Systemic, regional and cerebral hemodynamic effects of a new angiotensin converting enzyme inhibitor, imidapril, in healthy volunteers.

The effects of two single oral doses (5 mg and 20 mg) of a new angiotensin I-converting enzyme inhibitor, imidapril, on a) systemic hemodynamics (arterial pressure, heart rate, cardiac output), b) brachial and common carotid arteries' hemodynamics (diameter and blood flow, pulsed Doppler technique), c) cerebral hemodynamics (middle cerebral artery mean blood flow velocity, transcranial Doppler technique), and d) biological parameters (plasma converting enzyme activity, active plasma renin, plasma aldosterone, catecholamines, and atrial natriuretic factor) were investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double-blind, cross-over study performed in six healthy volunteers. Imidapril induced a strong, dose-dependent and sustained inhibition of plasma converting enzyme activity and at the 20 mg an increase in active plasma renin. Other investigated biological parameters were not drug-affected. Imidapril, whatever the dose, did not significantly affect systemic hemodynamic parameters. Imidapril, 20 mg, significantly increased common carotid artery blood flow and diameter and brachial artery diameter. Brachial blood flow also tended to increase but this was not significant. The middle cerebral artery mean blood flow velocity investigated in only five volunteers, underwent spontaneous variations after placebo, and these variations were not affected by imidapril, suggesting that imidapril, whatever the dose, does not influence cerebral blood flow. Thus, imidapril's vasodilating properties apparently affect only the muscular (brachial artery) and cutaneous (external carotid artery) territories, but do not influence the cerebral vascular bed.

Effects of an angiotensin converting enzyme inhibitor, ramipril, on intracranial circulation in healthy volunteers. off.

1. The effects of a single oral dose (10 mg) of ramipril on (a) systemic haemodynamics (arterial pressure, cardiac output), (b) carotid artery haemodynamics (blood flow and diameter, pulsed Doppler technique), (c) intracranial haemodynamics (middle cerebral artery mean blood velocity, transcranial Doppler technique), and (d) renin-angiotensin system (plasma converting enzyme and renin activities) have been investigated and compared with those of a placebo during the 24 h period following administration in a randomized, double-blind and cross-over study performed in six healthy volunteers. 2. Ramipril induced a strong and sustained inhibition of plasma converting enzyme activity (-96% at 4 h, -63% at 24 h) and an increase in plasma renin activity (+993% at 8 h). 3. As compared with placebo, ramipril did not significantly affect arterial blood pressure, heart rate, cardiac output and total peripheral resistance. 4. Ramipril significantly increased carotid blood flow (by 27% at 8 h) without significantly changing carotid artery diameter, indicating, given the unchanged arterial pressure, an arteriolar vasodilation in the carotid territory. 5. The middle cerebral artery mean blood flow velocity underwent spontaneous modifications during the placebo period but these changes were not affected by ramipril. This lack of influence of ramipril on intracranial haemodynamics suggests that the drug-induced arteriolar vasodilation and increase in carotid blood flow only concern the extracranial, musculo-cutaneous part of the carotid territory.

Non invasive study of systemic and regional haemodynamic and cardiac effects of a new calcium antagonist, SR 33557, in healthy volunteers.

The systemic and regional haemodynamic and cardiac effects of two oral doses (100 and 300 mg) of a new sulphone-indolizine calcium antagonist SR 33,557 (SR) and a placebo were non invasively investigated in a double-blind, cross-over study in 6 healthy male volunteers. Arterial pressure, heart rate, cardiac output, brachial and carotid artery diameters and flows and PR and QT intervals were studied. Stroke volume, total peripheral and forearm vascular resistance, regional cardiac output distribution indices and corrected QT intervals were calculated. SR did not produce any significant modification in systemic haemodynamics, although arterial pressure and cardiac output tended to decrease slightly after 300 mg. In contrast, at the regional level, ST produced strong vasodilatation and significantly increased brachial and carotid blood flow. SR-induced vasodilation affected only the arterioles, as shown by a significant decrease in forearm vascular resistance, but not the large arteries, as shown by lack of change in the brachial and carotid artery diameters. SR-induced vasodilation preferentially affected the brachial rather than the carotid vascular bed, resulting in a redistribution of cardiac output towards the musculo-cutaneous territories. SR caused a marked and long-lasting decrease in heart rate, but it did not affect the auriculo-ventricular conduction time.

