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Bitter taste receptors (Tas2rs), the members of the G-protein-coupled receptors, mediate the bitter taste and express in extra-oral tissues. Previous studies have shown that Tas2r mRNAs are expressed in the whole heart and cultured cardiomyocytes of neonatal rats. This study aimed to determine the expression of Tas2rs and their function in the adult rat hearts by using RT-qPCR techniques, Langendorff-perfused isolated hearts, and isolated sinoatrial (SA) nodes. The data presented here revealed the mRNA expression of Tas2rs and their coupled G-protein subunits in the SA node and left ventricle of adult rat hearts. Tas2r agonists, quinine and chloroquine, decreased the heart rate and increased the RR interval and QRS duration in Langendorff-perfused isolated rat hearts; they reduced the spontaneous beating rate of isolated SA nodes with pEC 50 values of 4.907 ± 0.045 and 4.968 ± 0.030, respectively. The blockade of Tas2r108 with abscisic acid, the inhibition of phosphodiesterases (PDEs) with 3-isobutyl-1-methylxanthine (IBMX), or the selective inhibition of PDE3 and PDE4 with a cocktail of cilostamide and rolipram, attenuated the negative chronotropic effects of quinine and chloroquine on the SA node. Furthermore, quinine and chloroquine suppressed the tachycardia effect of isoprenaline on the SA node and shifted the concentration-response curve of isoprenaline rightward. In summary, we provided a few lines of evidence that Tas2r agonists, quinine and chloroquine, decreased the heart rate by prolonging ventricular depolarization, and by attenuating the SA node pace in a PDE-dependent manner; they can counteract with β-adrenergic receptor activation and eliminate isoprenaline-induced tachycardia., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Factor Xa inhibitors reduce stroke in patients with atrial fibrillation. Pulmonary veins (PVs) and the sinoatrial node (SAN) are crucial for genesis of atrial fibrillation. However, the electrophysiological effects of factor Xa inhibitors (edoxaban and rivaroxaban) on PVs and the SAN remain unclear. Conventional microelectrodes were used to record the action potential in isolated rabbit PVs and SAN preparations before and after administration of edoxaban (0.1, 0.3, and 1 μM) or rivaroxaban (0.01, 0.03, 0.1, and 0.3 μM). A whole-cell patch-clamp was used to record the late sodium current (I Na-late ) in isolated single rabbit PV cardiomyocytes. Edoxaban significantly reduced PV spontaneous beating rates at 0.3 and 1 μM (N = 6 rabbits, P < 0.05), and reduced SAN beating rates at 1 μM (N = 6, P < 0.05). Similarly, rivaroxaban reduced PV spontaneous beating rates at 0.1 and 0.3 μM (N = 7, P < 0.05), and reduced SAN beating rates at 0.3 μM (N = 6, P < 0.05). However, neither edoxaban (1 μM) nor rivaroxaban (0.3 μM) reduced PV spontaneous beating rates in the presence of 1 μM BMS200261 (an inhibitor of protease-activated receptors type 1, PAR1 inhibitor) or 10 μM ranolazine (an inhibitor of late sodium current, I Na-late inhibitor). Edoxaban (0.3 and 1 μM) and rivaroxaban (0.1 and 0.3 μM) respectively decreased the I Na-late by 47%, 47%, 36%, and 49% (n = 9 PV cardiomyocytes from 5 rabbits, P < 0.05). In conclusion, Factor Xa inhibitors reduce PV spontaneous activities and may modulate occurrence of atrial fibrillation by inhibiting PAR1 and reducing the I Na-late in PVs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Since its approval in 1979 cisplatin has become one of the most extensively used chemotherapeutics in the clinic and although cell resistance and toxicity hinder its efficacy it continues to be a gold standard regimen. Cisplatin's side effects primarily include nephrotoxicity, gastrointestinal toxicity, neurotoxicity and ototoxicity. Cardiotoxicity is generally not defined as a side effect of cisplatin. However, over the past decade there has been a surge in the amount of clinical cases reporting a vast array of cardio-toxic events occurring during or shortly after cisplatin infusion, these range from angina to cardiac ischemia and chronic heart failure. This review intends to discuss the clinical cardiac manifestations of cisplatin specifically tachycardia and bradycardia which can be lethal and the possible mechanisms of action., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Angiotensin II (Ang II) plays an important role in the regulation of cardiac function, but its electrophysiological effects on sino-atrial (SA) node are not well understood. In this study, the immediate effect of Ang II on action potentials and ionic currents were investigated by using whole-cell patch-clamps in single guinea-pig SA node pacemaker cells. We demonstrated that Ang II exerted a negative effect on spontaneous firing rate, with a concomitant reduction in the slope of diastolic depolarization. The inhibitory effect of Ang II on spontaneous activity displayed a concentration-dependent manner in the range of 1-1000 nM, with IC50 of 8.34 nM. Ang II type 1 (AT1) receptor antagonist valsartan (1 μM) abolished the inhibitory effect. In contrast, Ang II type 2 (AT2) receptor antagonist, PD123319 (1 μM) didn't affect the action of Ang II. Ang II had no significant effect on hyperpolarization-activated current (If) in SA node cells. However, it significantly slowed the deactivation of the slowly activated delayed rectifier K+ current (Iks) and increased the tail current density. Furthermore, Ang II decreased the current density of L-type Ca2+ current in SA node cells. Our data demonstrate that Ang II reduces the auto rhythm of SA node cells via enhancing Iks and reducing ICaL. The result suggests a potential mechanism by which elevated levels of Ang II may be involved in the occurrence of SA node dysfunction in cardiac pathophysiology., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The effect of S(+)-efonidipine on sinus node action potential and calcium channel α-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S(+)-efonidipine (1 μM), slightly reduced by nifedipine (1 μM), but was not affected by R(-)-efonidipine. S(+)-efonidipine (1 μM), inhibited the expressed Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R(-)-efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S(+)-efonidipine may be explained by blockade of the Ca(V)1.3 channel current., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The structures of porcine and human beta(2)-adrenoceptors differ but the repercussions for porcine cardiac function are unknown. We investigated the function of porcine beta(2)-adrenoceptors in 3 cardiac regions, sinoatrial node, left atrium and right ventricle of newborn piglets. Both (-)-noradrenaline and (-)-adrenaline caused sinoatrial tachycardia: 60+/-10% and 62+/-7% of the maximum response (E(max)) to (-)-noradrenaline (-logEC(50)=9.0) and (-)-adrenaline (-logEC(50)=7.5) respectively, were resistant to antagonism by the beta(1)-selective CGP20712A (2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide) (300 nM) but antagonized by beta(2)-selective ICI118551 (erythro(+/-)-[1-(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) (50 nM), consistent with mediation through beta(2)-adrenoceptors. The phosphodiesterase3-selective inhibitor cilostamide and phosphodiesterase4-selective inhibitor rolipram did not affect catecholamine chronotropic potencies. Only small CGP20712A-resistant positive inotropic effects of (-)-adrenaline were detected in the left atria (13+/-2% of E(max)) and ventricular trabeculae (14+/-5% of E(max)). The atrial inotropic responses to (-)-noradrenaline and (-)-adrenaline faded; fades were prevented by rolipram but not cilostamide or concurrent cilostamide+rolipram respectively. (-)-Noradrenaline (ICI118551 present) increased left atrial cAMP levels through beta(1)-adrenoceptors that were markedly enhanced by rolipram but unaffected by cilostamide. Concurrent cilostamide+rolipram uncovered inotropic and cAMP responses to (-)-adrenaline (CGP20712A present). We conclude that sinoatrial beta(2)-adrenoceptors are more important than beta(1)-adrenoceptors in the mediation of tachycardia caused by both (-)-noradrenaline and (-)-adrenaline in the newborn piglet. beta(2)-adrenoceptors have only a minor role in the mediation of left atrial and ventricular inotropic effects of (-)-adrenaline. Catecholamine-evoked tachycardia is not controlled by PDE3 or PDE4. PDE4, but not PDE3, controls the atrial inotropic and cAMP beta(1)-adrenoceptor-mediated responses to (-)-noradrenaline. Both PDE3 and PDE4 blunt left atrial inotropic and cAMP responses to (-)-adrenaline through beta(2)-adrenoceptors., ((c) 2010 Elsevier B.V. All rights reserved.)

