The effects of slow channel blockers and beta blockers on atrioventricular nodal conduction

The PR interval on the electrocardiogram represents the time that it takes an impulse to travel through the atrium and atrioventricular (AV) conduction system to the ventricles. Normally, activation is slowest in the AV node, and variations in PR interval most commonly parallel changes in AV nodal activation time. The AV nodal conduction time and effective refractory period are rate dependent and, in adult humans, are usually prolonged with increasing atrial paced rates. In addition, alterations in autonomic tone effect AV nodal conduction as well as sinus rate. The effect is usually in the same direction but often to different degrees. In patients with normal AV nodal function, parasympathetic and sympathetic tone are balanced at rest, but in patients with abnormal AV conduction, the effect of the parasympathetic system is more marked. Drugs including the slow channel blockers and beta blockers, affect AV nodal function. Slow channel blockers inhibit the slow inward calcium current, which may prolong conduction and refractoriness in the AV node. However, whereas diltiazem and verapamil have been shown to prolong AV nodal conduction and refractoriness in humans, nifedipine, a potent vasodilator, cannot be used in doses large enough to affect the AV node. The increase in PR interval caused by verapamil is minimal, and at doses of less than 480 mg/d, AV block occurs infrequently. When AV block occurs, it is first degree block in most patients, and it is usually asymptomatic. The electrophysiologic effects of diltiazem are similar to those of verapamil. Beta blockers also have a negative dromotropic effect on the AV node. They prolong the AH interval and AV nodal refractory periods and may lengthen the PR interval. The prolonged PR interval rarely results in more than first degree AV block in patients receiving maintenance therapy. In selected patients, combination therapy with a slow channel blocker and a beta blocker rarely causes second-degree AV block.     

Effect of gradual rise in plasma calcium concentration on the impairment of atrioventricular nodal conduction due to verapamil

The possible reversal by calcium of the inhibitory action of verapamil on the atrioventricular (AV) node was investigated in anesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitory electrode and the AV node effective refractory period measured by the extrastimulus method. Calcium infusion was effective against the impairment of AV nodal conduction induced by verapamil, provided it remained moderate: the gradual rise in the plasma calcium concentration counteracted the effects of an infusion of verapamil on conduction time and effective refractory period in the AV node, as long as it did not exceed 5 mmol/L. However, beyond this level, calcium appeared less and less capable of reversing the effects of verapamil. Thus, the protective action of calcium had a bell-shaped dose-response curve, with the optimum at 5 mmol/L. This biphasic influence is consistent with the opposite opinions previously given concerning the antagonism between calcium and calcium blockers, depending on whether hypercalcemia brought into play was mild or major. In any case, the prominent role played by calcium in the slow inward current in the AV node accounts for the antagonism, observed in vivo, between calcium and verapamil. The pacemaker activity of the sinoatrial (SA) node was less influenced by both calcium blocker and calcium.     

The activity of nifedipine,diltiazem, verapamil,and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity

A characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazem, verapamil, and lidoflazine. All drugs produced relaxation of K⁺ depolarized guinea pig ileal longitudinal muscle strips and K⁺ depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration-response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA₂ estimates: nifedipine 9.5, diltiazem 7.65, verapamil 7.8, and lidoflazine 7.0. Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine-contracted rabbit aortae while weak effects were observed with verapamil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazem displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this regard.     

Circulatory and myocardial effects of different sodium antagonistic drugs in comparison to the calcium antagonist verapamil

