H. Geukens

The Antihypertensive Effects of a Pure and Selective Serotonin-Receptor Blocking Agent (R 41 468) in Elderly Patients

In a first experiment, an acute intravenous administration of 10 mg R 41 468, a pure serotonin-receptor blocking agent with high selectivity for blood vessels and thrombocytes and devoid of central effects, dramatically reduced systolic and diastolic blood pressure in 23 elderly hypertensive patients. Heart rate and cardiac output remained virtually unchanged. In a second double-blind placebo-controlled cross-over study a highly significant decrease of systolic and diastolic blood pressure was obtained in 14 elderly hypertensive patients during an 8-day oral treatment with 40 mg t.i.d. of R 41 468. No serious side-effects were observed. An oral maintenance therapy with R 41 468 for 3 weeks showed a further reduction of blood pressure, resulting in a normalization of blood pressure, taking into account the advanced age of the patients. R 41 468 most probably acts by decreasing the venous capacitance bed constriction. Essential hypertension might be causally related to an impair ment of venous function, in which serotonin might be an important pressor factor.

The Rheological Effects of Cinnarizine and Flunarizine in Normal and Pathologic Conditions

From the Clinical Research Unit, St. Bartholomeus, Antwerp, Belgium. Cinnarizine and its difluoro derivative, flunarizine, are long-lasting polyvalent antagonists of vasoconstrictive agents.’ They selectively inhibit the calcium transfer to the depolarized vascular smooth muscle.2~3 Both drugs improve exercise tolerance in patients with peripheral obliterative disease’ and enhance blood flow of the lower limbs in both healthy subjects’ and patients with vascular disease. 6-9

PLACEBO-CONTROLLED DOUBLE-BLIND TRIAL OF KETANSERIN IN TREATMENT OF INTERMITTENT CLAUDICATION

Ketanserin, a selective serotonin (5-HT) antagonist at 5-HT2 receptors, was investigated in a 3-month, double-blind, placebo-controlled study in twenty patients with intermittent claudication. Blood-pressure ratio (thigh/arm), reactive hyperaemia measured with an ECG-triggered venous occlusion plethysmograph, blood filterability, and claudication distance on a treadmill progressively and significantly improved during ketanserin therapy, whereas no such changes occurred in the placebo group. Mean claudication distance improved by 140%; four of the eleven patients on ketanserin were able to keep walking beyond the time limit of the exercise test. The beneficial effect of ketanserin suggests that 5-HT may be involved in the pathogenesis of peripheral arterial obstructive diseases. In an experiment comparing blood-pressure ratio measured by doppler velocimetry and by plethysmography, the plethysmographic values rose during ketanserin therapy only at thigh level, which suggests an improvement in the collateral circulation.

Comparison of the Subacute Hemodynamic Effects of Atenolol, Propranolol, Pindolol, and Nebivolol

In an observer-blind four-way crossover study, 7 healthy volunteers received in random sequence, one month apart, atenolol 100 mg od, propranolol (slow release) 160 mg od, pindolol 5 mg tid, and nebivolol 5 mg od for a period of seven days, followed by a single-blind placebo washout period of seven days. The decrease of peak exercise heart rate and systolic blood pressure was significant (p = 0.02) and comparable for the four drugs studied and varied between 15% and 23% for heart rate and between 15% and 20% for systolic blood pressure. Although no statistically significant difference was observed among the four drug regimens, the decrease of peak exercise heart rate was less pronounced with nebivolol than with the three reference beta-blocking agents. The ratio of the preejection period (PEPc) to the left ventricular ejection time (LVET c), an indirect measure of left ventricular performance, tended to increase with atenolol and propranolol and remained unchanged with pindolol. PEP c/LVETc progressively and significantly improved with nebivolol from a control value of 0.37 ± 0.012 to 0.31 ± 0.009 (p = 0.03) after seven days of treatment, owing to a decrease in PEPc and an increase in LVETc, suggestive of a combined effect both on preload and afterload. Postexercise LVETc, an index of the intrinsic positive inotropy of exercise, was significantly suppressed by atenolol, propranolol, and pindolol, but not during treating with nebivolol. These data suggest that nebivolol is a β1-selective adrenergic antagonist with an unusual hemodynamic profile, probably improving left ventricular compliance.