Blockade of sodium channels located in the sinoatrial node can slow diastolic depolarisation rate, recorded in vitro. The objective was therefore to determine whether these blockers could slow heart rate in vivo. The heart rate was firstly measured in spontaneously beating, isolated rat heart atria in the presence of different voltage gated sodium channel blockers. Tetrodotoxin and lidocaine slightly reduced heart rate whereas KC 12291 and R 56865, which mainly interact with the persistent component of the sodium current, concentration dependently and potently induced bradycardia. In the pithed rat, tetrodotoxin induced statistically significant decreases heart rate, maximal effects were: -32.2+/-6.1 beat per min. KC 12291 and R 56865 dose-dependently induced bradycardia (Delta heart rate obtained, -55.1+/-5.2 beat per min, P<0.05, and -71.9+/-8.5 bpm, P<0.05, respectively). In conclusion, voltage gated sodium channel blockers rather selective for the persistent current, exert a potent bradycardic effect in the rat.

As reported for cyclic nucleotide-gated channels in sensory neurons, we investigated the action of Ca2+-calmodulin and calmodulin antagonist (W7) on the apparent affinity of pacemaker (I(f)) channels for cAMP. In this study, we used the patch-clamp technique in inside-out macro-patch configuration in rabbit sino-atrial cells. Intracellular calmodulin perfusion had no effect on f-channel activity and did not change the cAMP-induced I(f) activation shift. Nevertheless, W7 decreased maximal conductance and induced a voltage shift of the current activation curve towards negative potentials. W7 did not modify the positive shift caused by cAMP, and cAMP did not prevent the effects of W7. Contrary to the cyclic nucleotide-gated channel, the f-channel is not directly modulated by Ca2+-calmodulin. The data suggest that W7 alters the voltage-dependent properties of I(f)independent of cAMP binding. This agent opens the pathway for a new family of bradycardic drugs.

We investigated whether substance P modulates pacemaker currents generated in cultured interstitial cells of Cajal of murine small intestine using whole cell patch-clamp techniques at 30 degrees C. Interstitial cells of Cajal generated spontaneous inward currents (pacemaker currents) at a holding potential of -70 mV. Tetrodotoxin, nifedipine, tetraethylammonium, 4-aminopyridine, or glibenclamide did not change the frequency and amplitude of pacemaker currents. However, divalent cations (Ni2+, Mn2+, Cd2+, and Co2+), nonselective cationic channel blockers (gadolinium and flufenamic acid), and a reduction of external Na+ from normal to 1 mM inhibited pacemaker currents indicating that nonselective cation channels are involved in their generation. Substance P depolarized the membrane potential in current clamp mode and produced tonic inward pacemaker currents with reduced frequency and amplitude in voltage clamp mode. [D-Arg1, D-Trp7,9, Leu11] substance P, a tachykinin NK1 receptor antagonist, blocked these substance P-induced responses. Furthermore, [Sar9, Met(O2)11] substance P, a specific tachykinin NK1 receptor agonist, depolarized the membrane and tonic inward currents mimicked those of substance P. Substance P continued to produce tonic inward currents in external Ca2+-free solution or in the presence of chelerythrine, a protein kinase C inhibitor. However, substance P-induced tonic inward currents were blocked by thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum or by an external 1 mM Na+ solution. Our results demonstrate that substance P may modulate intestinal motility by acting on the interstitial cells of Cajal by activating nonselective cation channels via the release of intracellular Ca2+ induced by tachykinin NK1 receptor stimulation., (Copyright 2004 Elsiever B.V.)

The action of the bradycardiac agents, cilobradine (DK-AH269) and zatebradine (UL-FS49), on the cardiac pacemaker current (If) was investigated on short Purkinje fibres from sheep hearts, using the two-microelectrode voltage-clamp technique, and on isolated rabbit sino-atrial cells with the patch clamp technique. These drugs reduce dose dependently the amplitude of the If, without modifying either the voltage dependence or the kinetics of channel activation. When voltage-clamp pulse trains were applied, cilobradine induced a use-dependent blockade of If that was stronger and faster than that with zatebradine. Recovery from blockade during prolonged hyperpolarization was significantly faster with zatebradine. Presumably, both drugs block the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel by gaining access to a binding site within the open channel pore, and are removed from the blocking site by strong hyperpolarization with large inward If through the open channel. Cilobradine, compared to zatebradine blocks If more effectively and faster in both preparations. Consequently cilobradine strongly reduces the pacemaker diastolic depolarization rate and the cell's firing frequency.

