Monitoring of nilvadipine (EscorR) treatment of 23 770 hypertensive patients.

The antihypertensive efficacy of Escor (nilvadipine) 8 mg (initial dose for n = 18 094) or 16 mg (initial dose for n = 3109), once daily, was evaluated in a multicenter drug monitoring study in 23 770 hypertensive patients over 10 months. Duration of treatment was 65 ± 24 days (mean ± s.d.). Mean age of patients was 63 ± 10 years, 51% males, 49% females, weight 78 ± 12 kg, height 170 ± 8 cm. Hypertension was known for 6 ± 6 years. The most frequent concomitant diseases were disturbances of lipid metabolism, ischemic heart disease, and arthrosis. 81% of patients were maintained on the initial daily dose of 8 mg nilvadipine, in 13% of patients the initial dose of 8 mg was increased to 16 mg per day, in 1% of cases an initial dose of 16 mg per day was reduced to 8 mg.29% of the patients reported full compliance with the nilvadipine drug regimen; 31% had rarely, 20% occasionally, 8% frequently, and 0.2% consistently not complied with the regimen. Compliance was improved vs. previous treatment by the once-daily regimen in 47% of patients. Therapy with Escor was continued in 76% of patients beyond study end because of efficacy of therapy and good tolerability. On a global assessment scale efficacy was rated excellent in 50%, good in 41%, moderate in 5%, insufficient in 2%. The ratio of responders, i.e., diastolic blood pressure > 95 mm Hg at baseline and < 90 mm Hg at end of study, or reduction of diastolic blood pressure by at least 10 mm Hg, was 59% at the first control visit and 84% at study-end visit. Diastolic blood pressure was lowered by 13 ± 9%, systolic blood pressure by 14 ± 8%.Adverse events had been documented in 7.9% of patients; most frequently the symptoms were associated with the therapeutic effect, i.e., vasodilatation (incidence 3.35%), headache (2.4%), tachycardia (1.18%), edema (0.95%), dizziness (0.78%). A relation of adverse events to Escor was rated very probable in 4%, probable in 2% and possible in 1%. Serious adverse events reportedly occurred in 0.2% (55) patients, including 36 cases of hospitalization or surgery; among the latter, 8 patients also experienced tachycardia, 3 vasodilatation, 2 increased sweating. Nine deaths were reported, but a relation to Escor treatment was denied. Tolerability was rated excellent in 52%, good in 40%, moderate in 3% and insufficient in 2% of patients.

[Pharmacology of modern anti-arrhythmia drugs in therapy of supraventricular tachycardia]. / Pharmakologie moderner Antiarrhythmika zur Therapie supraventrikulärer Tachykardien.

Prevention of recurrences of atrial fibrillation, slowing the ventricular rate during atrial fibrillation, and the acute management of atrioventricular junctional reentrant supraventricular tachycardia (paroxysmal supraventricular tachycardia) often require treatment with antiarrhythmic drugs. These drugs comprise a pharmacodynamically and pharmacokinetically heterogeneous group of agents whose individual properties determine correct use, contraindications and side effects. Stabilisation of sinus rhythm can be achieved with class IA and class IC sodium channel blocking drugs as well as with the class III agents amiodarone or sotalol. Verapamil, diltiazem, cardioselective beta-adrenoceptor-blocking drugs or cardiac glycosides can be used to slow the ventricular rate during atrial fibrillation. Rapid termination of paroxysmal supraventricular tachycardia is achieved with i.v. administration of adenosine, verapamil, ajmaline, diltiazem, propafenone, or flecainide. If atrial flutter complicates the preexcitation syndrome, this type of supraventricular tachycardia must not be treated with calcium antagonists, cardiac glycosides or lidocaine, since these agents decrease refractoriness of the accessory pathway which may precipitate fatal ventricular fibrillation.

Relation between veratridine reaction dynamics and macroscopic Na current in single cardiac cells.