The hemodynamic effects of intravenous class I and class IV antiarrhythmic drugs were investigated at different doses in comparison. In open-chest rats hemodynamic measurements in the intact circulation and isovolumic registrations 5 min after infusion of flecainide (2, 4, 8 mg/kg), disopyramide (1, 2, 4, 8 mg/kg), quinidine (5 and 10 mg/kg) and verapamil (0.35, 0.7, 1.5 mg/kg) were compared to saline controls. After clinically usual doses all investigated drugs had no effects on stroke volume, cardiac output, dp/dtmax and systemic resistance. The isovolumic pressure generating capacity of the left ventricle was not decreased at these doses. High intravenous doses of the drugs, however, caused a significant depression of myocardial performance (pressure generating capacity). Furthermore, flecainide decreased mean aortic pressure and heart rate, while disopyramide had no significant effect on the peripheral circulation. Blocking of the autonomic system (1 mg/kg propranolol and 0.1 mg/kg atropine) did not change significantly the action of disopyramide. Quinidine lowered heart rate and pressures. Verapamil reduced the heart rate and tended to decrease the mean aortic pressure. Besides the negative inotropic action of high doses the different hemodynamic profiles of class I and class IV antiarrhythmic drugs might be of importance for intravenous application in patients with left ventricular dysfunction.     

A comparison of the effects of nifedipine and verapamil on rat vas deferens.

Nifedipine preferentially blocks contractions of the prostatic end of the rat vas deferens to single pulse field stimulation, leaving the epididymal end largely unaffected. This action is not due entirely to antagonism of calcium influx. Verapamil unexpectedly potentiated the responses of the prostatic portion, and antagonized those of the epididymal end. The use of nifedipine may, therefore, allow investigations of adrenergic mechanisms on this tissue to be studied without the complications of non-adrenergic transmission.     

Interaction between calcium and slow channel blocking drugs on atrial rate

The relationship between extracellular calcium concentration and the chronotropic effect of prenylamine, verapamil and nifedipine was studied in isolated spontaneously beating rat atria. The three slow channel blocking drugs produced a concentration-dependent decrease in atrial rate, though with different relative potencies. The order of potency for decreasing atrial rate, independently of the calcium level (1.0, 3.0, 6.0 or 9.0 mmol/l) was: verapamil greater than nifedipine greater than prenylamine. Increasing calcium from 1.0 to 6.0 and 9.0 mmol/l increased atrial rate from 251 +/- beats . min-1 to 265 +/- 6 beats . min-1 and 285 +/- 9 beats . min-1 (mean +/- 1 standard error) respectively (P less than 0.05). Despite their positive chronotropic effect high calcium levels failed to reverse the negative chronotropic effect of the slow channel blockers. Furthermore, the negative chronotropic effect of both verapamil and nifedipine was enhanced at high calcium levels. Raising calcium from 1.0 to 6.0 mmol/l in the presence of verapamil (1 X 10(-7) mol/l) or nifedipine (3 X 10(-7) mol/l) increased 2-fold the negative chronotropic effect of the calcium channel blockers. In addition, the concentration-effect curves for verapamil and nifedipine shifted to the left by 0.50 +/- 0.14 and 0.50 +/- 0.16 log units, respectively, when calcium increased from 1.0 to 6.0 mmol/l. The data show that increasing calcium may produce positive or negative chronotropic effects depending on whether or not the calcium channels are blocked. This paradoxical effect of calcium ions can be produced either by opposite chronotropic effects on automatic cells or by shifting the pacemaker activity to a group of cells which respond in a different way to an increment of calcium.     

Renal effects of the new calcium channel blocking drug isradipine

Summary The acute effect of a single oral dose of isradipine 5 mg on blood pressure, renal haemodynamics, electrolyte excretion and plasma renin activity was studied in 10 healthy males.Isradipine did not produce a significant change in systolic or diastolic blood pressure, and glomerular filtration rate, renal plasma flow, renal vascular resistance, and urinary albumin excretion remained constant. There was a marked natriuretic and diuretic effect about 1–3 h after isradipine. Plasma renin activity showed a slight, insignificant increase 1 h after dosing. Uric acid clearance and 2-microglobulin excretion showed no significant changes, despite an increase in sodium clearance, suggesting an additional mechanism of action other than the proximal tubular natriuretic effect of isradipine in normotensive volunteers.     