Modulation by taurine of the pacemaking activity and the underlying ionic currents in rabbit sino-atrial nodal cells was investigated at low and high cellular Ca2+ concentrations ([Ca2+]i) using a patch-clamp technique. At both pCa 8 and 6, taurine depressed the spontaneous activity, more strongly at pCa 6 than at pCa 8. Taurine, 20 mM, markedly inhibited the L-type Ca2+ current: by 56.9+/-2.8% (n=6, P<0.001) at pCa 8, and by 97.6+/-3.8% (n=7, P<0.001) at pCa 6. Also at 20 mM, taurine decreased the delayed rectifier K+ current by 26.8+/-2.6% (n=6, P<0.01) at pCa 6, whereas taurine had less or no effect at pCa 8. The hyperpolarization-activated inward current also decreased at both pCa 8 and 6, by 18.3+/-1.3% (n=8, P<0.05) and by 20.8+/-3.3% (n=8, P<0.05) in 20 mM taurine, respectively. Taurine caused a more potent inhibitory effect at pCa 6. Taurine often elicited dysrhythmias, at 20 mM, in 3 of 17 cells at pCa 8 and in 12 of 16 cells at pCa 6. During washout, the incidence of dysrhythmias or arrest increased further. These results indicate that taurine exerts more potent inhibitory actions on ionic currents under Ca2+ overload conditions in rabbit sino-atrial nodal cells. However, taurine would possibly elicit a cellular Ca2+ overload, when taurine application was discontinued.

Modulation by class Ia antiarrhythmic drugs, cibenzoline and disopyramide, of the pacemaking activity and the underlying ionic currents in rat sino-atrial nodal cells was investigated using current-clamp and whole-cell patch-clamp techniques. Both drugs depressed the spontaneous activity and often caused sinus arrest. The negative chronotropic effect was significant at 10 microM cibenzoline and 30 microM disopyramide. The L-type Ca(2+) current (I(Ca)) and the hyperpolarization-activated inward current decreased by 69.7+/-3.2% and by 45.8+/-3.0% at 30 microM cibenzoline and by 51. 2+/-3.3% and by 48.3+/-2.7% at 100 microM disopyramide, respectively. The delayed rectifier K(+) current, which is composed of rapidly and slowly activated currents (I(Kr) and I(Ks)), also decreased. The IC(50) values of I(Kr) for cibenzoline and disopyramide were 8.8+/-1. 1 and 25.1+/-2.3 microM, respectively. In the presence of 5 microM E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine), the IC(50) values of I(Ks) for cibenzoline and disopyramide were 12.3+/-1.8 and 81.1+/-2.3 microM, respectively. The I(Ks) was completely blocked by 30 microM 293B (trans-6-cyano-4-(N-ethylsulphonyl-N-methtamino)-3-hydroxy-2 , 2-dimethyl-chromane). These results indicate that the ionic currents are more sensitive to cibenzoline than disopyramide in rat sino-atrial nodal cells, and that I(Ca) and I(Kr) make major contributions to pacemaking activity.

Biophysical and pharmacological characteristics of the delayed rectifier K(+) current (I(K)) of rabbit sinoatrial (SA) node and atrioventricular (AV) node cells have been studied using the whole-cell patch clamp technique together with a recently developed antiarrhythmic agent, ibutilide. Ibutilide is a potent blocker of the rapid delayed rectifier K(+) current, I(Kr). Superfusion with ibutilide (10(-7) M) caused a decrease in the spontaneous firing frequency, depolarization of the maximal diastolic potential and prolongation of the action potential duration in both SA and AV node cells. In whole cell voltage clamp experiments done on myocytes from SA node, ibutilide (10(-7) M) blocked I(K) strongly (40%) and had smaller effects on Ca(2+) current (10%) and hyperpolarization-activated inward current, I(f) (11%). In AV node cells, the corresponding reductions were I(K) (68%), I(Ca) (13%) and I(f) (10%), respectively. A 10-fold increase in the concentration of ibutilide further decreased I(K) in SA node cells (67+/-8%), and blocked I(K) almost completely in AV node cells. These results are consistent with the hypothesis that the delayed rectifier K(+) current in SA node cell is generated by both I(Kr) and I(Ks), whereas I(Kr) predominates in AV node cells. Knowledge of the differences in the distribution of I(Kr), as well as the different sensitivity to blockers of I(Kr) in nodal cells, is important for understanding modifications of the automaticity, conduction velocity, and refractoriness by class III antiarrhythmic agents.

To test the hypothesis that the Ca(2+) channel blocker mibefradil slows heart rate due to inhibition of T-type Ca(2+) current in pacemaker cells, we studied effects of mibefradil on action potentials and ionic currents of isolated rabbit sinus node cells using the patch clamp technique. Mibefradil (100 nM and 1 microM) reduced spontaneous rate, decreased action potential amplitude and finally stopped impulse initiation. This action was not due to the drug effect on hyperpolarization-activated pacemaker current, but can be explained by attenuation of both T- and L-type Ca(2+) currents, which were inhibited by mibefradil almost equally (55% and 64% inhibition with 1 microM for T- and L-types, respectively).

