Negative Inotropic Effect Of Verapamil Research Articles

The role of sarcoplasmic reticulum and sarcolemma in the regulation of cardiac contractility at different times and higher extracellur potassium in the cardiac muscle of catfish and toad.

The relative contribution of sarcoplasmic reticulum (SR) and sarcolemma in the regulation of cardiac contractility (twitch force, the rate of contraction and the rate of relaxation) at different time periods (10, 20 and 30 minuted) and at elevated extracellular potassium (5.omM) was assessed in the ventricular tissues of catfish and toad using adrenaline as an activator of SRCa2+ uptake, caffeine as an inhibitor of SRCa2+ uptake and verapamil as an inhibitor of sarcolemmal Ca2+ exchange. Cardiac contractility (twitch force, rate of contraction and the rate of relaxation – df/dt) tended to decrease with increasing of the time periods from 10 to 20 and 30 minutes in the catfish and toad ventricular tissues at 2.5 and 5.omMK+, Elevated extracellular K+ had a positive inotropic effect on the twitch force developed at 20 and 30 minutes in the catfish cardiac muscle, but it had non significant negative effect in the toad cardiac muscle at the same periods. The df/dt developed after 30 minutes was significantly lower in the presence of 5.omMK+ than that developed at 2.5mMK+ in the catfish cardiac muscle, whereas the effect of elevated K+ on df/dt was similar to that of 2.5mMKO at all the time periods applied in the toad cardiac muscle. Elevated K+ had a negative inotropic effect on the-df/dt developed at all time periods applied in the catfish cardiac muscle, but it had no effect on the-df/dt developed in the toad cardiac muscle at the same time periods. Adrenaline, like caffeine had a positive inotropic effect on the twitch force, df/dt and – df/dt developed after all the time periods applied at 2.5 and 5.omMK+ in the ventricular tissues of both animals, relative to that of control. But, the positive inotropic effect of caffeine on the cardiac contractility was significantly lower than that of adrenaline at 2.5 and 5.omMK+ O and at the different time periods applied (specially after 30 minutes) for both animals. Verapamil had a significantly negative inotropic effect on the cardiac contractility developed after all time periods applied at 2.5 and 5.omMK+ in both animals, relative to that of control. However the negative inotropic effect of verapamil on the cardiac contractility was significantly higher at elevated K+ than at 2.5mMK+. The twitch force developed after all time periods applied in the toad cardiac muscle was significantly lower than that in the catfish cardiac muscle after the same periods in either 2.5 or 5.omMK+. In the presence of adrenaline, the twitch force developed in the toad cardiac muscle after each period applied was non-significantly higher than that developed in the catfish cardiac muscle at 2.5 and 5.omMK,+ whereas it was significantly higher than that of catfish cardiac muscle in the presence of caffeine at 2.5 and 5.omMK+ after the same time periods. In the presence of verapamil, the twitch force developed after each time periods in the toad cardiac muscle was significantly and non- significantly higher than that of catfish cardiac muscle at 2.5 and 5.omMK+ respectively. The df/dt developed after each period applied in the catfish cardiac muscle was to somewhat similar to that developed in the toad cardiac muscle at 2.5 and 5.omMK+, but in the presence of adrenaline, it was significantly lower than that of toad cardiac muscle at 2.5 and 5.omMK+, whereas in the presence of caffeine, it was non-signifantly higher than that of toad cardiac muscle. In the presence of verapamil, the df/dt developed in the catfish cardiac muscle after the time period applied was significantly lower than that of toad cardiac muscle at 2.5 and 5.omMK+, also. The - df/dt developed in the catfish cardiac muscle after the time periods applied was similar to that of toad cardiac muscle at 2.5mMK+, but it was non-significantly lower than that of toad cardiac muscle at 5.omMK+. In the presence of adrenaline, the - df/dt developed after the time periods applied in the catfish cardiac muscle was significantly lower than that of the toad cardiac muscle at 2.5 and 5.omMK+, whereas the opposite situation was recorded in the presence of caffeine. In the presence of verapamil at 2.5mMK+, the-df/dt developed after the time periods applied in the catfish cardiac muscle was signifantly lower than that of the toad cardiac muscle, whereas it was similar in the cardiac muscle of both animals at 5.omMK+. So, it can be concluded that the cardiac contractility in the catfish and toad ventricular tissues is time dependent. Also, it seems that the sarcolemmal Ca2+ exchanges partake in the regulation of cardiac contractility in the ventricular tissue of both animal But, the contribution of sarcoplasmic reticulum in the regulation of cardiac force was higher in the toad cardiac muscle than that of catfish cardiac muscle. Elevated extracellular K+ had a positive inotropic effect on the cardiac contractility in both animals.