Effects of anipamil on myocardial sarcolemmal and mitochondrial calcium transport, comparison with verapamil and nifedipine

The calcium antagonists anipamil, verapamil and nifedipine inhibited, dose dependently, passive and ATP-driven 45Ca2(+)-uptake in purified rabbit ventricular sarcolemmal vesicles exposed to a wide range of free calcium concentration (from 0 to 200 microM). The IC50 values for passive binding were virtually identical for all calcium antagonists and the inhibition was relatively independent of the amount of free calcium employed. On the contrary, the order of potency for inhibition of the ATP-driven calcium uptake was: anipamil greater than verapamil greater than nifedipine. The inhibition of nifedipine, at free calcium concentrations lower than 80 microM, was preceded by a slight stimulation. The inhibitory effects of anipamil and verapamil, but not those of nifedipine, on the ATP-driven calcium uptake were more evident with increasing external calcium concentration. Verapamil and nifedipine failed to modify the initial rate of mitochondrial calcium transport either in the presence or in the absence of ADP; on the contrary, anipamil induced a dose-dependent inhibition of mitochondrial calcium transport. The inhibition occurred over the whole range of calcium concentrations tested, independent of the presence of ADP. The effects of anipamil, but not those of verapamil and nifedipine, on sarcolemmal and mitochondrial calcium transport were long lasting and survived membrane isolation.     

Pharmacodynamic comparison of verapamil and nifedipine in anesthetized dogs

The relationships between steady-state plasma concentrations of verapamil or nifedipine and the resultant hemodynamic and electrophysiologic effects were evaluated in anesthetized, instrumented dogs. In different groups of animals, the drugs were given intravenously by loading-maintenance infusions designed to rapidly achieve and sustain stable plasma drug concentrations, over four different target ranges which span those found in clinical use of these agents. Plasma levels of nifedipine varied from 5 to 125 ng/ml, and those of verapamil, from 40 to 500 ng/ml. Nifedipine produced no apparent effects on the surface electrocardiogram. Verapamil dosing resulted in progressive prolongation of the PR interval as plasma drug levels increased from 40 to 250 ng/ml; at higher drug levels, complete atrioventricular block occurred. At the highest plasma concentrations used, the maximal vasodilation produced by both drugs was approximately equal, with mean aortic pressure levels falling to 50-60% of control values. The effects of the two agents on cardiac pump performance, however, differed: nifedipine administration produced dose-related increases in cardiac output at all plasma drug concentrations studied; the effects of verapamil were critically dependent upon drug levels in plasma, with cardiac output increased above control values at drug concentrations between 40 and 250 ng/ml, and progressively depressed at higher plasma levels of the drug. As a result, the calculated systemic vascular resistance declined progressively during nifedipine administration, while after verapamil doses, this parameter varied inversely with observed effects on cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and evaluation of a new class of nifedipine analogs with T-type calcium channel blocking activity

We have synthesized a novel series of 18 dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates from anacardic acid, a natural compound found in cashew nut shells, and investigated their blocking action on L- and T-type calcium channels transiently expressed in tSA-201 cells. The IC(50) values for L-type calcium channel block obtained with the series ranged from 1 to approximately 40 microM, with higher affinities being favored by increasing the size of the alkoxy group on the 4-phenyl ring and ester substituent in the 3,5 positions. A detailed analysis of the strongest L-type channel blocker of the series (PPK-12) revealed that block was poorly reversible and mediated an apparent speeding of the time course of inactivation. Moreover, in the presence of PPK-12, the midpoint of the steady state inactivation curve was shifted by 20 mV toward more hyperpolarized potentials, resulting in an increase in blocking efficacy at more depolarized holding potentials. Surprisingly, PPK-12 blocked T- and L-type calcium channels with similar affinities. One of the weakest L-type channel inhibitors (PPK-5) exhibited a T-type channel affinity that was similar to that seen with PPK-12, resulting in a 40-fold selectivity of PPK-5 for T- over L-type channels. Thus, dialkyl 1,4-dihydro-4-(2'alkoxy-6'-pentadecylphenyl)-2,6-dimethyl-3,5 pyridine dicarboxylates may serve as excellent candidates for the development of T-type calcium-channel specific blockers.     

