The potencies and selectivities of four calcium antagonists as inhibitors of uterine contractions in the rat in vivo.

The potencies of four calcium antagonists (nifedipine, gallopamil, verapamil and diltiazem) at inhibiting uterine contractions in vivo have been assessed in the conscious ovariectomized, post-partum rat. Their selectivities for this action, relative to their effects on blood pressure and heart rate, have been compared with salbutamol. All compounds produced a dose-dependent inhibition of intra-uterine pressure cycles. The rank order of potency was salbutamol greater than nifedipine greater than diltiazem = gallopamil greater than verapamil. All compounds produced a dose-dependent fall of mean blood pressure. The rank order of potency was salbutamol greater than nifedipine greater than gallopamil greater than verapamil greater than diltiazem. Salbutamol and nifedipine produced a tachycardia, which was very marked with salbutamol. Gallopamil, verapamil and diltiazem induced a moderate tachycardia at low doses but temporary cessation of heart beat occurred at high doses. Nifedipine and diltiazem, like salbutamol, exhibited some selectivity for inhibition of uterine contractions relative to their cardiovascular actions. Gallopamil and verapamil showed no selectivity for the uterus.     

Effect of calcium-channel blockers on human thrombocyte aggregation induced by alpha-adrenoreceptor agonists

A comparative study of the effects of calcium channel blockers nifedipine and verapamil on platelet aggregation in healthy donors induced by adrenaline. A partial agonist of alpha 2-adrenoreceptors clofelin and also clofelin in combination with the threshold concentrations of ADP inducing aggregation was performed. It was found that verapamil is a more potent inhibitor of platelet aggregation induced by adrenaline as compared with nifedipine inhibiting this process only at high concentrations. The aggregation-inducing effect of a partial agonist of alpha 2-adrenoreceptors clofelin is eliminated at low concentrations in the aggregating mixture of nifedipine than verapamil.     

The effect of verapamil and nifedipine on cholesterol esterification and accumulation in macrophages]

Administration of verapamil and nifedipine in doses of 10-75 microM into the culture of mouse peritoneal macrophages incubated in a non-lipid medium with acetylated low density lipoproteins (50 g protein/ml) decreased the incorporation of 14C oleate into cholesterol esters by 50-90%, increased the content of intracellular free cholesterol by 19-79% and did not influence the content of total cholesterol in macrophages. Administration of verapamil and nifedipine in doses of 25 and 50 microM in the culture of macrophages previously enriched with cholesterol reduced the rate of cholesterol esterification by 22-62%. After combined administration of verapamil and nifedipine in doses of 25 microM into the medium the rate of cholesterol esterification in macrophages fell by 72.4%.     

Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine.

1. It was investigated whether the calcium antagonistic coronary drugs verapamil and nifedipine have similar antiarrhythmic properties. Their effects on functional refractory period and contractile force in the isolated left guinea pig atrium were compared. To assess their influence on myocardial excitability the relation between threshold voltage and pulse duration was studied in the left guinea pig atrium. Furthermore, the influence on AV conduction was investigated in the conscous dog in haemodynamically equieffective dose ranges. 2. Verapamil as well as nifedipine cause a dose-dependent prolongation of the functional refractory period in the isolated left guinea pig atrium. The slope of the dose-response curve of nifedipine is, however, significantly less steep than that of verapamil. Maximum prolongation of refractory period which can be induced by nifedipine is significantly inferior to that occurring after verapamil; under nifedipine this prolongation is, however, accompanied by a significantly greater reduction in contractility. 3. In the isolated left guinea pig atrium the voltage-duration curve is shifted to the right and the chronaxia value is significantly increased by verapamil. Even in the highest dose possible nifedipine has no effect on atrial excitability. 4. In the conscious dog verapamil considerably prolongs AV conduction time whereas a moderate yet dose-dependent shortening of PQ duration is observed with equieffective nifedipine doses regarding the decrease in blood pressure and increase in heart rate. 5. The results indicate that nifedipine does not exert antiarrhythmic effects comparable to those of verapamil.     