Veratridine modification of Na current was examined in single dissociated ventricular myocytes from late-fetal rats. Extracellularly applied veratridine reduced peak Na current and induced a noninactivating current during the depolarizing pulse and an inward tail current that decayed exponentially (tau = 226 ms) after repolarization. The effect was quantitated as tail current amplitude, Itail (measured 10 ms after repolarization), relative to the maximum amplitude induced by a combination of 100 microM veratridine and 1 microM BDF 9145 (which removes inactivation) in the same cell. Saturation curves for Itail were predicted on the assumption of reversible veratridine binding to open Na channels during the pulse with reaction rate constants determined previously in the same type of cell at single Na channels comodified with BDF 9145. Experimental relationships between veratridine concentration and Itail confirmed those predicted by showing (a) half-maximum effect near 60 microM veratridine and no saturation up to 300 microM in cells with normally inactivating Na channels, and (b) half-maximum effect near 3.5 microM and saturation at 30 microM in cells treated with BDF 9145. Due to its known suppressive effect on single channel conductance, veratridine induced a progressive, but partial reduction of noninactivating Na current during the 50-ms depolarizations in the presence of BDF 9145, the kinetics of which were consistent with veratridine association kinetics in showing a decrease in time constant from 57 to 22 and 11 ms, when veratridine concentration was raised from 3 to 10 and 30 microM, respectively. As predicted for a dissociation process, the tail current time constant was insensitive to veratridine concentration in the range from 1 to 300 microM. In conclusion, we have shown that macroscopic Na current of a veratridine-treated cardiomyocyte can be quantitatively predicted on the assumption of a direct relationship between veratridine binding dynamics and Na current and as such can be successfully used to analyze molecular properties of the veratridine receptor site at the cardiac Na channel.

Mutually exclusive action of cationic veratridine and cevadine at an intracellular site of the cardiac sodium channel.

Veratridine modification of Na current was examined in single dissociated ventricular myocytes from late-fetal rats by applying pulses to -30 mV for 50 ms every 2 or 5 s from a holding potential of -100 mV (20 degrees C) and measuring amplitude, Itail, and time constant, tau tail, of the post-repolarization inward tail current induced by the alkaloid. Increasing the pH of a 30 microM veratridine superfusate from 7.3 to 8.3 (which increases the fraction of uncharged veratridine molecules from 0.5 to 5% while decreasing that of protonated molecules from 99.5 to 95%) increased Itail by a factor of 2.5 +/- 0.5 (mean +/- SEM; n = 3). Switching from 100 microM veratridine superfusate at pH 7.3 to 10 microM at pH 8.3 did not affect the size of Itail (n = 4). Intracellular (pipette) application of 100 microM veratridine at pH 7.3 or 8.3 produced small Itail's suggesting transmembrane loss of alkaloid. If this was compensated for by simultaneous extracellular application of 100 microM veratridine at a pH identical to intracellular pH, Itail (measured relative to the maximum amplitude induced by a combination of 100 microM veratridine and 1 microM BDF 9145 in the same cell) at pHi 7.3 did not significantly differ from that at pHi 8.3 (84 +/- 4 vs. 70 +/- 6%; n = 3 each). Results from six control cells and five cells subjected to extra- and/or intracellularly increased viscosity by the addition of 0.5 or 1 molal sucrose showed that increasing intracellular viscosity 1.6- and 2.5-fold increased tau tail 1.5- and 2.3-fold, respectively, while a selective 2.5-fold increase of extracellular viscosity did not significantly affect tau tail.(ABSTRACT TRUNCATED AT 250 WORDS)

[New anti-arrhythmia agents]. / Neue Antiarrhythmika.

Use of class-I antiarrhythmic agents (encainide, flecainide or moricizine) to suppress asymptomatic ventricular premature depolarizations does not decrease, but rather increases mortality from cardiac events after myocardial infarction. These patients should not be treated with antiarrhythmic drugs until improved survival is shown in a controlled clinical trial. In other clinical conditions such as symptomatic tachyarrhythmias class-I agents should only be used if the expected benefit outweighs the risk of an adverse cardiac effect. The development of new class-I drugs does not seem promising. Esmolol is the first intravenous and ultrashort-acting beta-adrenoceptor blocker that can be used to treat supraventricular arrhythmias in the critical care setting; in addition, it displays high cardioselectivity. Specific class-III antiarrhythmic agents including sematilide and dofetilide have been shown to be effective against ventricular tachyarrythmias in preclinical studies, but their clinical value remains to be established. Torsades de pointes arrhythmia is an undesirable side-effect closely coupled to specific class-III action that may limit their future use. The known pharmacological profiles and limited controlled clinical studies make amiodarone and sotalol promising candidates for drugs that may improve survival of patients at risk for sudden cardiac death.