Modeling Cardiac Uptake and Negative Inotropic Response of Verapamil in Rat Heart: Effect of Amiodarone

To determine the effect of the P-glycoprotein (Pgp) modulator amiodarone on the pharmacokinetics and pharmacodynamics (PK/PD) of Pgp substrate verapamil in the perfused rat heart. In Langendorff-perfused rat hearts, the outflow concentration-time curve and inotropic response data were measured after a 1.5 nmol dose of [3H]-verapamil (infused within 1 min) in the absence and presence of the amiodarone (1 microM) in perfusate, as well as using a double dosing regimen (0.75 nmol in a 10 min interval). These data were analyzed by a PK/PD model. Amiodarone failed to influence the rapid uptake and equilibrium partitioning of verapamil into the heart. The time course of the negative inotropic effect of verapamil, including the 'rebound' above the original baseline after the infusion of verapamil was stopped, could be described by a PK/PD tolerance model. Tolerance development (mean delay time, 12 min) led to a reduction in predicted steady-state effect (16%). The EC50 and Emax values as estimated in single dose experiments were 16.4+/-4.1 nM and 50.5+/-18.9 mmHg, respectively. The result does not support the hypothesis that Pgp inhibition by amiodarone increases cardiac uptake of the Pgp substrate verapamil.

Effects of calcium chloride on verapamil- and diltiazem-pretreated isolated rat hearts

The effects of calcium chloride on cardiac responses to verapamil and diltiazem were investigated using isolated and perfused rat hearts with a Langendorff technique. Ionized calcium concentrations were increased approximately from 0.5 mM to 2.2 mM when the hearts were pretreated with 0.2 mg/L of verapamil or 0.28 mg/L of diltiazem, or were untreated with calcium blockers. Calcium significantly counteracted the negative inotropic effect produced by diltiazem and verapamil. In contrast, the negative chronotropic effects of both diltiazem and verapamil were potentiated by increasing concentrations of ionized calcium, and this potentiation was not eliminated by 1.0 mg/L of atropine. An atrioventricular block was induced by both verapamil and diltiazem when ionized calcium concentrations were lower than normal. It is suggested from this study that, although calcium chloride counteracts the negative inotropic effects of verapamil and diltiazem, abruptly increased ionized calcium may cause severe bradycardia clinically.

Thyroid control of contractile function and calcium handling in neonatal rat heart.

Newborn rats were rendered hyperthyroid (daily subcutaneous injections of L-triiodothyronine, 10 micrograms 100 g-1 body weight) or hypothyroid (0.05% 6-n-propyl-2-thiouracil in drinking water to nursing mothers) during the first 3 weeks of postnatal life. Compared with the euthyroid group, hyperthyroidism resulted in: (1) cardiac enlargement with right ventricular preponderance, (2) increased cardiac contractile function, (3) increased Ca2+ uptake by the sarcoplasmic reticulum (SR), (4) decreased sensitivity to the negative inotropic effect of verapamil and (5) greater inhibition of contractile function by ryanodine. Hypothyroidism generally resulted in opposite changes. The data suggest that the development of the heart and its contractile function during early postnatal life depends on the plasma level of thyroid hormones. In particular, the relative contribution of the SR and sarcolemmal Ca2+ transport to the control of cardiac contractility seems to be markedly affected by altered thyroid states. The postnatal maturation of the SR function is accelerated in hyperthyroidism but retarded in hypothyroidism. Consequently, hyperthyroid hearts appear to be less dependent and hypothyroid ones more dependent on trans-sarcolemmal Ca2+ fluxes when compared with age-matched euthyroid animals.