Effects of nifedipine, verapamil and diltiazem on renal function.

Eight healthy female volunteers were given single doses of nifedipine 10 mg, verapamil 80 mg, diltiazem 120 mg or placebo on 4 different study days. Urine and sodium output increased after all four drugs, but the increase after nifedipine was significantly greater than after verapamil or placebo. Nifedipine caused a significant increase in heart rate; none of the drugs caused any change in blood pressure. Potassium excretion, creatinine clearance, free water clearance and plasma renin activity did not change with any drug. The mechanism of the natriuresis and diuresis has still to be elucidated.     

Inhibitory effects of calcium channel blockers on intestinal motility in the dog

Calcium channel blockers are now widely used for the treatment of cardiovascular disorders. However, data concerning their effects on intestinal motility in vivo are still rather fragmentary. Therefore, we evaluated the effects of three prototype calcium channel blockers (nifedipine, verapamil and diltiazem) on intestinal motility in five fasting, conscious dogs fitted with electrodes and strain-gauges along the small bowel. The myoelectric data were analyzed by a recently developed and validated computer program which allows accurate monitoring of intestinal spike activity. The mechanical data were analyzed by calculating a motility index. After recording of at least two migrating motor complexes (control), an i.v. infusion of one of the following calcium channel blockers was maintained for 3 h: 0.29 or 0.87 mumol/kg per h nifedipine, 1.02 or 2.04 mumol/kg per h verapamil and 1.11 or 2.22 mumol/kg per h diltiazem. Nifedipine 0.29 mumol/kg per h significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. The higher dose suppressed migrating motor complex cycling and almost completely abolished both spike and mechanical activities. The two doses of verapamil had effects similar to those of the two doses of nifedipine. Both doses of diltiazem significantly reduced (P less than 0.05) spike activity and motility index during phases II and III without disrupting migrating motor complex cycling. We conclude that all the agents tested, apart from their well known cardiovascular effects, also have a profound inhibitory effect on intestinal motility in vivo, the order of potency being nifedipine greater than verapamil greater than diltiazem. The search for more selective calcium channel blockers for the treatment of intestinal motor disorders with minimal cardiovascular effects is warranted.     

Antibronchoconstrictor activity of the intracellular calcium antagonist HA 1004 in guinea pigs

HA 1004 is a calcium antagonist vasodilator that inhibits contraction in vascular smooth muscle and lowers arterial blood pressure. The effects of HA 1004 on guinea pig airway smooth muscle contraction were compared to the effects of the calcium antagonists, verapamil and nifedipine and the bronchodilator, albuterol. In vitro, HA 1004, verapamil, nifedipine and albuterol inhibited Ca2+-induced contractions of the depolarized guinea pig trachea. HA 1004 and albuterol also relaxed the basal tracheal tone, whereas verapamil and nifedipine were inactive. The bronchorelaxant activity of HA 1004 was not blocked by propranolol. In vivo, intravenous administration of HA 1004, verapamil, nifedipine and albuterol effectively blocked bronchoconstriction induced by intravenous histamine and methacholine. HA 1004 also reversed a histamine-induced bronchospasm, as did albuterol, verapamil and nifedipine. Intratracheal administration of HA 1004 and albuterol inhibited histamine-induced bronchoconstriction without effecting blood pressure, whereas intratracheal administration of verapamil and nifedipine caused a significant reduction of blood pressure at their pulmonary active doses. These results show that HA 1004 has the ability to relax airway smooth muscle, inhibit contractile responses in the guinea pig airways, and there is separation of its cardiovascular and pulmonary effects when HA 1004 is administered directly to the lungs. The results are discussed in terms of the regulatory enzymes and sources of calcium that are involved in airway smooth muscle contraction.     

Selective inhibitory effects of nifedipine and verapamil on oxidative metabolism: effects on theophylline.

