Slow Calcium Channel Research Articles

Inotropic and calcium kinetic effects of calcium channel agonist and antagonist in isolated cardiac myocytes from cardiomyopathic hamsters.

The mechanism by which heart cells of cardiomyopathic (CM) hamsters become calcium overloaded is not known. We examined the number of slow calcium channels, calcium uptake via slow calcium channels, calcium pool sizes, and the contractile response to Bay K 8644, verapamil, and nifedipine using isolated cardiac myocytes from 8-9-month-old CM hamsters (BIO 14.6) and age-matched normal controls. The number of dihydropyridine binding sites as assessed by specific binding of [3H]PN200-110 was similar in the two groups (control hearts: Bmax = 333 +/- 89 [mean +/- SD] fmol/mg; CM hearts: Bmax = 357 +/- 75 fmol/mg; n = 5 experiments, p = 0.6). Current density through L-type calcium channels was determined using the whole-cell clamp technique (at -50 mV holding potential and -10 mV test potential) and was the same in CM myocytes (17.8 +/- 1.5 [mean +/- SD] pA/pF) and control myocytes (18.6 +/- 2.1 pA/pF) (n = 5 experiments, p = 0.5). The current-voltage relation (test potentials varied from -40 to +50 mV) was also the same in CM and control cells, as was apparent threshold, peak current, and reversal potential. However, the initial rate of 45Ca influx as well as the size of the rapidly exchangeable calcium pool was significantly greater in myocytes obtained from CM than from normal hamsters. In both myocyte preparations, Bay K 8644 increased the rate of 45Ca uptake by 25% at 60 seconds; verapamil decreased 45Ca uptake at 60 seconds by 16% and 17% in normal and CM hamsters, respectively. A similar inhibitory effect was observed with nifedipine. The amplitude of cell motion in cells driven at 1.5 Hz as assessed by an optical-video system increased progressively with increasing concentrations of extracellular calcium or Bay K 8644 in cardiac myocytes from normal or CM hamsters. However, the concentration-effect curves for the two effectors were shifted to the left in CM cells compared with cells from normal hamsters. Both preparations demonstrated similar contractile responses to verapamil and nifedipine. These findings demonstrate that single enzymatically dissociated cardiac myocytes from CM hamsters have impaired contractile properties analogous to those seen in the intact heart and thus provide a useful experimental system in which to study underlying cellular mechanisms operative in this model of heart failure. Our results further indicate that calcium overload in CM hamster cardiac myocytes may not be due to increased calcium influx via dihydropyridine-sensitive calcium channels, as suggested previously, but rather to abnormalities of intracellular calcium homeostasis.

THE ROLE OF CALCIUM IN Chlamydomonas PHOTOMOVEMENT RESPONSES AS ANALYSED BY CALCIUM CHANNEL INHIBITORS

Phototaxis and light-induced stop responses in Chlamydomonas are known to be calcium dependent. We show that phototaxis is stereoselectively inhibited by dihyropyridines, verapamil, diltiazem, omega-conotoxin and pimozide, all inhibitors of slow L-type calcium channels. In contrast, the stop response in Chlamydomonas can be specifically reduced only by omega-conotoxin and pimozide. The light-regulated calcium uptake as detected by 45calcium can be completely suppressed by verapamil and omega-conotoxin but not by diltiazem or any of the dihyropyridine-type calcium channel inhibitors. We conclude that phototaxis and stop response in Chlamydomonas are regulated by three distinguishable drug receptor sites. One of them controls phototaxis and is sensitive to verapamil. The second site controls stop response and phototaxis and shows a high sensitivity to omega-conotoxin and pimozide. These two drug receptors seem to be localized in the plasma membrane and function as ion channels. In addition, calcium influences internal signal transduction from the photoreceptor to the flagella. This internal role of calcium is inhibited by the dihydropyridine binding to a dihydropyridine receptor protein. The arylazide-1,4-dihydropyridine[3H]azidopine binds with a Kd = 35 nM to a 50 kDa protein located in one of the internal cell membranes. Azidopine binding is fully reversible and can be partially inhibited by nimodipine and PN-200110. This protein is the first identified dihyropyridine receptor in an unicellular plant cell. It might serve as an internal calcium regulating channel in Chlamydomonas.

