J. Trap-Jensen

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.

Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans.

Abstract. The cardiovascular and adrenergic responses to cigarette smoking during acute selective and non‐selective beta adrenoceptor blockade were studied in seven young healthy volunteers in a double blind cross‐over fashion. Heart rate, arterial blood pressure, forearm blood flow and plasma levels of adrenaline and noradrenaline were determined before and during the terminal 5 min period of 15 min smoking test.

Effects of smoking on the heart and peripheral circulation

Cigarette smoking increases heart rate, arterial blood pressure, and plasma catecholamine levels. In healthy subjects the increase in heart rate occurs in the absence of peripheral vasoconstriction. In the studies reported here, short-term beta-blockade increased peripheral vascular resistance during smoking, more so for the nonselective beta-blocker propranolol than for the beta 1-selective blocker atenolol. However, after 3 months of continuous treatment of hypertensive patients with beta-blockers, smoking produced similar increases in blood pressure for atenolol and propranolol. Smoking attenuated the beneficial blood pressure-lowering effect of beta-blockers. Short-term clinical studies with the nonselective alpha-inhibitor phentolamine have suggested that blockade of arteriolar alpha-receptors may eliminate the increase in blood pressure response to smoking. Treatment with alpha-inhibitors also increased coronary sinus blood flow in patients with atherosclerotic artery disease. For patients who smoke, alpha-inhibiting drugs may provide beneficial therapy for hypertension and other cardiovascular disorders.

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.

99mTc-DTPA gamma-camera renography: Normal values and rapid determination of single-kidney glomerular filtration rate

A method for 99mTc-diethylenetriaminepentaacetate (DTPA) gamma-camera renography is presented. From each renogram, an uptake index (UI) proportional to the single-kidney glomerular filtration rate (SKGFR) is defined. If the proportionality factor between UI and SKGFR is the same in all patients, UI can be used as an accurate measure of SKGFR. In order to test this, 99mTc-DTPA renography was performed in 101 patients with glomerular filtration rates (GFR) varying between 4 and 172 ml/min. The sum of the right-and left-kidney UIs correlated well with the total GFR calculated from the simultaneously measured plasma clearance of 99mTc-DTPA after a single injection. The correlation coefficient was 0.97. The method was tested in a prospective study of 57 patients. The total GFR estimated from the renograms was not significantly different from the GFR calculated from the plasma clearance of 99mTc-DTPA. The coefficient of variation—a combination of inaccuracy and imprecision in the estimates as well as in the reference values — was 11.8% at a GFR of 100 ml/min. It is concluded that, in adults, the SKGFR can be calculated as part of the clinical routine from 99mTc-DTPA gamma-camera renography without determining the injected dose or collecting urine or blood samples. Normal values for some parameters of the renogram obtained in 25 normal subjects are given.

Acute hemodynamic effects of pinacidil and hydralazine in essential hypertension

In a double‐blind, randomized, crossover study, the effects of intravenous pinacidil, 0.2 mg/kg, were compared with those of hydralazine, 0.3 mg/kg, before and after β‐adrenoceptor blockade in six subjects with hypertension. Both drugs equally reduced total peripheral resistance by about 40%. Pinacidil reduced mean blood pressure by an average of 30 mm Hg, while the reduction after hydralazine was 10 mm Hg. The difference in antihypertensive effect resulted from greater increases in heart rate, cardiac contractility (systolic time intervals), and cardiac index (thermodilution) after hydralazine. These effects after hydralazine could not be fully abolished by β‐blockade, as could the effects after pinacidil. Pinacidil decreased pulmonary blood pressure, whereas there was a slight rise in pulmonary blood pressure after hydralazine. Forearm blood flow (venous occlusion strain gauge plethysmography) increased equally after both drugs; thus pinacidil decreased forearm vascular resistance more than hydralazine did. Serum concentrations of both drugs were within the therapeutic range and correlated with the fall in mean blood pressure. Five subjects complained of side effects after hydralazine, but none were reported after pinacidil. Hydralazine increased myocardial oxygen consumption (as estimated from the rate‐pressure product) by 35%; there was no change after pinacidil. It is suggested that hydralazine has direct cardiostimulatory effects that limit its antihypertensive effectiveness. These effects increase myocardial oxygen consumption and may be responsible for the common and sometimes severe cardiovascular side effects of hydralazine.

Effects of three beta-blockers with different pharmacodynamic properties on platelet aggregation and platelet and plasma cyclic AMP

SummaryThe effects of three different types of beta-adrenoceptor blocking agents on platelet aggregation and on platelet and plasma cyclic AMP content have been studied in 14 patients with mild hypertension given each drug in turn for two weeks. The drugs were a non-selective blocking agent with high intrinsic sympathomimetic activity, pindolol, the nonspecific blocking agent propranolol, and the beta1-selective metoprolol.The threshold values of ADP and adrenaline for irreversible platelet aggregation were significantly higher for pindolol and metoprolol than for propranolol.The cyclic AMP content of platelets was higher during pindolol and metoprolol than during propranolol treatment. Pindolol produced a substantial increase in plasma cyclic AMP relative to the other two drugs.Thus, platelet aggregation and cyclic AMP formation are influenced by beta-adrenoceptor blockade in proportion to intrinsic sympathomimetic activity and affinity for different beta-adrenoceptor subtypes.

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.

Platelet activation in major surgical stress: influence of combined epidural and general anaesthesia

Platelets are activated in surgery releasing vasoactive substances such as serotonin and thromboxane. Platelets become temporarily hypoaggregable during surgery followed by a postoperative hyperaggregability. Local anaesthetics are known to inhibit platelet function but earlier reports are conflicting. In order to study the impact of the combined use of general and regional anaesthesia on platelet function during major surgery 16 otherwise healthy patients were randomised to either general anaesthesia (GA) (n = 8) or GA combined with epidural anaesthesia (GA + EPI) (n = 8) for elective upper abdominal surgery. Cyclic 3′5′adenosine monophosphate, plasma glucose, plasma Cortisol and the rate pressure product (RPP) were markers of the stress response. ADP–induced platelet aggregation and the release products β‐thromboglobulin, serotonin and thromboxane 2 were measured in plasma before and during as well as for 3 days after surgery.

Effect of labetalol on plasma noradrenaline and adrenaline in hypertensive man

SummaryInjection i. v. of labetalol, a new adrenergic alpha- and beta-blocking agent, decreased arterial blood pressure in 9 hypertensive subjects resting in the supine position, when standing and during supine exercise. Heart rate after labetalol was unchanged in the resting supine position, and it fell in the latter two conditions. Plasma noradrenaline concentration was higher after labetalol in all three experiments as compared to a control study. Plasma adrenaline after labetalol was increased only in the standing position, when the highest plasma noradrenaline concentrations were observed. Blood glucose concentration tended to increase after labetalol, but the difference was not statistically significant. The changes in plasma noradrenaline and blood glucose after labetalol mimic findings observed after alpha-adrenergic receptor blockade. The beta-adrenergic receptor blocking property of labetalol is responsible for the reduced heart rate and it is likely to contribute to the higher plasma noradrenaline concentration observed when standing and during supine exercise.