Combined negative inotropic effects of calcium entry blockers and isoflurane on canine isolated heart muscles.

The combined negative inotropic effects of isoflurane and calcium entry blockers (verapamil, diltiazem, nifedipine, nicardipine) were studied utilizing isolated heart preparations of ventricular muscles from dogs. All of these calcium entry blockers exerted dose-dependent decreases in maximal velocity of shortening (Vmax), maximal developed isometric force (Fm), and the maximal first derivative of Fm (maximal dF/dt). Dose-dependent decreases of these variables of muscle mechanics were augmented in isoflurane-depressed myocardium. At equimolar concentrations, direct myocardial depression was demonstrated in the following order of severity: nifedipine > diltiazem = verapamil > nicardipine. Percent depressions of Vmax, Fm and maximal dF/dt were significantly greater in muscles when calcium entry blockers were combined with 1MAC isoflurane than in muscles of calcium entry blockers alone. These data suggest that the negative inotropic effects of verapamil, diltiazem, nifedipine, and nicardipine were potentiated by isoflurane.

The structurally novel Ca2+ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts

Ro 40-5967 is a structurally novel Ca2+ channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction. In isolated Langendorff hearts (without heart failure), no decrease of contractility was observed with Ro 40-5967 up to complete AV block. In contrast, verapamil decreased contractility with an IC50 of 100 nM. In isolated, electrically stimulated rat papillary muscles, the IC50 values for the decrease of contractile force were 15,000 and 440 nM for Ro 40-5967 and verapamil, respectively. In vivo, Ro 40-5967 did not decrease left ventricular contractility (as assessed by changes of dP/dt max +) in rats without and with heart failure. In contrast, verapamil was markedly negative inotropic in both conditions.

Hypertensive-diabetic cardiomyopathy in rats

Left ventricular papillary muscle function, transmembrane action potentials, myosin adenosinetriphosphatase (ATPase) and isoenzyme distribution, and myocardial pathology were studied in hypertensive (H), diabetic (D), hypertensive-diabetic (HD), and control (C) rats. There was approximately 50% relative left ventricular hypertrophy in H and HD rats. Relative lung and liver weights were greater in HD rats. Peak velocity of shortening tended to decrease progressively in H, D, and HD rats. The duration of contraction and relaxation was markedly prolonged in Ds and HDs. The length-developed tension relation was blunted in HDs. The negative inotropic effect of verapamil was similar in all groups. Resting membrane potential and amplitude were decreased in D and HD rats. Action potential duration was increased in H, D, and especially HD rats. The shortening of action potential duration with increased stimulus frequency was greater in H, D, and especially HD rats than in Cs. Left ventricular myosin ATPase and V1 isoenzyme content decreased progressively in H, D, and HD rats. Right ventricular V1 isoenzyme content was not affected in H rats but was markedly decreased in D and HD rats. Left (and right) ventricular pathology was unchanged in rats with diabetes but was increased in rats with hypertension. These data suggest that the combination of myocardial pathology (due to hypertension) and cellular dysfunction (caused mainly by diabetes) may result in cardiomyopathy and congestive heart failure in the HD rat.