Functional antagonism between PK 11195, a peripheral benzodiazepine receptor antagonist, and nicardipine at the vascular level in healthy subjects: a peripheral hemodynamic study.

The effects of PK 11195, a peripheral benzodiazepine receptor antagonist (200 mg orally), of nicardipine (20 mg orally), of their combination, and of a placebo on brachial and carotid arteries, diameters, and flows were determined and compared over a period of 8 h after drug intake during a double-blind and cross-over study performed on six healthy volunteers. Simultaneously, plasma concentrations of both drugs were measured. PK 11195 significantly increased carotid and more markedly brachial arteries, flows (20 and 39%, respectively), and diameters (4 and 7%, respectively) and decreased forearm vascular resistance. Thus, PK 11195 preferentially affected the resistance vascular beds where it dilated both large arteries and arterioles. The intensity and duration of the peripheral vasodilating effects of PK 11195 were similar to those of nicardipine. Simultaneous administration of PK 11195 and nicardipine abolished almost all the peripheral vasodilating effects of both drugs. This finding, which was not related to a pharmacokinetic interaction between PK 11195 and nicardipine, demonstrates that in humans a functional antagonism develops between these two drugs at the vascular level.

Comparison of the effects of Bay K 8644 and aortic constriction on regional myocardial blood flow and function in canine nonischemic and ischemic myocardium.

The effects of Bay K 8644, aortic constriction, and a placebo on regional myocardial blood flows (RMBFs) and contractile function (RCF) were compared in three groups of open-chest anesthetized dogs during coronary stenosis. Bay K 8644 was investigated in two doses: 0.1 micrograms/kg, which exhibited no systemic hemodynamic effect, and 1 microgram/kg, which significantly increased arterial pressure. Aortic constriction was performed to raise afterload to the same extent as Bay K 8644 1 microgram/kg. As compared with placebo, Bay K 8644 0.1 microgram/kg, significantly increased coronary resistance, decreased RMBFs without changing RCF in nonischemic myocardial zones, and affected neither RMBFs nor RCF in ischemic zones. In nonischemic myocardium, Bay K 8644 1 microgram/kg increased RMBFs without affecting RCF, whereas aortic constriction did not modify RMBFs but decreased RCF. In ischemic myocardium, both Bay K 8644 1 microgram/kg and aortic constriction increased RMBFs but did not affect RCF. Thus, the low dose of Bay K 8644 exerts a direct and selective coronary vasoconstrictor effect that has no deleterious consequences on nonischemic RCF. Despite this intrinsic coronary vasoconstrictor effect, the high dose of Bay K 8644 increases RMBFs and maintains RCF in both ischemic and nonischemic zones in relation with the drug-induced increases in coronary perfusion pressure (both zones) and in contractility (nonischemic zones).

Ketanserin: systemic and regional hemodynamics in spontaneously hypertensive rats. Role of alpha 1-adrenoceptor blockade.

The systemic and regional hemodynamic effects of ketanserin were investigated in spontaneously hypertensive rats (SHRs) using either the pulsed Doppler or the microsphere technique. In addition, the contribution of ketanserin alpha 1-adrenoceptor blocking properties to these hemodynamic effects was assessed. Ketanserin, directly after infusion or secondarily after bolus injection, induced dose-dependent decreases in blood pressure and regional vascular resistances. Peripheral vasodilatation was not homogeneous, affecting in a decreasing rank order: muscle = spleen greater than brain = kidney = total peripheral resistance = liver greater than mesentery = skin. Cardiac output and hindlimb blood flow increased, renal blood flow was maintained whereas mesenteric blood flow was decreased. Prazosin pretreatment, followed by PGF 2 alpha infusion in order to restore initial vascular tone, reduced the ketanserin-induced decrease in blood pressure (by about 70%) and abolished the drug-induced reductions in regional vascular resistances, indicating that these effects in SHRs were mostly due to the alpha 1-adrenoceptor blocking properties of the drug.

Arterial and venous effects of verapamil in normal volunteers.