Pharmacodynamics of nilvadipine, a new dihydropyridine-type calcium antagonist.

Nilvadipine is a new calcium antagonist of the dihydropyridine type. It reduces blood pressure by high-affinity blockade of calcium channels in arterial cells, which leads to relaxation of arterial vessels. Nilvadipine has both pharmacokinetic and pharmacodynamic advantages compared to nifedipine (the prototype of the dihydropyridines). The duration of action is longer and it has a 4- to 16-fold higher vasodilatory potency that is accompanied by less cardiodepression and adrenergic counterregulation. The higher vascular selectivity of nilvadipine is documented by its vascular/cardiac potency ratio of 251, which is 9- to 10-fold greater than that of nifedipine. When used therapeutically as an antihypertensive agent, even in patients with heart failure or concomitant beta-blockade, nilvadipine has no negative inotropic, chronotropic, or dromotropic effects. Nilvadipine has been shown to have a more potent antiatherogenic effect than that of nifedipine in vitro and in animal models.

Pharmacology of bipyridine phosphodiesterase III inhibitors.

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity.

Pharmacology of bipyridine phosphodiesterase III inhibitors.

The bipyridine phosphodiesterase III inhibitors amrinone and milrinone form a new class of positive inotropic vasodilator agents that are beneficial in the treatment of acute or decompensated heart failure. These agents inhibit the intracellular hydrolysis of cyclic adenosine monophosphate, thereby promoting cyclic adenosine monophosphate--catalyzed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. They have a wider therapeutic index than do the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoreceptor agonists, does not compromise the efficacy of phosphodiesterase inhibitors. The effectiveness of these new agents is, however, dependent on some degree of basal adenylate cyclase activity.

[New aspects of the molecular effect of anti-arrhythmia agents]. / Neue Aspekte der molekularen Wirkung von Antiarrhythmika.

Excitation propagation is mediated by the brief opening of voltage-dependent Na-channels in the plasma membranes of cells of the conduction system and working myocardium. The refractory period is a function of the re-availability of the Na-channel for renewed opening. Most antiarrhythmic agents block cardiac Na-channels and, consequently, affect the desired refractory period prolongation. At the same time, however, dependent on the concentration and the substance, they slow conduction; an effect which can facilitate reentry excitation in the injured heart. The Na-channel blocking drugs, class I antiarrhythmic agents, are distinguished from the beta-receptor blockers, class II, repolarizing prolonging drugs, class III, and the cardiac Ca-channel blocking drugs (class IV) (Table 1). MOLECULAR STRUCTURE OF THE CARDIAC NA-CHANNEL: Voltage-dependent Na-channels which have been structurally elucidated to date are glycoprotein macromolecules of about 2000 amino acids with a molecular weight of about 260,000. Beginning at the amino terminal, four consecutive homologous domains can be differentiated which are composed of six transmembranous segments each. The terminal portion of the chain as well as the connecting segments between the domains appear intracellular. There are important relationships between the molecular structure and the function of the Na-channel (Figure 1). On comparison of the primary structures of neuronal and cardiac Na-channels, domains I to IV as well as the connecting segment between domains III and IV, are nearly identical. Homology in all of the remaining molecular regions, in contrast, is less than 70%. These segments as well as the differing structure of the four S5-S6 connecting chains may be responsible for the varying functional response of the cardiac Na-channels. MOLECULAR SITE OF ACTION OF ANTIARRHYTHMIC AGENTS AT THE CARDIAC NA-CHANNEL: Since most antiarrhythmic agents are weak bases with pK values between 7.5 and 9.5, in the physiologic range of pH, they are present in part in the protonated, positively-charged form, in part as uncharged free base. It is assumed that the Na-channel of nerve and skeletal muscle has one receptor for local anesthetics at which both the protonated and the uncharged molecular forms bind. The receptor is thought to be located on the inner wall of the ion pore about half of the distance between the intracellular and the extracellular channel opening. The uncharged form of the Na-channel blocker penetrates directly from the lipid phase of the surrounding cell membrane, the protonated form only from the intracellular space during the short opening of the channel at the beginning of the action potential. Through binding on the receptor, the Na-channel is blocked. Dissociation of the molecular forms takes place in the same manner. The peptide region on which antiarrhythmic drugs bind, however, has not been identified. By means of the patch-clamp technique, it has been shown that on extracellular application of the quaternary lidocaine derivative QX-314 there is a rapid and marked reduction of Na-flux in cardiac Purkinje fibers in contrast to the effects at neuronal and skeletal muscle Na-channels. Intracellular application similarly leads to blockade but only in the course of repetitive depolarizations indicating that the cardiac Na-channel may have a second binding site for local anesthetics at the extracellular side.(ABSTRACT TRUNCATED AT 400 WORDS)