A method for in vivo assessment of calcium slow channel blocking drugs

A method is described, using the cardioaccelerator response in pithed rats, that distinguishes calcium entry blockers from other agents which have modes of action not involving direct blockade of calcium entry. Diltiazem (0.01-0.3 mg kg-1), verapamil (0.01-0.03 mg kg-1), nifedipine (0.1-1.0 mg kg-1), propranolol (0.003-0.3 mg kg-1), xylazine (0.01-1.0 mg kg-1), alinidine (0.03-1.0 mg kg-1), and, to a lesser extent, lignocaine (0.1-3.0 mg kg-1), reduced stimulation-evoked sustained cardioaccelerator responses in the pithed rat. BRL 34915 (0.3-10.0 mg kg-1) and nicorandil (1.0-10.0 mg kg-1) were without effect in this situation. Infusion of calcium gluconate (1.0 mg min-1) reversed the reduction of the cardioaccelerator responses by nifedipine (1.0 mg kg-1), verapamil (0.3 mg kg-1), and diltiazem (0.3 mg kg-1) but not to propranolol (0.1 mg kg-1), alinidine (0.5 mg kg-1), or xylazine (0.3 mg kg-1). Therefore, calcium gluconate is selective in reversing the effects of calcium slow channel blockers in this model, thereby making it a useful technique for distinguishing these drugs in vivo.     

Constitutional rho-kinase regulates atrioventricular nodal conduction and ventricular repolarization of the canine heart

Given the limited information, physiological roles of Rho-kinase in the cardiac conduction system and ventricular repolarization process were assessed in comparison with those in the coronary vascular tone. A specific Rho-kinase inhibitor Y-27632 was administered to the nutrient coronary artery of the canine isolated, blood-perfused atrioventricular node preparation under the monitoring of the ventricular monophasic action potentials. Administration of Y-27632 moderately suppressed the atrioventricular nodal conduction, slightly but significantly accelerated the repolarization process, and potently increased the coronary blood flow, whereas it hardly affected the intraventricular conduction. The estimated concentrations of Y-27632 causing the currently observed effects were enough to inhibit Rho-kinase. These results suggest that constitutional Rho-kinase functions to moderately facilitate the atrioventricular nodal conduction, slightly delay ventricular repolarization process, and significantly increase the coronary vascular tone.     

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 dihydropyridine calcium channel blocking drugs on rat brain muscarinic and alpha-adrenergic receptors

The dihydropyridine (DHP) Ca2+ channel blocking drugs nicardipine, nitrendipine, nimodipine, felodipine, nifedipine and nisoldipine were examined for activity in inhibiting specific (-)-[3H] QNB and [3H]WB4101 binding to the muscarinic and alpha-adrenergic receptors, respectively, of rat brain. Muscarinic receptor binding was affected most by nicardipine, with felodipine having less activity; the other DHP drugs were essentially inactive at 3 X 10(-5) M. The (+)-stereoisomer nicardipine (KI = 4.07 X 10(-7) M) was 27 times more potent than the (-)-isomer in inhibiting [3H]QNB binding, and this inhibition was found to be competitive. This inhibitory effect of nicardipine was not mediated via interaction with the high-affinity DHP binding site assumed to be associated with a Ca2+ channel. (+)-Nicardipine inhibited the binding of [3H]nitrendipine to this DHP binding site of brain, with a K1 of 9.01 X 10(-11) M, and was 10 times more potent than the (-)-isomer. Thus, the muscarinic receptor was 4200 times less sensitive to (+)-nicardipine than was this DHP binding site. Nicardipine was also the most potent DHP drug inhibiting [3H]WB4104 binding to the alpha-adrenergic receptor, although the other drugs were also somewhat active, in the rank order sequence listed above. This effect of nicardipine on the adrenergic receptor was also stereoselective, with (+)-nicardipine (KI = 3.46 X 10(-7) M) being about 3 times more potent than the (-)-isomer, in producing competitive inhibition of radioligand binding. These data suggest that the effects on brain receptors occur as a result of direct, stereospecific effects of DHP drugs on these receptors and are not due to Ca2+ channel blocking activity of these drugs.     