Use of nifedipine in hypertension and Raynaud's phenomenon

The reduction of transmembranous calcium influx into vascular smooth muscle cells by calcium antagonists leads to a reduction of tension development and vascular tone. Nifedipine reduces forearm vascular resistance dose-dependently when infused into the brachial artery in patients with essential hypertension, attesting to its potent arterial vasodilator effects. This effect can be successfully utilized for the treatment of essential hypertension, where nifedipine acts by reducing increased peripheral vascular resistance, thereby normalizing the main hemodynamic derangement of hypertensive patients. In contrast to other direct-acting vasodilators, the antihypertensive effect is not accompanied by sympathetic reflex activation or volume retention, making it feasible to use nifedipine as monotherapy for hypertensive patients. Although the pathophysiologic disturbances leading to vasospasm are not clear, blockade of slow calcium channels is also effective for the treatment of Raynaud's phenomenon, reducing attack frequency, digital pain, and functional disability in many patients, particularly those with primary Raynaud's phenomenon.

Reperfusion-induced arrhythmias in the anaesthetized rat effect of SR 33557, a novel slow calcium channel antagonist

Reperfusion-induced arrhythmias in the anaesthetized rat effect of SR 33557, a novel slow calcium channel antagonist

How Does Posture Influence the Haemodynamic Assessment of a Cardiovascular Drug? Experience with Nicardipine

The extent to which posture altered the haemodynamic response to slow calcium channel blocker nicardipine was evaluated in 22 male patients with angiographically confirmed coronary artery disease. Patients were randomly allocated to supine or upright posture and an otherwise identical protocol performed in each group. At rest, following a control saline period, four doses of the drug (log cumulative dosage: 1.25, 2.5, 5.0, and 10.0 mg) were administered by i.v. infusion over a total period of 40 min; haemodynamic indices were recorded during the 3-5 min following each 5 min infusion. The exercise effects of the drug, in each posture, were determined by comparison of a control predrug exercise with observations at the same workload following the maximal cumulative dose. Nicardipine reduced resting mean blood pressure (MBP) and systemic vascular resistance index (SVRI) in both postures, the decrease being more pronounced when upright (MBP, -12%, -18%; p less than 0.01: SVRI, -30%, -46%; p less than 0.01). The increases in cardiac index (CI) and stroke volume index (SVI) were higher when upright (29 and 54% vs. 10 and 27%; p less than 0.01). Pulmonary artery occluded pressure (PAOP) increased by 29% when upright, without change when supine. On exercise, the effects for HR, MBP, CI, SI, and SVRI responses were independent of posture; however, a qualitative difference was apparent for PAOP (-17% vs. +14%; p less than 0.05). Thus, although the actions of nicardipine were qualitatively similar, quantitative differences related to posture were confirmed. These differences appeared to relate to posture-related baseline haemodynamic differences between the groups but with similar postnicardipine absolute values.

Ca‐Cd interaction in the prymnesiophyte Cricosphaera elongata

Abstract. 45Ca and 109Cd uptake were followed in Criscosphaera elongata Prymnesiophyceae. In both cases, after a rapid increase for the first 5 min, the incorporation rate slowed during the hour of observation. Verapamil, a blocker of voltage‐dependent slow calcium channels, inhibited 45Ca uptake except during the first rapid phase when adsorption should predominate. Cadmium also decreased 45Ca labelling, suggesting that the two metals are antagonistic. However, verapamil was shown to augment 109Cd incorporation, contrary to what occurs in animals cells; this effect is detectable in continuous labelling as well as in pulse experiments. The data support the presence of calcium channels in the alga and suggest several processes in Cd accumulation: adsorption on peripheral envelopes and diffusion of uncharged Cd.

Inotropic Effect of Meperidine

Meperidine increases developed force in isolated rat atria. We initiated this study to determine if this positive inotropic effect was attenuated by commonly used receptor- and ion channel blockers. Neither naloxone (opioid blocker), phentolamine (alpha-adrenoceptor blocker), propranolol (beta-adrenoceptor blocker), polaramine (H1-receptor blocker), ranitidine (H2-receptor blocker), verapamil (calcium-channel blocker), nor lidocaine (fast sodium-channel blocker) attenuated the positive inotropic effect of meperidine. However, after lidocaine pretreatment meperidine increased contractile force by 57% (27%-80%) (median and 95% confidence interval), which is significantly more (P less than 0.001) than the 21% (13%-35%) increase seen after pretreatment with saline. After Na,K-pump inhibition by ouabain, meperidine caused no further increase in contractility, but the atria still responded to isoproterenol with an increase in developed force. Conversely, meperidine prevented the positive inotropic effect of ouabain. These findings suggest that the positive inotropic effect of meperidine is mediated by an increase in intracellular sodium activity and not by regulation of the slow inward calcium channel.