The effect of the dihydropyridine derivative, 1,4-dihydro-2,6-dimethyl-4-(fluorenon-4-yl)pyridine-3,5-dicarboxyl ic acid diallyl ester (fluodipine) was studied in vitro in different rabbit, rat and guinea pig preparations and in vivo in the rabbit in order to characterize its pharmacological profile at cardiac and at vascular sites. Compared to nifedipine, fluodipine showed a similar cardiodepressant activity, and a much lower inhibitory activity on vascular contraction. The highest tissue selectivity was observed in guinea pig preparations: fluodipine was about 2-3 times more effective than nifedipine on chronotropism and inotropism in isolated atria, and about 150 times less effective on aortic strip contraction. Accordingly, fluodipine (i) showed high-affinity binding to guinea pig ventricular L-type cardiac Ca2+ channels (Ki=2.57 nM), (ii) was about 80 times less effective than nifedipine to inhibit Ca2+ influx in vascular smooth muscle cells and (iii) induced a significant reduction of heart rate in the anesthetized rabbit (ID25=8.5 mg kg(-1), i.v.) without affecting the blood pressure up to 20 mg kg(-1), whereas nifedipine showed a significant hypotensive effect at very low doses (ID25=0.18 mg kg(-1), i.v.). The pacemaker current If of rabbit sino-atrial node myocytes was not affected by fluodipine. These findings demonstrate that fluodipine exerts selective cardiodepressant activity, likely due to a higher affinity for cardiac than for vascular Ca2+ channels.

Effects of efonidipine, a dihydropyridine phosphonate Ca2+ channel antagonist, on the guinea-pig heart were compared with those of nifedipine. In the sino-atrial node, 1 microM efonidipine produced increase in cycle length accompanied by prolongation of the phase 4 depolarization which was not prominent with 0.1 microM nifedipine. In ventricular myocytes, both efonidipine and nifedipine produced inhibition of the L-type Ca2+ current, nifedipine being tenfold more potent than efonidipine. Efonidipine also inhibited the T-type Ca2+ current at higher concentrations but nifedipine did not. Both Ca2+ channel antagonists had no or only a weak effect on K+ currents. In addition, 40 microM Ni2+, which selectively inhibited the T-type Ca2+ current, had no effect on myocardial Ca2+ transients and contractile force. In conclusion, efonidipine was shown to have inhibitory effects on both L- and T-type Ca2+ currents, which may contribute to its high negative chronotropic potency.

The effects of the two isomers, (+)-S 16257 and (-)-S 16260, of a new bradycardic agent, (+/-)-S 15544 (7,8-dimethoxy 3-[3-[[(4.5-dimethoxybenzocyclobutan-1-yl)methyl] methylamino]propyl]1,3,4,5-tetrahydro-2H-3-benzazepin-2-one), were compared in vitro and in vivo on cardiac spontaneous rate and repolarization time. In the isolated rabbit sino-atrial node, the three compounds (3 microM) were equi-effective to reduce the action potential firing rate. In anesthetized pigs, both isomers (0.03, 0.1, 0.3 and 1 mg kg(-1) i.v.) were equipotent to reduce heart rate. For all compounds, the negative chronotropic effect resulted from a reduction in the slope of diastolic depolarization of pacemaker cells. In sino-atrial node cells, (-)-S 16260 (3 microM) increased action potential duration while (+)-S 16257 had a smaller effect. In driven guinea-pig papillary muscles exposed to increasing concentrations of compounds (0.1 to 10 microM) a small prolongation of action potential duration was observed. This prolongation was more marked in rabbit Purkinje fibers stimulated at a low rate. In all cardiac preparations the highest prolongation was observed with (-)-S 16260. In vivo, (-)-S 16260 prolonged QTc at the two highest doses tested while (+)-S 16257 had no effect. In conclusion, resolution of (+/-)-S 15544 into its two enantiomers yielded compounds with the same bradycardic effects. Of the isomers, (+)-S 16257 has an increased specificity with minimal direct effect on action potential repolarization.

Effects of various Ca2+ channel antagonists on the action potential configuration of rabbit sino-atrial node tissue were examined with standard microelectrode techniques. All Ca2+ channel antagonists decreased the maximum rate of phase 0 depolarization (Vmax) and increased the cycle length. The potency order to increase the cycle length was nisoldipine = verapamil > nifedipine = clentiazem > efonidipine > diltiazem. The potency order to decrease Vmax and to shift the threshold potential to a positive direction was the same as that to increase the cycle length, indicating that the major mechanism of negative chronotropism was inhibition of the L-type Ca2+ current. All Ca2+ channel antagonists except efonidipine shifted the maximum diastolic potential to the positive direction, decreased the action potential amplitude and prolonged the action potential duration. The effects of nifedipine were slightly weaker than those of other drugs when compared at equally bradycardiac concentrations. These differences may reflect differences in drug effects on currents other than the L-type Ca2+ current. A characteristic feature of efonidipine was selective suppression of the later phase of pacemaker depolarization with no effect on action potential amplitude and duration. Similar suppression of the later phase was observed with 50 microM Ni2+, which is reported to inhibit the T-type, but not L-type, Ca2+ current. Thus, efonidipine appears to suppress selectively the later phase of pacemaker depolarization through inhibition of both L- and T-type Ca2+ currents, which may be the underlying mechanism for its reported potent negative chronotropic but weak inotropic activity.

We investigated the sympathetic-parasympathetic interactions involved in SA nodal pacemaker activity and AV conductivity in the anesthetized dog heart. Stimulation of the intracardiac parasympathetic nerves to the SA nodal region (SAPS) and stimulation of the intracardiac parasympathetic nerves to the AV nodal region (AVPS) induced negative chronotropic and dromotropic responses, respectively. Cardiac sympathetic stimulation, aminophylline, 3-isobutyl-1-methylxanthine (IBMX, a relatively pure nonselective phosphodiesterase inhibitor) and methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-p iridine-5-carboxylate (Bay k 8644, a Ca2+ channel agonist) increased sinus rate and decreased AV conduction time. Sympathetic stimulation augmented the negative chronotropic response to SAPS but not the negative dromotropic response to AVPS, IBMX augmented both responses, Bay k 8644 augmented the chronotropic response and attenuated the dromotropic response, and aminophylline did not affect the chronotropic response to SAPS and inhibited the dromotropic response to AVPS. Additionally, when Bay k 8644 directly given via the AV node artery decreased AV conduction time, it attenuated the negative dromotropic response to AVPS and carbachol injected into the AV node artery. These results suggest that the differential sympathetic-parasympathetic interactions on sinus rate and AV conduction are at least partly induced by an interaction between changes in slow inward Ca2+ current or intracellular Ca2+ and the cardiac effects of acetylcholine in the heart in situ.