Sodium channel comodification with full activator reveals veratridine reaction dynamics.

Veratridine association and dissociation rates were determined at single sodium channels in outside-out patches of cultured ventricular myocytes obtained from late-fetal rat hearts. In single cardiac sodium channels depolarized from -110 to -30 mV, intracellular veratridine induced a long lasting (tau = 0.48 sec) open state with small current amplitude (-0.3 pA, i.e., 1/4 of normal) and frequent closing transitions, giving it a burstlike appearance, in agreement with reports on other types of sodium channel. Veratridine-associated and veratridine-free states of a single sodium channel were monitored by comodifying it with an allosteric activator, BDF 9145 (1 microM), that induced a burst with normal open channel current amplitude (-1.2 pA at -30 mV) upon veratridine dissociation. Veratridine and BDF 9145 interacted with reciprocal synergism at the single sodium channel such that veratridine-induced bursts (called P-bursts for partially activated) alternated with BDF 9145-induced bursts (called F-bursts for fully activated) many times following a single depolarization to -30 mV. P-bursts and F-bursts within such trains of bursts had exponentially distributed durations. The reciprocal time constant for F-bursts, tau F-1, increased linearly with veratridine concentration (0.3-30 microM), whereas tau P was insensitive. We conclude, therefore, that P-bursts reflect veratridine occupancy and F-bursts reflect the veratridine-free state; if veratridine and BDF 9145 bind to a sodium channel simultaneously, veratridine exerts conformational dominance, i.e., retains its property to reduce channel conductance. For the single cardiac sodium channel activated (i.e., deprived of inactivation) by BDF 9145, we have determined a veratridine association rate constant k1 = 4.3 x 10(6) M0-1 sec-1, dissociation rate constant K-1 = 2.2 sec-1 and equilibrium dissociation constant KD = 5.1 x 10(-7) M (20 degrees, -30 mV membrane potential).

Interaction between DPI 201-106 enantiomers at the cardiac sodium channel.

The modification of cardiac sodium channels by DPI 201-106, its S-enantiomeric form (S)-DPI, and its R-enantiomeric form (R)-DPI was investigated with whole-cell voltage-clamp recording in single cultured ventricular myocytes obtained from late-fetal rats. From a holding potential of -100 mV, depolarizing pulses to -30 mV of 50-msec duration were applied at 0.2 Hz. Extracellular [Na] was reduced to 70 mM; temperature was 20 degrees. Drugs were administered directly on the cell by a double-barrelled microsuperfusion system. Sodium current inactivation was progressively slowed when the concentration of DPI 201-106 was increased from 0.3 to 3 microM. At 10 microM DPI 201-106, this effect was followed by a blocking effect on peak inward sodium current (INa), and at 30 microM inward sodium current was fully blocked within 2 min. The slowing of inactivation was produced by (S)-DPI (maximally effective at 3 microM), whereas (R)-DPI had little effect on inactivation at 3 microM. Conversely, (R)-DPI reduced INa at 10 microM, whereas (S)-DPI did not reduce INa at 3 microM. The effects of both (S)-DPI and (R)-DPI were partially reversed by washout. (R)-DPI retained its blocking activity on INa when the interval between depolarizing pulses was prolonged to 90 sec. In order to test whether the different sodium channel modifications produced by (S)-DPI and (R)-DPI were mutually exclusive, the INa-reducing activity of (R)-DPI was measured in the absence of (S)-DPI and after equilibration with a maximally effective (S)-DPI concentration. In the absence of (S)-DPI, 3 microM (R)-DPI reduced INa by 35% and in the presence of 3 microM (S)-DPI, by 51%. Thus, modification by (S)-DPI of sodium channels did not prevent their block by (R)-DPI. The INa-reducing activity of (R)-DPI was even significantly augmented by (S)-DPI after a 1-sec depolarization to -30 mV. During such prolonged pulses, (R)-DPI accelerated the monoexponential decay of the (S)-DPI-induced slow phase of sodium current inactivation. The results are consistent with an irreversible binding reaction between (R)-DPI and (S)-DPI-modified open sodium channels (association rate constant, 4.7 x 10(5) M-1sec-1). We conclude that (R)-DPI reduces INa by interacting both with resting sodium channels and with (S)-DPI-modified open sodium channels. The corresponding receptor site is stereoselective and distinct from and allosterically coupled to the (s)-DPI receptor that mediates slowing of inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacology of positive inotropic phosphodiesterase III inhibitors.