Haemodynamic and radionuclide effects of amlodipine in coronary artery disease.

1. The haemodynamic and radionuclide effects of a new long-acting slow-calcium channel blocking agent, amlodipine, were evaluated in 32 patients with coronary artery disease. 2. Haemodynamic measurements in 24 patients were made at rest and 10 to 15 min after 20 mg i.v. amlodipine. Amlodipine significantly reduced systemic arterial blood pressure and vascular resistance index with an increased heart rate and augmented cardiac index. Cardiac stroke volume index rose and stroke work fell without change in pulmonary artery occluded pressure (PAOP). 3. The exercise effects were determined by comparison of measurements during 4 min of supine bicycle exercise at a fixed workload before and after drug treatment. During dynamic exercise, amlodipine reduced systemic arterial pressure and vascular resistance index. Exercise cardiac index, stroke volume index and heart rate were higher. The left ventricular filling pressure was significantly reduced. 4. Radionuclide parameters were studied in 16 patients at rest and on exercise; ejection fraction was unaltered following amlodipine. 5. Pre-therapy haemodynamic values correlated with response following amlodipine for resting mean blood pressure, systemic vascular resistance and exercise PAOP. 6. Thus, the immediate impact of amlodipine in stable coronary artery disease was to reduce left ventricular afterload and thereby improve cardiac pumping performance.

Induction of the vesicular monoamine transporter by elevated potassium concentration in cultures of rat sympathetic neurons

The expression of the vesicular monoamine transporter was studied in newborn rat sympathetic neurons and compared to that of the catecholamine biosynthesis enzymes tyrosine hydroxylase and dopamine-β-hydroxylase. The vesicular monoamine transporter was assayed using the specific ligand [ 3H]dihydrotetrabenazine. In cultures grown for 10 days in the presence of 35 mM K +, tyrosine hydroxylase activity and the density of [ 3H]dihydrotetrabenazine binding sites were increased by a similar 2–3-fold factor, while dopamine-β-hydroxylase activity and protein level were unchanged. Under these conditions, choline acetyltransferase activity was depressed by 90%. The induction of the vesicular monoamine transporter by high K + was dependent upon Ca 2+ entry through slow calcium channels since it was inhibited by the diphenylbutylpiperidine antagonist fluspirilene and by 20 mM Mg 2+, and was enhanced by the dihydropyridine agonist, Bay K8644. The induction of the vesicular monoamine transporter by neuronal depolarization indicates the existence of a Ca 2+-independent mechanism of coregulation for this intrinsic component of monoaminergic synaptic vesicles and tyrosine hydroxylase. On the other hand, the apparent absence of dopamine-β-hydroxylase induction is probably due to the continuous secretion of this intravesicular enzyme by the depolarized sympathetic neurons, an effect already observed in trans-synaptically stimulated adult sympathetic ganglion and adrenal medulla.

Contrasting effects of verapamil and procainamide on rate-dependent bundle branch block: Pharmacologic evidence for the role of depressed sodium channel responses

The mechanisms responsible for intermittent bundle branch block are still under debate. The role of the time-dependent behavior of the slow calcium channel has recently been emphasized. To test this hypothesis and ascertain the possible involvement of the fast sodium channel, the effects of the slow calcium channel blocker verapamil and the fast sodium channel blocker procainamide were compared in 10 patients with intermittent bundle branch block. All 10 patients showed bundle branch block during spontaneous sinus rhythm. Maneuvers to slow cardiac rate (that is, carotid sinus massage, Valsalva maneuver) were performed to identify normal conduction as well as phase 4 bundle branch block.Thus, the ranges of diastolic intervals (RR) resulting in phase 3 (tachycardia-dependent) bundle branch block, phase 4 (bradycardia-dependent) bundle branch block and normal conduction were measured in two control studies performed before intravenous administration of verapamil (control 1) and procainamide (control 2) and at the peak effect of both drugs. In the control studies, all 10 patients showed phase 3 bundle branch block, whereas phase 4 bundle branch block occurred in only 4 patients. The ranges of phase 3 bundle branch block, phase 4 bundle branch block and normal conduction were very similar in control studies 1 and 2. The phase 3 bundle branch block range was slightly shortened by verapamil (983 ±83.5 ms in control 1; 930 ±69.4 ms at the peak effect of verapamil), whereas phase 4 bundle branch block remained unchanged. In contrast, conduction was systematically worsened by procainamide. The phase 3 bundle branch block range was prolonged 80 to 1,770 ms in five of the six patients with apparently isolated phase 3 bundle branch block, and rate-independent bundle branch block occurred in all four patients with both phase 3 and phase 4 bundle branch block as well as in one patient showing an isolated phase 3 bundle branch block.The absence of any depressing action of verapamil and the marked effects induced by procainamide strongly support the view that clinical intermittent bundle branch block is related to depressed fast responses and not to slow calcium-mediated responses. Hence, these conduction disturbances probably occur in tissues operating at a subnormal but still relatively high level of membrane potential.