We studied the cardiac electrophysiological effects of falipamil, a specific bradycardic agent, in conscious dogs, in comparison with those of alinidine. Sinus rate, corrected sinus recovery time, and Wenckebach point were measured in six intact dogs. Atrial rate, ventricular rate, and atrial effective refractory period were measured in six atrioventricular-blocked dogs. In both groups, blood pressure was also monitored. Each dog received, with at least a three-day interval, falipamil (hydrochloride) and alinidine (hydrobromide) in four successive intravenous injections, 30 min apart, at 0.5, 0.5, 1, and 2 mg kg-1. Falipamil increased sinus rate and atrial rate, but decreased ventricular rate, whereas alinidine decreased sinus rate and ventricular rate, but increased atrial rate. Falipamil shortened corrected sinus recovery time and increased Wenckebach point, whereas alinidine lengthened corrected sinus recovery time and decreased Wenckebach point. Falipamil and alinidine increased atrial effective refractory period. Neither falipamil nor alinidine modified mean blood pressure in either group. Overall, these results show that (a) falipamil exhibits effects on the electrical activity of the heart, reflecting the predominant direct vagolytic effect of this drug, (b) alinidine exhibits effects reflecting the marked antiarrhythmic potential of this agent, and (c) thus indicate that two drugs with almost identical specific bradycardic properties can produce quite different electrophysiological effects in the conscious dog.

The chronotropic actions of Na+, K+, Cl- cotransport were investigated by studying the effects of the loop diuretics bumetanide and furosemide, specific inhibitors of the cotransporter, on an isolated rat sino-atrial node preparation. Application of bumetanide decreased the cycle length from 0.334 s (+/- 0.087 S.D.) to 0.279 s (+/- 0.083, n = 16, P = 6.5 x 10(-6)) in Hepes-buffered physiological salt solution (PSS). Similar decreases were recorded in bicarbonate-buffered PSS. Chloride channel blockers indicate that the tachycardia evoked by loop diuretics is not due their blocking of chloride channels. Thus, 4,4'-dinitrostilbene-2,2'-disulphonic acid (DNDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) had a negative chronotropic action and 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihydro-2-methyl-1-oxo-1H-inden -5-yl) oxy] acetic acid (IAA-94) produced no change in cycle length. Pharmacological manoeuvres indicate that the positive chronotropic action of loop diuretics is associated with catecholamine release. The positive chronotropic action of bumetanide was inhibited by the beta-adrenoceptor antagonists, propranolol and atenolol, but was unaffected by atropine.

To investigate cellular electrophysiologic alterations due to lipid peroxidation of the cell membrane by free radicals as a possible cause of coronary reperfusion arrhythmias, we studied the effects of t-butyl hydroperoxide on the spontaneous action potential and membrane currents of the rabbit sinoatrial and atrioventricular node preparations (0.2 x 0.2 x 0.1 mm). 1-5 min of superfusion with t-butyl hydroperoxide (100-500 microM) caused a transient increase in the spontaneous firing frequency by 9%, accompanied by a 4% increase in the action potential amplitude and a 33% increase in the maximal rate of depolarization (P < 0.05, n = 6). t-Butyl hydroperoxide then gradually suppressed physiological automaticity, but induced abnormal repetitive firing due to early and delayed after-depolarizations. 15 min of superfusion with t-butyl hydroperoxide caused a complete standstill of nodal cells at a resting potential of -46 +/- 3 mV (n = 12). Such effects of t-butyl hydroperoxide on the spontaneous action potential were attenuated by pretreating the cells with butylated hydroxytoluene, a lipid peroxidation inhibitor. Voltage clamp experiments using double microelectrode methods revealed that t-butyl hydroperoxide transiently increased the Ca2+ current by 22% after 5 min of superfusion but subsequently reduced it to 46% of the control value after 15 min (P < 0.05, n = 6). Similar biphasic changes were observed in the delayed rectifying K+ current and hyperpolarization-activated inward current (n = 6). Background current was progressively increased without any change in its reversal potential (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

E4080, a novel bradycardic agent acts on various ionic currents including the hyperpolarization-activated inward current (I(f)), L-type Ca2+ current (ICa) and ATP-sensitive K+ (K+ATP) current in mammalian heart and vascular tissues. We thus investigated the chronotropic and inotropic effects of E4080 and its interaction with the positive cardiac responses to norepinephrine, 3-isobutyl-1-methyl-xanthine (IBMX) and Bay k 8644 in the isolated, blood-perfused dog right atria and left ventricles. E4080 (0.01-1 mumol) decreased the sinus rate and atrial and ventricular contractile forces in a dose-related manner. Glibenclamide (3 mumol) partly blocked the decrease in atrial force but not the decreases in sinus rate and ventricular force induced by E4080. Atropine (10 nmol) did not affect the negative cardiac responses to E4080. E4080 (0.01-1 mumol) inhibited the positive chronotropic responses to norepinephrine and IBMX dose dependently, but did not inhibit the positive inotropic ones in isolated atria. E4080 affected neither positive chronotropic nor inotropic responses to Bay k 8644. These results suggest that (1) the activation of K+ATP channels by E4080 is partly related to the decrease in atrial force but not the decreases in sinus rate and ventricular force, and (2) the selective inhibition of E4080 of the cyclic AMP-dependent positive chronotropic responses but not inotropic ones is probably due to the inhibition of I(f) rather than other properties, e.g., activation of K+ATP channels and inhibition of ICa in the dog heart.

The cardiohemodynamic effects of E4080, a novel bradycardiac agent with a coronary vasodilating feature, were studied in anesthetized open-chest dogs. E4080 (0.3 and 1 mg/kg i.v.) decreased heart rate (HR), mean aortic pressure (MAP) and total peripheral resistance, and increased coronary blood flow (CBF) without affecting cardiac output and the electrocardiogram. The maximum rate of rise in left ventricular pressure decreased at 1 mg/kg. In addition, E4080 (0.3 and 1 mg/kg i.v.) decreased myocardial oxygen consumption. On administration in sinus node artery, E4080 (10 and 30 micrograms) selectively decreased HR. Glibenclamide, an ATP-sensitive K+ channel blocker (5 mg/kg i.v.), inhibited both the increase in CBF and the decrease in MAP caused by E4080 (1 mg/kg i.v.) but did not inhibit the bradycardia. These results suggested that E4080 has both bradycardiac and coronary vasodilating effects, and that activation of ATP-sensitive K+ channel contributes to the vasodilating action of E4080 but not to the bradycardiac action.