残存β‐ブロッカーが上室性不整脈治療剤ベラパミールの心筋抑制作用に及ぼす影響

残存β‐ブロッカーが上室性不整脈治療剤ベラパミールの心筋抑制作用に及ぼす影響

Role of extracellular calcium on heart muscle energetics: effects of verapamil

The mechanical and energetic effects of verapamil (VER) and reduction of extracellular Ca concentration ([Ca]o) were studied in the interventricular rabbit septa and the dog papillary muscle. Even though the negative inotropic effects of VER [i.e., decrease in developed tension (T), maximal rates of contraction (+T) and relaxation (-T), and tension time integral] qualitatively resemble [Ca]o reduction, VER also elicited an anti-relaxant effect (decrease in -T/T and prolongation of the last phase of relaxation) that was not found with [Ca]o reduction. Resting heat production was similar in both preparations and remained unaffected either by changes in [Ca]o or by the presence of VER. The ratio between T and active heat production per beat (H'a) under constant fiber length decreased with VER, and this decreased economy of contraction was more marked with the increase in contraction frequency. Conversely, the T/H'a remained unaltered with changes in [Ca]o. Tension-independent heat decreased in the presence of VER and, although muscle economy can be improved by increasing muscle length in a VER-treated muscle, it is not possible to achieve either the maximal T or the maximal contraction economy that can be obtained by stretching a nontreated muscle. It may be concluded that at constant fiber length and frequency of contraction VER decreases myocardial contractile force, impairs relaxation, and decreases contraction economy. Neither the mechanical nor the energetic effects of VER can be explained solely on the basis of a reduced extracellular Ca availability, so that either the density of the Ca that enters through the channel is different from that of other sources of Ca or VER has an effect on the cross-bridge cycling mechanism.

Effects of hypoxia, elevated K+ and acidosis on the potency of verapamil, diltiazem and nifedipine in the guinea-pig isolated papillary muscle.

1 The effects of the structurally diverse calcium channel blockers verapamil, nifedipine and diltiazem were investigated on the force of contraction of guinea-pig, electrically stimulated papillary muscles in vitro. 2 Calcium channel blocking potency was assessed either as a direct negative inotropic effect or as the ability of the drugs to antagonise the positive inotropic effects of added calcium (Ca2+). By either method, the rank order of potency was found to be nifedipine greater than verapamil greater than diltiazem. 3 Various factors which mimic some of the consequences of acute ischaemia in vivo, namely low pH, hypoxia and elevated K+, in combination, but not singly, enhanced the negative inotropic potency of verapamil and to lesser extent that of diltiazem, but not that of nifedipine. 4 Whilst the various interventions, especially in combination, produced a profound negative inotropic effect themselves, this was not responsible per se for the potentiation of the negative inotropic effects of verapamil and diltiazem, since the negative inotropic effects of nifedipine and dinitrophenol were not potentiated under the 'ischaemic' conditions. 5 By use of antagonism of the positive inotropic action of exogenous Ca2+ as an alternative measure of potency, the differential influence of 'ischaemia' on calcium channel blocker potency was confirmed. The effect of verapamil was potentiated some 9 fold, that of diltiazem about 2 fold, and that of nifedipine was unchanged. 6 The differential effect of 'ischaemia' on the potencies of the calcium channel blockers was unexpected. Verapamil (but not nifedipine) is thought to bind to the calcium channel at a specific site not easily accessible from the extracellular space. 'Ischaemic' conditions may cause membranal perturbations which allow verapamil easier access to its binding site thus increasing its negative inotropic potency.

Prolonged protective effect of the calcium antagonist anipamil on the ischemic reperfused rabbit myocardium: Comparison with verapamil