Dihydropyridine calcium channel antagonists block and agonists potentiate high potassium contractures but not twitches in frog skeletal muscle.

The effects of two dihydropyridine calcium channel antagonists (nitrendipine and nifedipine) and two agonists (Bay K8644 and CGP-28392) were tested on high K(+)-induced contractures of frog's toe muscles. All four drugs depressed or blocked maximum contractures induced by 123 mM K+. Agonist effects, i.e., an increase in contracture amplitude, were found with smaller contractures produced by lower high K+ concentrations (i.e., 10, 20, and 25 mM). Bay K8644 produced its maximum agonist effect at 10(-7) M and only depressed contractures with 10(-6) M. CGP-28392 had its greatest agonist effect with 10(-9) M and had only antagonist effects with 10(-7) M or more. Nitrendipine had no agonist effects but nifedipine produced agonist effects with all concentrations tested (10(-9) to 10(-4) M). These results support previous results indicating that these contractures are initiated by extracellular Ca2+ ions entering via the voltage-sensitive, slow calcium channels in the t-tubules. The results obtained in the present study also are consistent with the known pharmacological effects of these drugs on calcium channels.

Drug Interactions

The calcium channel blocker nifedipine and the new phosphodiesterase (PDE) inhibitor enoximone are used in the treatment of cardiovascular diseases. Since both substances are acting on slow calcium channels and because systemic elimination of these two agents is dependent on oxidative drug metabolizing enzyme activity, this study was performed in order to investigate hemodynamic changes and effects on plasma levels when both substances are given simultaneously. Forty-five patients undergoing aortocoronary bypass grafting were randomly subdivided into three groups: (a) group (n = 15) received 0.3 micrograms/kg/min of nifedipine as an infusion (N patients); (b) group (n = 15) received 0.5 mg/kg of enoximone as a bolus (E patients); and (c) group (n = 15) received nifedipine and enoximone in the same dosages (E + N patients). In addition to various hemodynamic variables, plasma levels of nifedipine, enoximone, and enoximone sulfoxide were measured until the end of the operation. Injection of enoximone was followed by an increase in cardiac index and right ventricular ejection fraction, decrease in pulmonary artery pressure, pulmonary capillary pressure, and systemic vascular resistance, whereas heart rate and mean arterial pressure remained almost unchanged. These changes were comparable for E and E + N patients. Plasma concentrations of enoximone and enoximone sulfoxide were not affected by nifedipine infusion and showed a comparable course in E and E + N patients. Nifedipine plasma level dropped to values less than 15 ng/ml at the end of extracorporeal circulation in N and E + N patients. It can be concluded that enoximone improved hemodynamics even in patients pretreated with nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Flunarizine allows differentiation between mechanisms of arrhythmias in the intact heart.

