similar, which suggests that the agent is suitable both for acute and long-term treatment of hypertension, at least from a haemodynamic point of view.

Leg muscle blood flow during reactive hyperemia

SummaryIn normal man at rest transition from the supine to the upright body position is accompanied by autoregulation of the blood flow to tissues in the dependent extremities.In 11 young healthy males the influence of postural changes and external pressure changes on the blood flow in the anterior tibial muscle during reactive hyperemia was studied. The muscle blood flow was evaluated by means of the Xenon-133 wash-out technique. Transmural pressure changes in the resistance vessels were estimated by measuring the systolic blood pressure at ankle level, using the strain-gauge plethysmograph technique. The mean leg muscle blood flow increased from 48 ml·100 g−1·min−1 in a body position with the legs elevated 65 cm above heart level, to 101 ml·100 g−1·min−1 in the supine position, and to 151 ml·100 g−1·min−1 in a sitting position with dependent legs 70 cm below heart level. The muscle blood flows increased from 92 ml·100 g−1·min−1 at ambient pressure to 139 ml·100 g−1·min−1 at a subatmospheric pressure of −50 mm Hg. The differences were highly significant (P<0.001). Systemic blood pressure measured at heart level did not change during postural changes and external pressure changes. The post-ischemic muscle blood flow was found to increase with the increasing vascular transmural pressure.It is concluded that during reactive hyperemia the normal compensatory vaso-reactions can be inactivated, so that the vessels react passively to changes in transmural pressure.

Effect of adrenergic beta receptor blockade on ethanol elimination and on ethanol-induced changes in carbohydrate and lipid metabolism in man.

SummaryThe effect of adrenergic beta receptor blockade on the elimination rate of ethanol was studied in seven healthy young men. The studies were performed before and after 14 days of propranolol 240 mg/day: the ethanol was given perorally — 0.8 mg/kg b.w. The blood concentration of ethanol, glucose, lactate and glycerol, and the plasma concentration of free fatty acids and triglycerides were followed in samples from the superior vena cava taken every 20 min for four hours. The splanchnic hepatic blood flow was estimated with a single i.v. injection of indocyanine green. The absorption rate, absorption fraction and elimination rate of ethanol were not changed by propranolol. The splanchnic hepatic blood flow was significantly reduced (mean 19 per cent) during beta receptor blockade. The ethanol-induced change in the concentration of glucose, lactate and free fatty acids was affected by propranolol, the time-concentration curves for glucose and lactate being significantly elevated and that for free fatty acids being significantly reduced. The time-concentration curves for glycerol and triglycerides did not differ in the two studies.

Haemodynamic and metabolic effects of diazoxide during rest and forearm exercise

SummaryThe immediate haemodynamic and metabolic effects of acute dose of diazoxide 300 mg i.v. were studied in six healthy subjects at rest and during dynamic forearm exercise. Control periods of rest, exercise and recovery were compared with corresponding periods after drug administration. Resting forearm blood flow was almost doubled after diazoxide, and during forearm exercise it increased by about 24%. Systolic blood pressure did not change significantly, but diastolic blood pressure was moderately decreased (5–10 mm Hg). The mean heart rate increased from 57 to 92 beats/min immediately after diazoxide administration, and remained about 20% higher throughout the study. There was a sustained increase in arterial blood glucose of almost 1 mmol/l. The arterial concentration of free fatty acids increased transiently just after diazoxide and then returned to the pre-drug level. The arterial concentration of triglycerides after diazoxide was decreased by about 15% throughout the study. Arterial blood lactate remained unchanged. Forearm uptake of oxygen and glucose tended to increase during the exercise and recovery periods, whereas lactate release remained unchanged.