The effects of mepirodipine, a new 1,4-dihydropyridine calcium antagonist, on the membrane potentials were examined on spontaneously beating rabbit sino-atrial (SA) node cells and on the membrane currents under voltage-clamped conditions. Mepirodipine 3 x 10(-9) M significantly decreased the action potential amplitude and the maximum rate of depolarization. The action potential duration and the cycle length were prolonged. Sinus arrest occurred at 10(-8) M in all of five preparations. In voltage-clamped SA node cells, mepirodipine in concentrations higher than 3 x 10(-9) M decreased the slow inward current. It did not affect the steady state outward current and the hyperpolarization-activated inward current. Verapamil, diltiazem and nifedipine produced similar changes in the action potential parameters, but at a concentration of 10(-6) M. At concentrations higher than 10(-5) M, they elicited sinus arrest. These results suggest that mepirodipine is a more potent inhibitor of spontaneous calcium-dependent SA node impulse generation than the three other calcium antagonists tested.

The effects of adenosine and adenosine triphosphate (ATP) on sinus cycle length (SCL) and sinoatrial conduction time (SACT) estimated by constant atrial pacing were studied in isolated, blood-perfused canine right atria. Adenosine and ATP were infused into the sinus node artery at a rate of 1, 2 and 4 micrograms/min. Both adenosine and ATP caused an increase in SCL and SACT in a dose-dependent manner and decreased atrial developed tension. There was no significant difference between the effect of adenosine and that of ATP on SCL and SACT. The prolongation of SACT induced by 4 micrograms/min of adenosine and ATP was significantly inhibited by a single injection of 1 to 3 mg of aminophylline, although this dose level of aminophylline did not significantly suppress the prolongation of SCL produced by adenosine and ATP. From these results it is concluded that both adenosine and ATP lengthen SCL and SACT in a dose-related manner, and that aminophylline blocks the increase in SACT much more easily than that in SCL.

The effects of L 9394, a new compound closely related to amiodarone, were investigated in 44 patients by electrophysiological studies. Thirty two patients were given an intravenous injection of one of the following doses: 0.5, 1, 1.5 or 2 mg/kg. Conduction times of the A-V node (A-H interval) and of the His-Purkinje system (H-V interval) were measured by recording the His bundle potential. Refractory periods were determined by the extrastimulus technique. In the remaining 12 subjects, the action of L 9394 on sinus node was assessed. Sinus node recovery time was measured by rapid atrial stimulation and estimated atrial-sinoatrial conduction time deduced from the effects of atrial premature stimulation on sinus node activity. Results were as follows: (1) A-V nodal conduction was depressed after L9394. The A-H interval increased in direct proportion to the dose. Similarly, the effective and functional refractory periods of the A-V node were prolonged, more markedly after higher doses. (2) No change was shown in the His-Purkinje system. The H-V interval was unaltered. (3) L 9394 had no significant effects on the atrial or ventricular muscle. (4) Sinus cycle length as well as sinus node recovery time did not change significantly. In 7/12 patients, results of premature atrial stimulation suggested the formation of a sinoatrial block.

Two new substances, alinidine (St 567) and AQ-A 39, previously described as 'specific bradycardic agents' were investigated with respect to their effects on the rate of electrical discharges from sinus nodes of isolated right guinea-pig atria. Both substances decreased the discharge rate concentration dependently within a wide range (3-100 micrograms/ml). Low external Ca2+ (0.18 mM) increased and low external NaCl (62 mM) decreased the rate lowering effect of alinidine as well as of AQ-A 39. In contrast, the reference compound verapamil (an inhibitor of slow inward current) was less effective in low Ca2+ and more effective in low NaCl. The similar reactions of alinidine and AQ-A 39 are discussed with respect to their different chemical structure and different electrophysiological action patterns as described so far.

The effects of bepridil and nifedipine, newly developed Ca2+ antagonists, were studied on the spontaneous action potentials of the true pacemaker cell preparations (0.5 X 0.5 mm) obtained from the rabbit sino-atrial (SA) node. At the lower concentrations, bepridil (10(-6) M) and nifedipine (10(-8) M) decreased the spontaneous activity in accordance with the decrease of the maximum rate of rise of the action potential (Vmax), without changing the maximum diastolic potential (MDP) and the 50% action potential duration ( APD50 ). At the high concentrations, bepridil (5 X 10(-6) M) and nifedipine (5 X 10(-8) M) stopped the sinus automaticity with the depolarization of the MDP. The action potential could not be induced by the hyperpolarizing electrical stimulation in the presence of the higher concentration of these drugs. The results suggest that bepridil and nifedipine have a primary effect of the blocking action on the SA node slow channels, similar to the action of verapamil. This can account for their negative chronotropic action.

The effects of the muscarinic antagonist gallamine were studied in anesthetized dogs via selective perfusion of the SA and AV nodal arteries. Before gallamine, acetylcholine injected into the SA node artery induced asystole while injection into the AV node artery induced heart block. After gallamine, acetylcholine via the AV node artery was without effect while, via the SA node artery, acetylcholine still induced negative chronotropic effects. Thus the muscarinic receptors of the SA and AV nodes may be inhomogeneous.

The electrical activity of the sino-atrial node was studied after the selective cannulation of its artery in the intact open-chest dog. After tetrodotoxin infusion and despite cardiac arrest, a slow rhythmic activity was recorded from the sinus epicardial electrode.

The isolated blood-perfused preparations of canine atrium were suspended in a bath and perfused with arterial blood led from the carotid artery of the heparinized donor dog. Disopyramide caused dose-related negative chronotropic and inotropic effects in a dose range of 30-1000 microgram when injected directly into the cannulated sinus node artery of the isolated atrium. The order of potencies for inducing the negative chronotropic effect in isolated atrium preparations was verapamil greater than propranolol greater than lidocaine = quinidine greater than phenytoin greater than or equal to disopyramide greater than procainamide. On the other hand, the order of potencies for inducing the negative inotropic effect was verapamil = propranolol greater than lidocaine greater than or equal to phenytoin greater than disopyramide greater than procainamide greater than or equal to quinidine. When disopyramide (1 mg/kg or 3 mg/kg) was administered i.v. into the jugular vein of the donor dog, the systemic blood pressure of the donor dog was markedly decreased. However, the tension developed and sinus rate of the isolated atrium were only slightly decreased. Disopyramide produced greater suppression at higher frequencies and slightly depressed the calcium chloride-induced positive inotropic effects.