The calcium antagonist flunarizine suppresses pathologic accumulation of calcium intracellularly without affecting the fast sodium or the slow calcium channel. To establish its value in differentiating between mechanisms of arrhythmias in the canine heart, the effect of flunarizine was investigated on ventricular tachycardia (VT) induced by ouabain intoxication or occurring 16-24 hours after occlusion of the left anterior descending coronary artery. Four groups of dogs were studied. Group 1 consisted of 13 animals with VT induced by ouabain intoxication (triggered-activity group). Group 2 included nine dogs in whom VT developed 16-24 hours after occlusion of the left anterior descending coronary artery (abnormal automaticity group). Group 3 included six dogs with normally conducted sinus beats, whereas group 4 consisted of six animals having a ventricular escape rhythm. With the exception of group 3, all dogs had surgically induced complete atrioventricular block. All animals were studied while conscious and without premedication. In groups 1 and 2, 2-3 mg/kg flunarizine was given intravenously after VT had persisted for at least 20 minutes. In groups 3 and 4, 2 mg/kg flunarizine was given after the rhythm was registered for 20 minutes. The cycle lengths of the different rhythms were compared before and after flunarizine. In group 1, flunarizine increased the cycle length of the VT from 300 +/- 30 to 410 +/- 50 msec (p less than or equal to 0.001). Termination of VT was seen in 11 out of 13 animals. In group 2, flunarizine resulted in a nonsignificant shortening of the RR interval from 450 +/- 60 to 440 +/- 60 msec. Persistent termination was observed in only one of nine dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Barium-induced nondriven action potentials as a model of triggered potentials from early afterdepolarization: Significance of slow channel activity and differeing effects of quinidine and amiodarone

Triggered activity due to early afterdepolarizations in the content of prolonged repolarization is believed to cause torsade de pointes. The nature of such triggered activity is not clearly defined. Spontaneous action potentials developing from depolarized membrane potentials were studied in canine Purkinje fibers with use of a standard microelectrode technique. Action potentials due to abnormal automaturity and additional depolarizations developing over the repolarization phase were induced by 5 m-M barium superfusion. These action potentials were abolished by 1.0 × 10−5M verapamil and by calcium-free solution, whereas action potential amplitude (Vmax) and spontaneous firing frequency were markedly enhanced by 2.0 × 10−6M isoproterenol. High calcium solution shortened the action potential duration and precluded additional depolarizations.Quinidine, 1.0 × 10−5M, reduced action potential amplitude (6.9 ± 1.8 %: p < 0.01), Vmax (15.7 ± 4.0 %; p < 0.05) and spontaneous firing frequency (18.5 ± 2.1%; p < 0.01), but it increased action potential duration measured at −40 mV (19.1 ± 5.9 %; p < 0.01), which produced additional depolarizations. Amiodarone, 5.0 × 10−5M, reduced action potential amplitude (23.4 ± 3.6 %; p < 0.01), Vmax (44.6 ± 3.9 %; p < 0.01) and spontaneous firing frequency (41.9 ± 5.1 %; p < 0.01). Amiodarone obviated the development of additional depolarizations without effect on action potential duration.The data indicate that 1) triggered potentials from early afterdepolarizations are slow calcium channel dependent; 2) the duration of the plateau phase mediates the development of triggered activity from low membrane potential; 3) the effects on plateau currents but not direct effects on triggered potentials may contribute to the arrhythmogenic action of quinidine; and 4) the known associated slow channel blocking property of amiodarone may account for the low incidence of torsade de pointes during long-term amiodarone therapy.

Metabolic Effects of Various Antihypertensive Agents

Mortality resulting from coronary artery disease and sudden death has not been significantly reduced by the use of antihypertensive medications in patients with hypertension, despite evidence that hypertension is a major risk factor for myocardial infarction. One possible reason is that the drugs used may have adverse metabolic effects that negate the beneficial effect of lowering blood pressure. Diuretics and beta-blocking agents produce a wide range of biochemical or metabolic alterations-e.g., changes in plasma potassium and in lipoprotein profiles. In general, fewer or less marked alterations are associated with the use of angiotensin-converting enzyme inhibitors, alpha-adrenergic blockers, and slow calcium channel blocking drugs. The effects of these agents alone and in combination and their potential relationship with coronary adverse events are reviewed. Although the clinical relevance of these alterations has yet to be fully determined, it is rational to suggest that given or current knowledge, the antihypertensive agent selected for use should be an effective, well-tolerated drug with a minimum of adverse biochemical or metabolic effects.