Cardiac phosphodiesterase III (PDE) inhibitors derived from pyridinone, imidazolone, pyridazinone and related structures form a new class of positive inotropic vasodilator agents (e.g. milrinone) that are beneficial in the treatment of acute and chronic heart failure. These agents inhibit the intracellular hydrolysis of cyclic AMP, thereby promoting cyclic AMP-catalysed phosphorylation of sarcolemmal calcium channels and activating the calcium pump. Drugs such as milrinone have a wider therapeutic index than the cardiac glycosides. They also have vasodilator and lusitropic actions and are devoid of the central stimulant actions that narrow the therapeutic index of theophylline and other methylxanthines. Receptor down-regulation, which curtails the inotropic efficacy of beta-adrenoceptor agonists, does not compromise the efficacy of PDE inhibitors. The effectiveness of these new agents is, however, dependent upon some degree of basal adenylate cyclase activity. Individual PDE inhibitors differ in terms of both chronotropic and extracardiac properties. The reasons for this are not yet fully understood.

Imidazopyridines: roles of pyridine nitrogen position and methylsulfinyl oxygen for in vitro positive inotropic mechanism and chronotropic activity.

The role of structural features of sulmazole, an imidazo(4,5-b)pyridine, in its inotropic action was examined by comparison with its reduced (4-methylthiophenyl) analog EMD 46512 and the corresponding imidazo(4,5-c)pyridine isomers isomazole and EMD 41000 on isolated guinea-pig papillary muscles and right atria and on Na,K-ATPase and phosphodiesterase III isolated from guinea-pig hearts. The pyridine nitrogen position in sulmazole was crucial for affinity to Na,K-ATPase (IC50 = 350 microM) because the imidazo(4,5-c)pyridines had little effect. Participation of Na,K-ATPase inhibition in sulmazole's inotropic effect (EC50 = 180 microM) was suggested by synergism with the Na channel activator germitrine. The methylsulfinyl oxygen at the phenyl ring decreased the affinity to Na,K-ATPase of sulmazole 40-fold: The reduced analog EMD 46512 was a potent inhibitor of Na,K-ATPase (IC50 = 8.5 microM) and a more potent inotropic agent (EC50 = 8.2 microM) that appeared to act predominantly through Na,K-ATPase inhibition. Micromolar through Na,K-ATPase inhibition. Micromolar IC50s for inhibition of phosphodiesterase III were 49 (sulmazole), 34 (EMD 46512), 18 (isomazole), and 13 (EMD 41000). Participation of this mechanism in the inotropic effect of sulmazole, isomazole, and EMD 41000, but not EMD 46512, was indicated by augmentation of slow action potentials, synergism with histamine, inhibition by carbachol, and (with the exception of EMD 41000) a positive chronotropic effect on the right atrium. Sulmazole appeared to combine the actions of its 4-methylthiophenyl analog EMD 46512 (an inhibitor of Na,K-ATPase) and of its imidazo(4,5-c)pyridine isomer isomazole (an inhibitor of phosphodiesterase III).

Tetrodotoxin block of single germitrine-activated sodium channels in cultured rat cardiac cells.