Electrophysiological effects of alinidine on rabbit sino-atrial node cells were examined. Alinidine was applied in concentrations between 0.3 and 100 micrograms/ml and decreased the spontaneous frequency in a dose-dependent manner. The maximum rate of rise and the amplitude of action potentials of the spontaneously beating rabbit sino-atrial node were decreased in the presence of alinidine concentrations higher than 10 and 100 micrograms/ml, respectively. The maximum diastolic potential was depolarized by alinidine at 100 micrograms/ml. The main effect of alinidine was a dose-dependent decrease in slope of diastolic depolarization (a prolongation of the cycle length) and a delayed repolarization of the action potential. In voltage clamp experiments, alinidine suppressed the slow inward current (Is) and the outward current (Ik) dose dependently, without altering steady-state inactivation of Is (f infinity) and the activation of Ik (p infinity). The hyperpolarization-activated inward current (Ih) was also reduced. These results suggested that alinidine decreased Is, Ik and Ih due to reduction in the conductance of these current systems. The changes in the ionic currents in the presence of alinidine can explain the changes in configuration of the action potential and must contribute to the negative chronotropic action of alinidine.

The effects of cyproheptadine (0.1-10 microM) on the membrane potentials and currents of rabbit sinoatrial node were examined with the double-microelectrode voltage clamp technique. Cyproheptadine reduced the heart rate, maximum rate of depolarization and action potential amplitude. It also decreased the slope of phase 4 depolarization. On the current systems, cyproheptadine decreased the slow inward current (Isi), the time-dependent potassium outward current (Ik) and the hyperpolarization-activated current (Ih). The reduction of Isi was the major effect. Furthermore, Isi was progressively decreased by repetitive membrane depolarization during administration of cyproheptadine, an effect suggestive of frequency-dependent block of Isi. These electrophysiological observations indicate that cyproheptadine has a calcium antagonistic property, and additionally, decreases Ik and Ih in rabbit sinoatrial node.

The electrophysiological effect of dilazep (1 X 10(-7) -3 X 10(-6) M), a coronary vasodilator, was examined on rabbit sinoatrial node cells using glass microelectrode and double microelectrode voltage clamp methods. Dilazep exerted a negative chronotropic effect and decreased the maximum rate of depolarization of the upstroke of the action potential and the amplitude of the action potential. The action potential duration at half-amplitude was prolonged after the drug perfusion. The voltage clamp experiment showed that dilazep reduced the slow inward current (Isi), the potassium outward current (IK), and the hyperpolarization-activated current (Ih). The recovery time constant of Isi was also prolonged. In conclusion, it is indicated that dilazep has no specific effect on the current system, but the drug depresses specifically the electrical activity of sinoatrial node cells.

Transmembrane potentials of pacemaker fibers of the sinus node were recorded to analyze the effect of harmaline (HME) on cardiac automaticity. A short exposure to HME 2.1 X 10(-5) or 8.3 X 10(-5) M produced a long lasting non-cholinergic depression of the automaticity: the slope of diastolic depolarization of the pacemaker fibers was depressed, but the maximum diastolic potential remained unmodified. The automaticity of the sinus node was not abolished by prolonged exposure to HME 8.3 X 10(-4) M, but a reversible sino-atrial block developed.

The sinus node of the guinea pig was perfused in vitro and potassium uptake was studied in the absence and in the presence of several nicotinic agonists and antagonists. The following results were obtained: (1) the decrease in K uptake caused by a low (10(-9)M) concentration of acetylcholine was changed to an increase when acetylcholine was given in the presence of nicotinic blockade; (2) a small concentration (10(-10)M) of atropine potentiated the decrease in K uptake induced by a low concentration of acetylcholine and 10(-8)M atropine abolished it: (3) a small concentration of nicotine (10(-10)M) decreased K uptake; (4) 1,1-dimethyl-4-phenylpiperazinium (DMPP) did not modify K uptake; (5) the lack of effect of DMPP was not affected by hexamethonium; (6) trimethylphenylammonium (TMPA) decreased K uptake; and (7) the inhibitory effect of TMPA was abolished by decamethonium. It is concluded that a nicotinic receptor in the sinus node mediates the inhibitory action of a low concentration of acetylcholine on K uptake.

The effects of mexiletine (1-100 microM) were examined on membrane potential and current of rabbit sinoatrial node cells by means of conventional microelectrode and double microelectrode voltage clamp techniques. Mexiletine decreased, in a dose-dependent manner, the maximum rate of depolarization of the action potential and the action potential amplitude, and increased the spontaneous cycle length. The slope of the diastolic depolarization (phase 4) was also reduced. In the voltage clamp experiment, mexiletine (40-100 microM) reduced the slow inward current (Isi), the potassium outward current (IK) and the hyperpolarization-activated current (Ih). The kinetic variable of IK was not altered by the drug. These results suggest that mexiletine does not have a specific effect on a single-current system, but that relatively high concentrations of mexiletine exert an inhibitory effect on the electrical activity of the sinoatrial node cells.

The action of amiodarone (1.5 X 10(-5) M) on sinus node activity of spontaneously beating isolated right atria of rabbit at 30 degrees C was investigated using a microelectrode technique. The drug significantly increased the action potential duration and decreased the slope of diastolic depolarization, both effects leading to a reduction of the sinus rate. In contrast to beta-blocking agents, amiodarone reduced but did not completely abolish the adrenergic effects on the sinus node activity. It is concluded that the amiodarone-induced bradycarida observed in clinical trials might be due to a direct effect of the drug on the sinus node.