1. The effects of verapamil (120 mg orally) and a placebo on arterial pressure, heart rate, PR interval, arterial flows and diameters of the brachial and carotid arteries (pulsed Doppler technique), forearm vascular resistance, and venous diameter and compliance (cutaneous microstrain gauge and plethysmography) have been compared over a 10-hr period in six healthy volunteers during a double-blind and cross-over study. 2. Verapamil reduced diastolic blood pressure by approximately 10 mm Hg, did not affect heart rate and increased PR interval by approximately 15%. 3. Verapamil significantly increased brachial and carotid arterial blood flows by 56% (P less than 0.01) and 16% (P less than 0.05), respectively, but the diameters of these vessels were not significantly modified (+7 and +4%, respectively, NS). Forearm vascular resistance decreased by 40% (P less than 0.01), indicating that verapamil preferentially dilates small arteries. All these effects peaked at 2 h after drug intake and lasted for 6 h. 4. Verapamil increased hand dorsal vein diameter and flow by 95% (P less than 0.05) and 80% (P less than 0.05), respectively, from 2 to 4 h after drug intake but venous compliance, assessed by the venous diameter/venous flow ratio, was not significantly modified (from 0.71 to 0.69, NS), thus indicating that veins are not directly affected by this drug.

Beta-adrenoceptor blocking effects and plasma levels of bornaprolol and propranolol in man.

The beta-adrenoceptor blocking effects and pharmacokinetics of bornaprolol (FM 24), a new beta-adrenoceptor blocking agent, have been compared with those of propranolol and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate, systolic and diastolic blood pressures and peak expiratory flow rate were measured at rest and at the end of 3 min vigorous exercise on a bicycle ergometer, before and 2,24 and 48 h after single oral doses of bornaprolol (120, 240 and 480 mg) and propranolol (40, 80 and 160 mg). Plasma renin activity at rest and the plasma concentrations of the two drugs were determined. Bornaprolol significantly reduced resting heart rate, dose-dependently lowered exercise-induced tachycardia and decreased peak expiratory flow rate and plasma renin activity. In addition, exercise-induced tachycardia was significantly reduced by bornaprolol up to 48 hours after drug intake (pharmacodynamic half-life approximately 63-86 h) and there was a correlation between this reduction and the log plasma bornaprolol concentration over the 48-h period. Thus, bornaprolol behaved in man as a non-cardioselective and long-lasting beta-adrenoceptor blocking drug, probably devoid of intrinsic sympathomimetic activity.

Comparative beta-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man.

The beta-adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective beta-adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its Tmax and T 1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac beta-adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.

Nicardipine: pharmacokinetics and effects on carotid and brachial blood flows in normal volunteers.

The effects of nicardipine, 20 mg, three times daily, nicardipine slow release, 30 mg, twice daily and a placebo on brachial and carotid arteries diameters and flows have been investigated by the pulsed Doppler technique during a single blind and cross-over study performed in six healthy volunteers. Simultaneously, nicardipine plasma levels and relative bioavailability were determined. Nicardipine significantly increased brachial and carotid arteries diameters (by 16 and 10% respectively) and flows (by 60 and 35% respectively). These effects peaked after 4 h and lasted no longer than 6 h. Forearm vascular resistance was significantly decreased. Hence nicardipine dilated both large and small arteries. Nicardipine slow release elicited the same effects on brachial and carotid arteries diameters and flows as nicardipine. These effects peaked at 6 h and lasted up to 10 h. Although the profiles of the pharmacodynamic effects and of the kinetics of nicardipine were almost parallel in each individual after administration of both nicardipine formulations, there was no correlation between the nicardipine plasma relative bioavailability and its effects on brachial and carotid arteries blood flows when considering all subjects together.

Influence of heart rate on the effects of prenalterol on regional myocardial blood flow and function during coronary stenosis in dogs.

The effects of prenalterol, a selective beta 1-adrenoceptor agonist with potent cardiac positive inotropic properties have been investigated on regional myocardial blood flow (RMBF) (microspheres) and contractile function (ultrasonic crystals) during partial circumflex coronary artery stenosis in 8 open-chest anaesthetized dogs. Prenalterol was investigated at two intravenous doses: 5 micrograms kg-1, which increased myocardial contractility (dP/dt max: +29%) more than heart rate (+12%, up to 150 beats min-1) and 20 micrograms kg-1 which induced almost similar increases in contractility (+35%) and heart rate (+31% up to 175 beats min-1). The induced modifications of regional flow and function were then compared to those produced in another series of 6 dogs by atrial pacing at 150 and 175 beats min-1 respectively. Prenalterol significantly increased RMBF and segment length (SL)-shortening in a dose-dependent manner in the nonischaemic zone. In the ischaemic zone, RMBF was maintained and SL-shortening increased with prenalterol, 5 micrograms kg-1 whereas both RMBF and contractile function were severely decreased with prenalterol, 20 micrograms kg-1. Atrial pacing had almost no effect on RMBF and SL-shortening in the nonischaemic zone. In the ischaemic zone, atrial pacing rate-dependently decreased both RMBF and SL-shortening. Thus, a significant increase in contractility, associated with little tachycardia (prenalterol, 5 micrograms kg-1), induces beneficial effects on RMBF and function in both the nonischaemic and ischaemic myocardium. In contrast, a strong tachycardia, whether accompanied by positive inotropic effects (prenalterol, 20 gig kg-') or not (atrial pacing at 175 beats min-1) induces deleterious effects on RMBF and cardiac function in the ischaemic myocardium.