To assess whether pretreatment with the calcium antagonist anipamil protects the heart against ischemic and reperfusion damage and to establish how long the protection persists after cessation of the therapy, rabbits were injected subcutaneously twice daily for 5 days with 2 mg/kg body weight of this drug. The heart was then isolated 2, 6, or 12 hours after the last injection and was perfused by the Langendorff technique during a control period and 90 minutes of total ischemia (37 degrees C), followed by 30 minutes of reperfusion. Diastolic and developed pressure was monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK); mitochondria were harvested and assayed for respiratory activity, ATP production, and calcium content; and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate were determined. The data obtained with anipamil were compared with those obtained with verapamil administered to the rabbit at the same dose and following the same procedure. Pretreatment with anipamil induced a negative inotropic effect under normoxic conditions; reduced the rate and extent of depletion of ATP and creatine phosphate during ischemia, with an incomplete restoration of the nucleotides after reperfusion; maintained mitochondrial function and calcium homeostasis during ischemia and reperfusion; reduced the rate of CPK release; and improved the recovery of ventricular function on reperfusion. The protective effects of anipamil persisted for as long as 12 hours after the last administration. In contrast, the protective and negative inotropic effects of verapamil were no longer apparent in heart isolated 6 or 12 hours after the last dose of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Ontogenetic changes of the negative inotropic effect of verapamil in the isolated rat heart

Ontogenetic changes of the negative inotropic effect of verapamil in the isolated rat heart

Effects of verapamil on haemodynamic function and myocardial metabolism in patients with hypertrophic cardiomyopathy.

The effect of 20 mg dose of intravenous verapamil was studied over a range of heart rates in 12 patients with hypertrophic cardiomyopathy. Six patients had an appreciable left ventricular outflow tract gradient and six did not. The drug reduced myocardial oxygen consumption in proportion to a reduction in the development of left ventricular pressure. The negative inotropic effect of verapamil was counteracted by the drug's non-specific vasodilator activity, so that cardiac index was unaltered at any heart rate and as a result myocardial efficiency was unaffected by the drug. Verapamil did not consistently alter myocardial metabolism. Some patients showed improvement in anaerobic myocardial metabolism after verapamil but an equal number showed impairment of lactate metabolism. It was not possible to predict from clinical features, echocardiographic findings, or haemodynamic variables measured before administration of verapamil which patients would demonstrate haemodynamic or metabolic improvement after the drug. In this short term study no mechanism was demonstrated by which patients with hypertrophic cardiomyopathy might obtain a consistent improvement from treatment with verapamil.

Ionization and Surface Properties of Verapamil and Several Verapamil Analogues

We have investigated the ionization and surface properties of verapamil (5-[(3, 4-dimethoxyphenethyl)methylamino]-2-(3, 4-dimethoxyphenyl)-2-isopropylvaleronitrile, 1) and several verapamil analogues since these properties appear to be involved in the biologic activities of these compounds. Our results show that verapamil and its analogues are surface-active and bind to amphiphilic surfaces. The affinity toward, as well as the capacity of, an amphiphilic surface for verapamil and its ionizable analogues is pH dependent, with the surface having both higher affinity and capacity for the neutral form of the molecules. Thus, verapamil exists as protonated and neutral forms, both of which are free in solution and adsorbed to the interface, and the ionization of verapamil at an interface changes with respect to its ionization in solution. From analyses of the pH dependency of surface binding and of solution and interfacial ionizations, we determined the values of the four equilibrium constants. These equilibrium constants permit correlative studies between the pH-dependent abundance of each species and biologic activity. We discuss preliminary studies which indicate that the negative inotropic effect of verapamil is mediated by the membrane-bound neutral form of the drug.

Inotropic effects of Ca2+ channel agonist and antagonists in neuraminidase‐treated left atria of rats