1. The open time of single Na+ channels in excised (outside-out) patches from cultured late-fetal rat ventricular myocytes was prolonged to several minutes by germitrine (0.5 mM) in order to analyse tetrodotoxin (TTX) blocking kinetics. 2. The germitrine modification appeared during depolarizing pulses that activated normal Na+ channels. Following repolarization to -100 mV, the modified Na+ channel remained activated for 136 +/- 186 s (mean +/- S.D., n = 54) with an open-channel current amplitude of -0.5 pA. The predominant open state with a mean open time of 0.13 s was interrupted by brief closing events lasting for milliseconds. Replacing extracellular Na+ by Cs+ decreased the current amplitude to -0.1 pA. 3. Extracellular superfusion with TTX (3 x 10(-7) M) of a single germitrine-activated Na+ channel induced full channel closures lasting seconds (blocked events) separated by channel reopenings (unblocked events) that were indistinguishable in terms of amplitude and gating kinetics from the germitrine-activated state in the absence of TTX. 4. Cumulative probability histograms of blocked and unblocked events (n greater than 140) collected during long-lasting germitrine modifications at 10(-7) and 3 x 10(-7) M-TTX are well described by single exponentials. The 3-fold increase in [TTX] decreased the time constant of the unblocked state, tau o, from 11.9 to 4.7 s, while the time constant of the blocked state, tau c, was not significantly altered from 8.6 to 9.7 s. A microscopic association rate constant of 7.7 x 10(5) M-1 s-1, dissociation rate constant of 0.11 s-1, and equilibrium dissociation constant of 1.4 x 10(-7) M (at -100 mV) were calculated (20 degrees C). 5. Increasing [TTX] to 10(-5) M decreased tau o to 86 ms. This argues against the existence of a slower conformational step interposed between the binding of TTX to an open channel and the resultant channel closure. 6. Setting the membrane potential to -50 or 0 mV subsequent to a germitrine modification at -100 mV did not significantly alter TTX (3 x 10(-7) M) blocking kinetics: tau o was 6.7 s at -50 mV and 5.2 s at 0 mV; tau c was 8.9 and 8.1 s, respectively. 7. These results suggest that blocked events correspond to the random times that a TTX molecule resides on the Na+ channel before it dissociates, and unblocked events correspond to the random waiting times of an unoccupied channel before it binds another toxin molecule.(ABSTRACT TRUNCATED AT 400 WORDS)

In vitro investigations on a new positive inotropic and vasodilating agent (BM 14.478) that increases myocardial cyclic AMP content and myofibrillar calcium sensitivity.

BM 14.478 (7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H pyrrolo[2,3-f]benz-imidazol-6-one) was investigated in several in vitro experiments to elucidate its positive inotropic and vasodilating efficacy and its mode of action. A direct positive inotropic action was achieved in papillary muscles (10(-6) to 5 X 10(-4) M) and electrically driven atria (10(-8) to 5 X 10(-4) M) from guinea pig hearts. The effect was not affected by propranolol, cimetidine, or tetrodotoxin, but diminished by carbachol. The effect of isoprenaline was amplified by threshold concentrations of BM 14.478 (10(-6) M). There was only a slight intrinsic chronotropic activity in spontaneously beating guinea pig atria. Atrial cyclic AMP (cAMP) was increased from 1.46 +/- 0.06 to 1.97 +/- 0.03 pmol/mg wet wt, at 3 X 10(-6) M. This might be due to an inhibition of cardiac phosphodiesterase(s) (PDE). IC50 of bovine PDE was 7.2 X 10(-5) M (5.4 X 10(-5) M to 9.7 X 10(-5) M). BM 14.478 shortened the duration of transmembrane action potential (90% repol.) by 8% and increased the Vmax of slow action potentials by 32% at 3 X 10(-4) M. In skinned porcine heart muscle fibers an increase in calcium-activated force up to 43 +/- 7% was observed (10(-7) to 10(-4) M). Rat aortas were relaxed by about 75% maximally (10(-7) to 10(-4) M). It is concluded that BM 14.478 is a potent inotropic drug which acts via an increase in myocardial cAMP content and in calcium sensitivity of contractile proteins.

Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade.