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.

Pharmacological analysis of beta adrenoceptor blockade-induced coronary blood flow redistribution in dogs using l-penbutolol.

The effects of l- and d-penbutolol on regional myocardial blood flow (assessed by means of tracer microspheres) and on ST-segment elevation in ischemic and nonischemic areas of the canine left ventricle have been investigated under different experimental conditions. l-Penbutolol reduced transmural coronary blood flow and induced its redistribution from the epicardium to the endocardium in both ischemic and nonischemic areas. This favorable effect was abolished under atrial pacing or after bilateral stellectomy or in the presence of phenoxybenzamine. d-Penbutolol did not induce coronary blood flow redistribution. These results indicate that the redistribution phenomenon occurs only if both a beta adrenoceptor blockade-induced bradycardia and a beta adrenoceptor blockade-induced reinforcement of alpha adrenoceptors-mediated coronary vasoconstrictor tone are simultaneously achieved l-Penbutolol alone or in the presence of phenoxybenzamine decreased ST-segment elevation in ischemic areas, but this effect was abolished by atrial pacing, confirming the major role of bradycardia in the reduction of ischemic injury.

[Nitroglycerin ointment v.s. sublingual nitroglycerin on peripheral venomotricity in man (author's transl)]. / Nitroglycérine percutanée et nitroglycérine sublinguale. Effets sur la veinomotricité périphérique chez l'homme.

Topical administration of nitroglycerin ointment (NGO) was suggested as a useful therapeutic approach for angina pectoris in man. In six healthy volunteers the effects of NGO (15 mg) on venous motricity (VM) were compared to those of a placebo ointment and of the sublingual form (NGS) (0.75 mg). VM was assessed at regular intervals by an original atraumatic technique involving simultaneous measurement of dorsal hand vein diameter (HVD) and whole hand volume changes (VH) during short inflation periods of a sphygmomanometer cuff around the upper arm. A venous distensibility ratio (VDR = HVD/VH) was used as VM index. With NGS, the maximum increase in VDR (from 0.60 to 2.30)(230.6 +/- 13.9%) occurs after 10 min but the effect completely disappears after 1.5 hours. With NGO, the increase in VDR is slightly less marked (from 0.81 to 1.80) (120.1 +/- 4.2%) but occurs as early as with NGS; subsequently VDR stabilizes at a plateau value of 1.6 for at least 6 hours, thus demonstrating the early and long-lasting efficacy of NGO.

[Hand blood flow at rest and during submaximal exercise in acute and chronic heat stress (author's transl)]. / Modifications du débit sanguin de la main et de la réactivité vasculaire avec l'acclimatation à la chaleur

Three groups of subjects, Europeans without any heat acclimation (called EE), Europeans after 3 weeks of acclimatization in India (EI), and Indians in their natural environment (II) were studied during exposure to an ambient temperature of 33 degrees C. Hand blood flow (Q), rectal temperature (Tre), mean cutaneous temperature (Tsk) were simultaneously recorded at rest and during 2 periods of muscular exercise (0.44 and 0.7 Vo2 max) of 35 mn duration. The results showed (1) at rest, Q was very high in EE, quite low in both EI and II; (2) at the onset of exercise, a hand vasoconstriction was observed in all cases; (3) during exercise, there was a progressive increase of Q until 200% maximum above rest values; (4) at the end of exercise, Q was proportional to the intensity of the exercise for each group and inversely proportional to the duration of heat exposure, the highest Q was observed in EE, the lowest in II and an intermediate value for EI close to the latter). These differences in hand blood flow could not be explained by differences in deep and/or superficial temperatures between subjects. Thus, during chronic heat exposure, there is, especially for an exercising man, a progressive modification of heat transport in the body: that is, a reduction of skin perfusion and a greater Tre-Tsk difference which are both adaptative responses. The value of hand blood flow as an estimation of whole superficial circulation is discussed.