Nine healthy male volunteers were studied to assess the possibility of an interaction between theophylline and nifedipine or verapamil using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly with and without nifedipine 20 mg 12 hourly and verapamil 80 mg 8 hourly. Nifedipine treatment reduced mean total theophylline clearance by 9%, due to decreased clearances via 1- and 3-demethylation. Verapamil treatment reduced mean total theophylline clearance by 14%, due to decreased clearances via 1- and 3-demethylation and 8-hydroxylation. Verapamil and nifedipine at usual clinical doses are unlikely to cause clinically significant changes in theophylline disposition.     

Organic and inorganic calcium antagonists reduce vasoconstriction in vivo mediated by postsynaptic α 2-Adrenoceptors

The influence of various calcium antagonists and divalent metal cations on the pressor responses induced by the selective alpha 1-adrenoceptor agonist methoxamine and the selective alpha 2-adrenoceptor stimulating agent B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) was studied in pithed rats. 1. The calcium antagonists verapamil, D 600 and nifedipine, when given intraarterially (i.a.) in doses up to 1 mg/kg did not influence the pressor effects of methoxamine. Only higher amounts of these calcium antagonistic drugs (1 - 3 mg/kg i.a.) somewhat reduced this pressor response. 2. The vasoconstriction due to B-HT 920, as reflected by the increase in diastolic pressure, was markedly inhibited by verapamil, D 600 and nifedipine in a dose-dependent manner. In low doses a parallel displacement to the right was observed, whereas in higher amounts the shift was non-parallel. 3. The divalent cations MN2+, Ni2+ and Co2+ (0.05 - 0.15 mmol/kg i.a.) hardly affected the pressor effect of methoxamine, whereas B-HT 920-induced vasoconstriction was highly sensitive to these metal ions. La3+ and Mg2+ were ineffective. 4. The calcium antagonists verapamil, D 600 and nifedipine displayed only minor affinities for [3H]prazosin (alpha 1) as well as [3H]clonidine (alpha 2) binding sites of rat brain membranes. 5. It is concluded that an influx of extracellular Ca2+ is necessary for the vasoconstriction in vivo initiated by stimulation of vascular postsynaptic alpha 2-adrenoceptors. On the other hand, vasopressor responses to alpha 1-adrenoceptor stimulation are not directly dependent on a transmembrane influx of calcium ions.     

Direct effects of diltiazem, nifedipine and verapamil on peripheral sympathetic nerve function, cardiac impulse conduction and cardiovascular function in anesthetized dogs subjected to ganglionic blockade

The Ca2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P less than 0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct beta-adrenoceptor stimulation by isoproterenol (0.1 microgram/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25-35 V, 5 ms), but not high frequency (10 Hz, 25-35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical use of Ca2+ blockers as compared to other direct-acting vasodilators.     

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.     

Effects of verapamil and nifedipine on mechanisms of arrhythmia in an in vitro model of ischemia and reperfusion.

The effects of verapamil and nifedipine on cellular mechanisms of arrhythmia were examined in isolated canine Purkinje fiber-papillary muscles. Microelectrode recordings were made simultaneously from both tissues. Preparations were superfused with Tyrode's solution modified to mimic specific conditions of ischemia for 40 min with or without calcium channel blockers. Verapamil or nifedipine resulted in significantly greater depolarization of Purkinje tissue in response to ischemic conditions and increased the incidence of inexcitability or conduction block in Purkinje and muscle tissues. These calcium channel blockers caused only minor changes in ischemia-induced depolarization of muscle. In Purkinje tissue, return to nonischemic conditions in the absence of drugs caused, in sequence, oscillatory afterpotentials, temporary depolarization to inexcitability, and a phase of automaticity at low membrane potential. These events did not occur in muscle. Verapamil or nifedipine abolished oscillatory afterpotentials and low membrane potential automaticity in Purkinje tissue. However, reperfusion-induced depolarization and inexcitability of Purkinje tissue was delayed but not attenuated. This study demonstrates that verapamil or nifedipine exacerbate depolarization and depression of conduction in Purkinje tissue exposed to ischemic conditions. However, verapamil and nifedipine suppress some but not all potential mechanisms of arrhythmia induced by reperfusion.     