Teratogenic effects of some calcium channel blocking agents in Xenopus embryos

Xenopus embryos, treated for three days from the early cleavage stage with the calcium channel blocking drugs nifedipine, diltiazem, verapamil or nicardipine continue to develop in water. By the seventh day many developmental abnormalities appear, the most reproducible affecting the central nervous system, failure of forebrain development, synophthalmia and neural tube defect. Other anomalies include failure of mandibular growth and malrotation of the gut. Failure of water and electrolyte transport are indicated by severe oedema in some animals. The defects appear to relate to calcium ion antagonism, and provide a pharmacological model for some forms of teratogenesis in which large populations can be studied readily.     

Comparison of the calcium-antagonistic effects of terodiline, nifedipine and verapamil

Studies were carried out on the Ca-antagonistic effects of terodiline and its enantiomers on the potassium-stimulated mesenteric and coronary arteries, on the spontaneous myogenic activity and norepinephrine- and acetylcholine-induced contractions of the protal vein and on electrically stimulated papillary muscle. The effects were compared with those of the Ca-antagonists, nifedipine and verapamil. Terodiline is relatively weak as a Ca-antagonist, having IC50-values between 5 X 10(-6) and 2 X 10(-5)M for all the tissues studied. Nifedipine is the most potent Ca-antagonist on vascular smooth muscle (IC50 3-6 X 10(-9) M), but is considerably less potent on the papillary muscle (IC50 10(-7)M). Verapamil is most potent on the papillary muscle (IC50 7 X 10(-8)M and the portal vein (IC50 6 X 10(-8)M, but is 10 times less potent on the mesenteric and coronary arteries (IC50 3-5 X 10(-7)M). Nifedipine is 1000 times and verapamil and (-)-terodiline 10 times more potent on the slow component of the K-induced contraction while (+/-)- and (+)-terodiline are almost as active on the fast as on the slow component of K-induced contractions on the mesenteric artery. Furthermore, (+/-)-and (+)-terodiline are 10 times more potent in antagonizing acetylcholine- and norepinephrine-induced contractions, whereas (-)-terodiline is equally potent and nifedipine and verapamil are 10 times more potent in blocking the myogenic activity of the portal vein. On the Ca2+-nifedipine and verapamil. However, nifedipine and verapamil, but not terodiline, in concentrations which blocked the maximal norepinephrine-induced response in non-depleted muscle, antagonized the contractions induced by norepinephrine together with Ca2+ in the Ca2+ depleted portal vein. These results show that terodiline blocks the uptake of Ca2+ and, in addition, blocks the utilization of some intracellular stores of Ca2+.     

A comparison between calcium channel blocking drugs with different potencies for T- and L-type channels in preventing atrial electrical remodeling

Calcium overload plays a key role in the development of atrial electrical remodeling. The effect of an L-type Ca channel blocker in preventing this remodeling has been reported to be short lasting, partly due to down-regulation of this channel and persisting Ca entry through the T-type Ca channel. To prove if efonidipine, a dual L- and T-type Ca channel blocker exerts a greater effect than an L-type Ca channel blocker verapamil, 21 dogs underwent rapid atrial pacing at 400 bpm for 14 days, pretreatment with efonidipine in 7 (E), verapamil in 7 (V), and none in 7 (C). We measured the atrial effective refractory period (ERP) serially during 14 days of rapid pacing. In response to rapid pacing, ERP decreased progressively in C. In contrast, in E and V, ERP remained greater than ERP in C (P < 0.01) on days 2 through 7. However, on the 14th day, ERP in V decreased to the level seen in C, whereas ERP in E remained significantly longer than ERPs in C or V (P < 0.01). The blockade L-type Ca channel alone is not sufficient, but the addition of a T-type Ca channel blockade shows a more sustained effect to prevent atrial electrical remodeling.