Subacute Hemodynamic Effects of Nebivolol in Man at Rest and During Exercise

In a subacute experiment 7 apparently healthy volunteers received a daily oral dose of 5 mg nebivolol for seven days, followed by a seven-day washout period with placebo. From the first day during treatment with nebivolol, peak exercise heart rate and systolic blood pressure, as measured during a standard ized submaximal treadmill exercise, significantly decreased by 15% and 19% respectively. A prolonged treatment for one week did not further increase the response of exercise heart rate and systolic blood pressure to nebivolol. How ever, the ratio of preejection period (PEPc) to left ventricular ejection time (LVETc), an indirect and valuable measure of left ventricular performance, pro gressively and significantly decreased during the seven-day treatment period with nebivolol from a mean value of 0.37±0.012 to 0.31±0.009. The improve ment of systolic time intervals resulted from a shortening of the PEPc and a lengthening of the LVETc. At rest, heart rate did not change significantly with nebivolol, whereas both systolic and diastolic blood pressure gradually and sig nificantly lowered. The postexercise LVET c significantly shortened during treat ment with nebivolol, and this shortening was more pronounced after seven days of treatment. After discontinuation of treatment with nebivolol, all these effects persisted for more than thirty hours after the last intake and gradually returned to pretreatment values thereafter. From these data it appears that nebivolol effectively reduces blood pressure at rest and during exercise in healthy volun teers, beneficially influencing preload and afterload, as measured by systolic time intervals. The negative influence on myocardial contractility during the exercise test, generally observed with beta-adrenergic antagonists, does not oc cur with nebivolol. Presumably this is due to an ancillary property of nebivolol, neutralizing the negative inotropic effect due to beta blockade.

Hemodynamic Effects of Nebivolol in Men: Comparison of Radionuclide Angiocardiography with Systolic Time Intervals:

In a subacute experiment the au thors studied the effects of a four teen-day treatment with nebivolol, 5 mg once a day, in 10 healthy male vol unteers with a mean age of thirty- one, twenty-five to thirty-nine years, by comparing the results of the rest ing ratio of the preejection period (PEPc) to the left ventricular ejection time (LVETc), as measured by sys tolic time intervals (STI), with the results obtained by equilibrium ra dionuclide angiocardiography (ERNA), using technetium 99m-la beled autologous red blood cells as a marker. A submaximal treadmill ex ercise test performed before and dur ing treatment demonstrated that nebivolol significantly (p s 0.01) re duced peak exercise heart rate and systolic blood pressure from a mean value of 158 ± 5.4 bpm to 131 ± 4.3 bpm and from 171 ± 4.9 mmHg to 144 ± 4.5 mmHg respectively. The data from the STI and ERNA were calculated and analyzed indepen dently by two observers. A highly sig nificant (r=0.8182, p=0.0038) correlation was found between the changes of stroke volume (SV) and PEPc/LVETc during treatment with nebivolol. Furthermore end-diastolic volume significantly (p=0.03) in creased from a mean value of 177 ± 10.1 ml to 198 ± 6 ml and stroke vol ume significantly (p=0.01) increased from 120 ± 6.8 ml to 136 ± 6.3 ml. Systemic vascular resistance tended to decrease from a mean value of 11.4 ± 1.28 units to 10.6 ± 1.10 units. No changes could be observed either in ejection fraction or in cardiac output. The ratio of the PEPc/LVETc, as mea sured with STI, significantly (p=0.03) improved from a mean value of 0.34 ± 0.011 to 0.30 ± 0.010, and these changes were due to both a decrease of PEPc and an in crease of LVETc. The postexercise LVETc, which is a marker of the posi tive inotropy of the exercise, signifi cantly (p=0.002) shortened with 49 ± 4.6 msec in control conditions and also during treatment with nebivolol with 30 ± 4.6 msec (p=0.002). From all these data it appears that nebivolol, unlike classical beta-block ers, beneficially influences cardiac function at rest, owing to a combined effect on both preload and afterload. These ancillary hemodynamic activi ties of nebivolol may be useful in the treatment of elderly hypertensive pa tients with left ventricular damage.

Noninvasive Cardiac Haemodynamics of Nebivolol

SummaryTreatment with nebivolol, a novel β1-adrenergic antagonist, significantly improved left ventricular function, as measured by systolic time intervals (STIs) in normal volunteers, and in patients with essential hypertension, acute myocardial infarction, ischaemic cardiomyopathy, or acute congestive heart failure. These effects on STIs were mainly due to changes in the pre-ejection period, suggesting an improvement in diastolic function, and were not seen with placebo or with classical β-blocking agents (e.g. propranolol, pindolol, atenolol and metoprolol). Experiments in volunteers with the 2 enantiomers of nebivolol showed that these beneficial effects on STIs were due to an interaction between the d-isomer, which has β-blocking properties, and the l-isomer, which is devoid of β-blocking properties. Addition of the l-isomer to atenolol did not produce these effects on STIs in normal volunteers. A study in volunteers, comparing STIs with radionuclide angiocardiography confirmed these beneficial effects on cardiac function and revealed that the peak filling rate of the diastolic function was increased with nebivolol and not with atenolol. Finally, a study in patients with ischaemic cardiomyopathy, using transmitral Doppler echocardiography, showed that the ratio of the maximal early peak velocity to the maximal late peak velocity increased with nebivolol. All these data suggest that an improvement in diastolic function underlies these favourable effects.

The Effect of Nebivolol in Patients with Left Ventricular Diastolic Dysfunction

Nebivolol is a novel ,61-adrenergic antagonist with an unusual haemodynamic profile (Van de Water et al. 1988). In contrast to classical ,6-blocking agents, nebivolol improves left ventricular function as measured by systolic time intervals (STls) in normal subjects and in patients with a damaged left ventricle (De Cree et al. 1989). The purpose ofthis study was to compare the influence of nebivolol on diastolic function and STis in patients with ischaemic cardiomyopathy. 1. Patients and Methods