The negative inotropic effect and the effect on action potential configuration were investigated for TTX and 7 class 1 antiarrhythmic drugs (aprindine, AR-LH 31, CCI 22277, disopyramide, mexiletine, quinidine and sparteine) in the isolated guinea-pig papillary muscle contracting at 1 Hz. The ratio of the molar concentration producing 50% reduction of Vmax to that reducing force of contraction by 50% ranged from 0.23 (sparteine) to 2.2 (disopyramide) showing that some of the drugs were more potent Na channel blockers than negative inotropic agents, while the reverse was true for others. With the exceptions of sparteine and AR-LH 31, all the drugs produced a larger negative inotropic effect than TTX at concentrations equieffective in reducing Vmax. Thus, blockade of Na channels can account for only part of the negative inotropic effect of aprindine, CCI 22277, disopyramide, mexiletine and quinidine. Even sparteine and AR-LH 31 showed a negative inotropic property independent of Na channel blockade because, unlike TTX and like all other agents, they retained their negative inotropic activity after inactivation of Na channels by elevated extracellular K concentration (24 mmol/l). Relative negative inotropic effects of lorcainide, Org 6001 and propafenone were similar at 5.9 and 24 mmol/l (K)o. In contrast, the -log molar IC50(Fc) of flecainide, prajmalium bitartrate and tocainide was significantly decreased (by 0.35 to 0.81 log units) if Na channels were inactivated by K depolarization. Ouabain-sensitive Na,K-ATPase was not inhibited by sparteine, while mexiletine and AR-LH 31 produced partial inhibition (each at 1 mmol/l). We conclude that the negative inotropic effect of class 1 antiarrhythmic drugs represents the sum of their Na channel blocking and additional drug-dependent inotropic properties. Quinidine, aprindine and mexiletine appear to be combined Na channel and Ca channel inhibiting agents thus causing a larger negative inotropic effect than TTX. However, a superimposed positive inotropic mechanism may also be operative in some antiarrhythmic drugs (sparteine, AR-LH 31, high concentrations of mexiletine).

The contribution of Na channel block to the negative inotropic effect of antiarrhythmic drugs.

The specific Na channel blocker tetrodotoxin (TTX) produces a direct negative inotropic effect on the isolated guinea-pig papillary muscle stimulated at 1 Hz. The toxin is significantly more potent in reducing maximal upstroke velocity of the transmembrane action potential (Vmax, an index of the available Na conductance) than in reducing force of contraction (Fc), the IC50 for Vmax divided by the IC50 for Fc being 0.23 (95% confidence interval, 0.16-0.43). This IC50 ratio defines the negative inotropic influence of Na channel blockade per se, because TTX has no known action other than blocking Na channels. Vmax-reducing to negative inotropic concentration ratios were also obtained for 5 widely used and 2 experimental antiarrhythmic agents belonging to the Na channel-blocking class (class 1). Five of these drugs (aprindine, CCI 22277, disopyramide, mexiletine, and quinidine) differed significantly from TTX in that the Na channel block was associated with a stronger negative inotropic effect. It is concluded that one or more mechanisms in addition to Na channel blockade are involved in the negative inotropic effect of these antiarrhythmic drugs. If the antiarrhythmic activity of class 1 agents depended solely on Na channel block, more selective agents with less negative inotropic action could conceivably be developed.

Positive inotropic and electrophysiological effects of APP 201-533 can be explained by an increase of cardiac cyclic AMP.

The possible mechanism of action of the positive inotropic agent APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated. In guinea pig papillary muscles, APP 201-533 increased force of contraction concentration dependently at 10(-4)-10(-3) M. The effect was associated with an abbreviation of contraction and relaxation time. In guinea pig papillary muscles partially depolarized with 22 mM K+, APP 201-533 in concentrations of 10(-4) and 10(-5) M restored slow action potentials, which were not influenced by cimetidine, propranolol, and prazosin but were blocked by the Ca2+ antagonist PY 108-068 and by carbachol in an atropine-sensitive manner. The concentration-effect curve of histamine was shifted to the left in the presence of APP 201-533. These actions can be explained by the increase in cardiac cyclic AMP level that was found in rabbit papillary muscles and guinea pig left atria treated with APP 201-533 due to the known phosphodiesterase inhibitory effect of pyridinones. APP 201-533 increased the inotropic potency of dihydroouabain in guinea pig papillary muscles. It seems possible that this effect is based on an increased Ca2+ sensitivity of myocardial contractile structures as described previously for APP 201-533.