Cardiovascular responses to verapamil and nifedipine in hypoventilated and hyperventilated rats.

1. The influence of hypoventilation or hyperventilation on blood pressure and pulse rate responses to verapamil and nifedipine was studied in chloralose-anaesthetized rats. 2. Artificial ventilation with room air at a fixed volume of 10 ml kg-1 successfully induced combinations of hypoxaemia, hypercarbia and acidosis at a ventilator rate of 37 strokes min-1 and of hyperoxaemia, hypocarbia and alkalosis at 160 strokes min-1. 3. Hypoventilation caused significant decreases in both the blood pressure and pulse rate, whereas hyperventilation produced significant increases in these parameters. 4. In the controls, intravenous injections of graded doses of either verapamil or nifedipine caused dose-dependent decreases in mean blood pressure. The effects on pulse rate were not marked. 5. The hypotensive effects of verapamil were significantly more intense in hyperventilated rats, whereas those of nifedipine were significantly less pronounced in hypoventilated animals. The hypoventilated rats exhibited a significant dose-dependent decrease in pulse rate in response to verapamil administration. 6. It is concluded that cardiovascular responses to verapamil, nifedipine and probably other calcium antagonists are altered in the presence of blood gas abnormalities.     

Calcium channel inhibitors prevent apomorphine- and oxytocin-induced penile erection and yawning in male rats

The effect of i.p. injection of the calcium channel inhibitors, verapamil, flunarizine, nifedipine, nimodipine and nicardipine, on penile erection and yawning induced by the dopamine agonist, apomorphine, or by oxytocin was studied in male rats. The five compounds antagonized in a dose-dependent manner the behavioral responses induced either by apomorphine or oxytocin. Nimodipine and nicardipine were found to be the most potent, being active in doses between 5 and 20 mg/kg, while nifedipine, verapamil and flunarizine were active in doses higher than 15 mg/kg. The results suggest that calcium is involved in the expression of the above-mentioned behavioural responses.     

Effects of calcium channel antagonists and Bay K 8644 on the analgesic response to pentazocine and U 50488H.

1. The effects of diltiazem, nifedipine and verapamil and the calcium channel agonist Bay K 8644 on the analgesic responses to the subcutaneous (s.c.) or intracerebroventricular (i.c.v.) administration of pentazocine and U 50488H were investigated in mice. 2. The three calcium channel antagonists and Bay K 8644 reduced the number of writhes induced by the intraperitoneal administration of acetic acid. 3. The analgesic responses to the low doses of pentazocine (s.c.) were additive with the effects of diltiazem, nifedipine or Bay K 8644; while, in contrast, the higher doses produced underadditive responses. Only verapamil increased the effects of the i.c.v. administration of the opioid. 4. The effects of U 50488H (s.c.) were additive with those of diltiazem and Bay K 8644; verapamil only increased the response to the lower dose of the opioid. Nifedipine plus pentazocine always induced underadditive responses. The i.c.v. effects of U 50488H were only increased by verapamil. 5. These findings are discussed in relation with a possible interaction of kappa agonists with calcium channels in the central nervous system.     

Calcium Channel Blockade: Central Hemodynamic Effects

Abstract: Despite differences in vasodilatation, inotropy and chronotropy between verapamil, nifedipine and diltiazem when tested in vitro, these drugs will produce similar central hemodynamic effects in healthy young or middle-aged individuals, provided they are given in equipotent doses. The individual profiles of hemodynamic action of these calcium channel blockers are briefly reviewed and discussed.     