Role of intracellular calcium in priming of human peripheral blood monocytes by bacterial lipopolysaccharide

To determine the role of intracellular calcium ([Ca2+]i) in the priming of monocytes (M phi) by bacterial lipopolysaccharide (LPS), the membrane expression of two functional proteins and phagocytosis and respiratory burst were examined by microfluorimetry. LPS induced a significant increase in HLA-DR and C3bi receptor (CR3) expression within 2 h of its addition to whole blood. The enhanced expression of both antigens by LPS was dose-dependent, with concentrations as low as 0.1 ng/ml producing a response. The involvement of [Ca2+]i was demonstrated by loading isolated M phi with the intracellular calcium chelator quin-2 or the inhibitor of intracellular calcium redistribution TMB-8 prior to addition of LPS. Both compounds inhibited the LPS-induced increase in HLA-DR and CR3 expression. No role for extracellular calcium, for calcium slow channel flux, or for the calcium-calmodulin complex in LPS priming was demonstrated when LPS was added in the presence of EGTA, trifluperazine (TFP), or verapamil. The addition of the calcium ionophores A23187 or ionomycin failed to increase expression of either antigen. Prior exposure to LPS primed M phi for enhanced phagocytosis and respiratory burst activity. These functions were inhibited by TMB-8, but not by TFP or verapamil. Addition of LPS to isolated M phi increased [Ca2+]i by 23% at 30 sec and 42% at 5 min, as measured by the calcium-sensitive, intracellular probe indo-1. These results suggest that intracellular Ca2+ mobilization is necessary, but not sufficient, for LPS-induced priming of human peripheral blood monocytes.

Massive verapamil ingestion: A report of two cases and a review of the literature

This report describes two patients who were victims of massive verapamil ingestion and then reviews the available literature. Because verapamil blocks the slow calcium channels of the heart and blood vessels, the use of calcium as a treatment would be logical. In the two cases reported here, calcium was only transiently effective in maintaining cardiac output and blood pressure. Several other agents were then used and most were ineffective. This is similar to experience reported in the literature that suggests that no single agent is capable of reversing verapamil's negative inotropic, dromotropic, chronotropic, and vascular smooth muscle effects.

Voltage-dependent inactivation of slow calcium channels in intact twitch muscle fibers of the frog.

Inactivation of slow Ca2+ channels was studied in intact twitch skeletal muscle fibers of the frog by using the three-microelectrode voltage-clamp technique. Hypertonic sucrose solutions were used to abolish contraction. The rate constant of decay of the slow Ca2+ current (ICa) remained practically unchanged when the recording solution containing 10 mM Ca2+ was replaced by a Ca2+-buffered solution (126 mM Ca-maleate). The rate constant of decay of ICa monotonically increased with depolarization although the corresponding time integral of ICa followed a bell-shaped function. The replacement of Ca2+ by Ba2+ did not result in a slowing of the rate of decay of the inward current nor did it reduce the degree of steady-state inactivation. The voltage dependence of the steady-state inactivation curve was steeper in the presence of Ba2+. In two-pulse experiments with large conditioning depolarizations ICa inactivation remained unchanged although Ca2+ influx during the prepulse greatly decreased. Dantrolene (12 microM) increased mechanical threshold at all pulse durations tested, the effect being more prominent for short pulses. Dantrolene did not significantly modify ICa decay and the voltage dependence of inactivation. These results indicate that in intact muscle fibers Ca2+ channels inactivate in a voltage-dependent manner through a mechanism that does not require Ca2+ entry into the cell.

Double-blind crossover comparison of amlodipine at three dose levels and placebo in chronic stable angina

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Hemodynamic and adrenergic effects of combined [formula omitted] blockade versus combined β-receptor and slow channel calcium blockade in patients with ischemic heart disease

The effects of combined α β- adrenoceptor blockade and of β-receptor/slow channel calcium blockade on systemic and pulmonary hemodynamics and on adrenergic activity were compared in 2 matched groups of men suffering from ischemic heart disease. They were studied at rest supine and during ischemia-inducing exercise in the seated posture using invasive percutaneous techniques. Fourteen patients received 200 mg labetalol as a single oral dosis, 15 metoprolol (100 mg) plus nifedipine (10 mg). Both regimens reduced pressures in the systemic and pulmonary circulation under all conditions. At rest, stroke volume and cardiac output slightly decreased after labetalol and increased after metoprolol/nifedipine. During exercise the changes induced by the two regimens were virtually identical: heart rates and vascular resistances were reduced, stroke volume increased, cardiac output was not significantly changed. Plasma renin activity was lowered by labetalol, unchanged by metoprolol/nifedipine. Plasma adrenaline increased after metoprolol/nifedipine only, noradrenaline with both regimens. Both combinations significantly lowered stroke work and the rate pressure product and had similar beneficial effects on the onset and the duration of angina. It is concluded that both combinations attenuate or offset the potential adverse hemodynamic effects of β-receptor blockade alone without loss but rather enhancement of symptomatic efficacy.