The effects of removal of sialic acid from cardiac sarcolemma on contractile functions and on inotropic responses to Ca2+ channel agonist and antagonists were investigated in rat left atria. About 64% of the total sialic acid content of the left atria was removed during a 90 min exposure to neuraminidase (2 u ml-1). The removal of sialic acid neither affected the development of twitch tension induced by stimulation at a frequency of 0.5 Hz, nor altered the interval-dependent changes in contractility such as the force-frequency relationship and post rest contractions. The positive inotropic effects produced by isoprenaline, and by an increase in extracellular Ca2+ concentration were the same in the neuraminidase-treated preparations as those in the untreated preparations. Bay K 8644, a Ca2+ channel agonist, induced an increase in contractility in the neuraminidase-treated preparations comparable to that in the untreated ones. Neuraminidase treatment significantly attenuated the negative inotropic effects of verapamil and diltiazem, whereas it had no effect on that of nifedipine. The results indicate that sialic acid removal modifies neither the basal contractile functions nor the positive inotropism which is associated with an enhancement of the slow inward Ca2+ current. However, sialic acid, which constitutes the glycocalyx of the cardiac sarcolemma, may be involved in the mechanism of the Ca2+ channel antagonistic actions of verapamil and diltiazem, but not that of nifedipine. Thus, our results provide pharmacological evidence that verapamil and diltiazem behave differently from the dihydropyridine compounds.

Interaction of calcium antagonists with beta-adrenoceptor blocking agents.

Responsiveness to verapamil, the best studied calcium antagonist, was examined in cardiac preparations of rabbits pretreated with beta-adrenoceptor blockers (propranolol 2 mg/kg or oxprenolol 4 mg/kg s.c.) twice daily for either one or six weeks. Using this dose-regimen, the degree of cardiac beta-adrenoceptor blockade in conscious rabbits was substantial and similar for propranolol and oxprenolol. When administered for one week, neither propranolol nor oxprenolol affected to any marked extent the electrical and mechanical response to verapamil, diltiazem or fendiline in tissues isolated from various parts of the heart. In contrast, pretreatment with propranolol for six weeks resulted in a significant aggravation of the negative inotropic effect of verapamil in both atrial and ventricular muscle, and the verapamil-induced delay in atrio-ventricular and intra-ventricular conduction also became more pronounced. The same long-term administration of oxprenolol, one of the beta-blockers with "intrinsic" sympathomimetic activity, did not alter the atrial or ventricular contractile response to verapamil and did not significantly increase the lengthening of atrio-ventricular conduction time occurring in the presence of verapamil. It is concluded that from the point of view of adverse direct cardiac interactions with verapamil prolonged administration of oxprenolol appears to be less dangerous than chronic treatment with propranolol. It is also assumed that in those cases in which acute administration of verapamil may be necessary, concomitant chronic blockade of cardiac beta-adrenoceptors is less dangerous if drugs known to possess not only beta-adrenoceptor blocking properties, but also some "intrinsic" sympathomimetic activity are applied.

The link between myocardial contraction and relaxation: The effects of calcium antagonists

In isolated rat hearts perfused at constant coronary flow and heart rate the amount of shortening in their major axis (L), the developed tension (T) and their time derivatives (L and T) were measured after different interventions. Relative changes of maximal velocities of contraction (+L, +T) and relaxation (-L, -T) were assessed by the ratio between both velocities (+L/-L, +T/-T). After the interventions, cAMP intracellular levels and cAMP dependent protein kinase activity were measured. The negative inotropic effect of verapamil (10(-7) M) and nifedipine (5 X 10(-7) M) was accompanied by a relatively greater decrease in maximal velocity of relaxation. Consequently the ratio +L/-L increased. Verapamil increased +L/-L from 1.27 +/- 0.07 to 1.57 +/- 0.08 (P less than 0.001). Nifedipine increased +L/-L from 1.25 +/- 0.05 to 1.77 +/- 0.12 (P less than 0.001). Whereas nifedipine increased intracellular cAMP levels from 0.403 +/- 0.036 pmol/mg wet weight to 0.534 +/- 0.047 (P less than 0.05), verapamil did not alter them. Neither verapamil nor nifedipine affected cAMP protein kinase activity. Increasing Ca2+ in the perfusate did not change the ratio +L/-L. A decrease in extracellular Ca2+, on the other hand, produced a greater decrease in -L than in +L, so that the ratio +L/-L increased from 1.27 +/- 0.05 to 1.49 +/- 0.10 (P less than 0.05). No changes were detected in cAMP levels or its protein kinase activity. Similar results were obtained when +T/-T was analyzed. To offset the negative inotropic effect caused by calcium antagonists, either increased extracellular Ca2+ or isoproterenol can be used.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.

Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_

Comparative effects of calcium-channel blocking agents on left ventricular function during acute ischemia in dogs with and without congestive heart failure

To examine the relative potencies of verapamil, nifedipine and diltiazem on left ventricular (LV) function under ischemic conditions, 20 conscious closed-chest dogs that had partial occlusion of their circumflex coronary arteries were studied. Myocardial blood flow was measured by microspheres, LV function by radionuclide angiography. Drug effects were compared at doses causing equal decreases in mean arterial pressure (MAP) and in coronary vascular resistance of the nonischemic zone. Global ejection fraction (EF) and EF of the ischemic region were significantly decreased by verapamil (p < 0.002) and increased by nifedipine (p < 0.001); diltiazem caused no significant changes. Verapamil significantly increased peak diastolic filling rate (p < 0.001); nifedipine also increased diastolic filling rate but only at doses that markedly decreased MAP and coronary vascular resistance. Diltiazem was not significantly different from placebo. For doses causing an equal decrease in MAP, verapamil decreased heart rate (p < 0.001), and diltiazem and nifedipine increased heart rate (p < 0.05). Myocardial ischemic zone flow remained unchanged during placebo, verapamil, diltiazem or nifedipine infusion. To study the influence of heart failure on the hemodynamic effects of the calcium-channel blocking agents, 6 foxhounds underwent total occlusions of the left anterior descending coronary artery, resulting in myocardial infarction, volume loading to increase left atrial pressure and partial occlusion of the circumflex coronary artery. Verapamil depressed global left ventricular ejection fraction and increased left atrial pressure to as high as 40 to 45 mm Hg. In contrast, nifedipine decreased left atrial pressure and increased global EF. To evaluate whether the negative inotropic effect of verapamil or the positive inotropic effect of nifedipine was beneficial or detrimental to ischemic tissue, intramyocardial pH in dogs that had regional myocardial acidosis after acute coronary occlusion was studied. Pretreatment with verapamil decreased the degree of acidosis of ischemic myocardium as it depressed LV function, whereas nifedipine caused no change in the degree of acidosis as it increased LV function. These findings suggest that the negative inotropic effects of verapamil can protect ischemic myocardium.

Accentuated negative inotropism of verapamil after ischaemic intervention in isolated working rat heart.

We examined the effects of a clinically relevant concentration (2 X 10(-7) mol . litre-1) of verapamil on the cardiac functions of isolated working rat hearts during global ischaemia (15 min) and reperfusion (30 min). The aorta and the left atrium of each heart of male Sprague-Dawley rats were cannulated for perfusion with Krebs-Henseleit solution, and a soft elastic catheter was introduced into the left ventricle through the left atrial cannula. Verapamil slightly increased the left ventricular end-diastolic pressure, and slightly decreased the left ventricular dP/dt, but did not reduce the left ventricular peak systolic pressure before ischaemia. During the early phase of ischaemia and reperfusion, verapamil (n = 6) lowered the left ventricular peak systolic pressure and the left ventricular dP/dt in comparison with the controls (n = 6) (left ventricular peak systolic pressure 45.4 +/- 16.9 versus 60.9 +/- 15.2 mmHg: p less than 0.05; left ventricular dP/dt 1256 +/- 484 versus 2108 +/- 829 mmHg . s-1: p less than 0.05, after 30 min of reperfusion). Fifteen min of ischaemia resulted in no increase in the creatine kinase release during reperfusion. The creatine kinase release was not different in the two groups during the experiment. Thus, the negative inotropic effect of verapamil was accentuated by the ischaemic intervention. Myocardial protection may be achieved by reducing the left ventricular peak systolic pressure and thereby the oxygen consumption. On the other hand, in clinical application to patients with extensive myocardial ischaemia, verapamil may cause untoward deterioration in cardiac functions.