Pharmacokinetics of Calcium Channel Blocking Agents

Abstract: Verapamil and nifedipine are the most frequently used calcium channel blocking agents in Sweden at present time. The pharmacokinetics of verapamil has been described both in healthy volunteers as well as in patients with supraventricular arrythmias, angina pectoris, liver cirrhosis, hypertrophic cardiomyopathy or hypertension. Intravenous pharmacokinetics of nifedipine has been investigated in healthy volunteers and oral pharmacokinetics in healthy volunteers as well as in patients with hypertension. The pharmacokinetics of verapamil and of one of its metabolites, norverapamil, is changed after multiple oral dosing as has been described in patients with supraventricular tachyarrythmias, angina pectoris or in patients with essential hypertension. Plasma concentration-effect relationships have been established for verapamil in different clinical situations and in a few cases also for nifedipine. An update of the pharmacokinetics of these two important calcium channel blocking agents is presented.     

Effects of calcium-antagonistic coronary vasodilators,nifedipine and verapamil,on ventricular automaticity of the dog

Summary In isolated, blood-perfused canine papillary muscles intra-arterial injection of calcium-antagonistic coronary vasodilators, nifedipine and verapamil, produced a dose-related decrease in force of contraction. The ventricular rate of about 40 beats/min was not significantly changed by nifedipine even in doses which profoundly decreased the force of contraction. Verapamil changed the ventricular rate in a biphasic manner, but the changes remained as small as about 10% of the basal rate in doses which markedly suppressed the force of contration. Calcium chloride elicited an increase in force of contraction but depressed automaticity. The present results show that in response to nifedipine, verapamil and calcium ions, ventricular automaticity has characteristics different from those of the sinus node.     

Effects of calcium antagonists on phencyclidine behaviors

The calcium antagonists nifedipine and verapamil were evaluated for their potential behavioral interactions with phencyclidine induced changes in mouse rotarod performance and motor activity. Nifedipine (2 and 10 mg/kg) and verapamil (2 mg/kg) significantly potentiated impairment of rotarod performance produced by phencyclidine. These doses of nifedipine and verapamil did not by themselves affect rotarod performance. This action does not appear to be dependent on the hypotensive properties of these drugs, since hypotensive doses of prazosin did not alter the effect of phencyclidine on rotarod performance. Nifedipine, 4.0 mg/kg, antagonized increases in ambulatory motor activity, and potentiated decreases in vertical motor activity (rearing) induced by phencyclidine. The effects of calcium antagonists to alter the behavioral actions of phencyclidine in mice may occur through an interaction with the dihydropyridine calcium antagonist binding site present in the central nervous system.     

Nifedipine toxicity is exacerbated by acetyl l-carnitine but alleviated by low-dose ketamine in zebrafish in vivo

Calcium channel blocker (CCB) poisoning is a common and sometimes life-threatening emergency. Our previous studies have shown that acetyl l -carnitine (ALCAR) prevents cardiotoxicity and developmental toxicity induced by verapamil, a CCB used to treat patients with hypertension. Here, we tested whether toxicities of nifedipine, a dihydropyridine CCB used to treat hypertension, can also be mitigated by co-treatment with ALCAR. In the zebrafish embryos at three different developmental stages, nifedipine induced developmental toxicity with pericardial sac edema in a dose-dependent manner, which were surprisingly exacerbated with ALCAR co-treatment. Even with low-dose nifedipine (5 μm ), when the pericardial sac looked normal, ALCAR co-treatment showed pericardial sac edema. We hypothesized that toxicity by nifedipine, a vasodilator, may be prevented by ketamine, a known vasoconstrictor. Nifedipine toxicity in the embryos was effectively prevented by co-treatment with low (subanesthetic) doses (25-100 μm added to the water) of ketamine, although a high dose of ketamine (2 mm added to the water) partially prevented the toxicity.As expected of a CCB, nifedipine either in the presence or absence of ketamine-reduced metabolic reactive oxygen species (ROS), a downstream product of calcium signaling, in the rapidly developing digestive system. However, nifedipine induced ROS in the trunk region that showed significantly stunted growth indicating that the tissues under stress potentially produced pathologic ROS. To the best of our knowledge, these studies for the first time show that nifedipine and the dietary supplement ALCAR together induce adverse effects while providing evidence on the therapeutic efficacy of subanesthetic doses of ketamine against nifedipine toxicity in vivo.