The effects of 4-aminopyridine (4-AP, 0.3 to 300 micrograms) on atrial rate and atrial muscle contractile force were investigated in the isolated, blood-perfused dog atrial preparation. Low doses (less than 30 micrograms) of 4-AP injected into the sinus node artery caused a dose-dependent positive inotropic response and a negligible positive chronotropic response. A higher dose (300 micrograms) of 4-AP induced a transient positive chronotropic response followed by a negative response and positive and negative inotropic responses. The negative cardiac responses to 4-AP were completely inhibited by an adequate dose of atropine and were potentiated by physostigmine. TTX or C6 suppressed partly, but significantly the negative responses induced by 4-AP. On the other hand, the negative responses to electrical stimulation (ES) were inhibited by atropine, C6 and TTX and those to ACh were blocked by atropine but not by C6 or TTX. The positive responses to 4-AP were not affected by propranolol but were potentiated by atropine. The positive inotropic response to 4-AP was significantly suppressed by a calcium channel blocker, diltiazem. From these results, it is concluded that the cardiac responses to 4-AP are composed of direct positive responses and negative responses which are related to activation of parasympathetic ganglionic neurotransmission.

The electrophysiological effects of bunazosin, a novel alpha-adrenoceptor antagonist, were examined on isolated spontaneously beating sinoatrial node preparations of the rabbit by means of a double-microelectrode voltage clamp method. Bunazosin (above 10 microM) reduced the beating frequency, and the maximum rate of rise and the amplitude of action potentials. The slope of the diastolic depolarization (phase 4) was also decreased by the drug whereas the action potential duration at 50% repolarization was prolonged. Bunazosin decreased the slow inward current (Isi) and the time-dependent potassium outward current (IK). However, the major effect was the reduction of Isi. The results indicate that bunazosin, an alpha-adrenoceptor antagonist, depresses the action potential and automaticity of the sinoatrial node by inhibition of Ca channels.

The effects of pentobarbital on heart rate, reflexly mediated vagal activity and the automaticity (intrinsic rate) of the sinoatrial (SA) node were investigated in rabbits. When administered in three cumulative doses (10 mg/kg i.v. each) at 15 min intervals, each dose produced transient hypotension which was not modified by prior muscarinic receptor blockade (MRB), beta-receptor blockade (BRB), or combined MRB and BRB. Subanesthetic doses (10 mg/kg) of pentobarbital produced tachycardia in normal rabbits, as well as in rabbits with prior BRB. After pentobarbital, MRB failed to increase the heart rate, indicating total loss of resting vagal tone. Failure to induce tachycardia in rabbits with prior MRB indicated the absence of sympathetic stimulation in pentobarbital-induced tachycardia. In rabbits with prior BRB, pentobarbital enhanced the hypotensive effects of acetylcholine and nitroglycerin and abolished nitroglycerin-induced tachycardia without significant effects on the magnitude of reflex bradycardia produced by norepinephrine. Pentobarbital had minimal, transient depressant effects on the intrinsic rate of the SA node. These results indicate that pentobarbital produces total loss of resting vagal tone without major impairment of reflex vagal activation.

The cardiovascular effects of atriopeptins (AP) I, II and III were compared in spontaneously beating or electrically stimulated guinea pig atria and in rabbit aortic strips precontracted by various agonists. Atriopeptins did not significantly affect sinus nodal rate or atrial contractility. AP II and III, although more potent than nitroprusside, exhibited similar vasorelaxant profiles against vascular strips maximally stimulated by norepinephrine, high [K+]0 or Ca2+ ionophore A23187. The ability of atriopeptins and nitroprusside to relax ionophore-induced vascular tension implies an intracellular mechanism of action.

The effects of the two neuroleptics, melperone (a butyrophenone) and thioridazine (a phenothiazine), were compared on the electrical and mechanical activity of isolated rat atria. Both electrically stimulated and spontaneously beating atria were used. Melperone was found to prolong the effective refractory period while the threshold for electrical stimulation i.e. the excitability, was almost unaffected. Thioridazine caused a similar prolongation of the effective refractory period, but also decreased the excitability significantly. In contrast to melperone, thioridazine had a negative inotropic effect. The spontaneous pacemaker activity was depressed and the sinus node recovery time increased to a greater extent after melperone than after thioridazine. The results taken together with other recent data support the hypothesis that melperone may be a type III anti-arrhythmic according to the classification of Vaughan Williams, in contrast to thioridazine which has a quinidine-like action (type I). The results also indicate that melperone in addition to prolonging the effective refractory period, may act as an anti-arrhythmic agent by depressing automaticity.

The effects of propafenone (1-50 micrograms/ml) on the membrane potential and currents of the rabbit sino-atrial node were studied using the voltage clamp technique. Propafenone decreased the heart rate, amplitude of the action potential and maximum rate of depolarization. It also depolarized the maximum diastolic potential and the resting potential and prolonged the action potential duration dose dependently. On the current systems of the sino-atrial node, propafenone reduced the outward current (ik), the inward current activated by hyperpolarization (ih) and the slow inward current (is) dose dependently. The decrease in is and ik by propafenone was due to the reductions in their conductance, not to the changes in the voltage dependence of the inactivation of is or activation of ik. The decrease in ik might be the ionic mechanism of the negative chronotropic effect of propafenone.

Possible adrenergic mechanisms involved in acetylcholine (ACh) induced potassium movements in the sinus node have been investigated using a tracer potassium (42K) and a microelectrode technique. The ACh-induced increase in 42K uptake was enhanced by propranolol and was unaffected by phentolamine. Reserpinization neither prevented the ACh-induced increase in 42K uptake nor the enhanced effect in the presence of propranolol. In reserpinized preparations, ACh-induced 42K uptake was the same before and after norepinephrine (NE) administration, but was greater after acute reserpinization. NE alone induced an increase in 42K uptake but the simultaneous administration of ACh and NE provoked an increase in 42K uptake similar to that obtained with ACh alone. When both neuromediators and atropine were given simultaneously, an increase in 42K uptake did not occur. Thus, the ACh induces an increase in 42K uptake independently of NE. ACh antagonizes the NE effect on 42K uptake independently of a muscarinic interaction.

The effects of a new antiarrhythmic, bunaphtine, on the electrical and mechanical activity of isolated rat atria were compared with those of quinidine and amiodarone. Both electrically stimulated and spontaneously beating atria were used. In spontaneously beating double atria bunaphtine produced a dose-dependent decrease in the rate, contractile force, work index and maximum following frequency at which the atria could respond to electrical stimulation, depressed the pacemaker activity and increased the sinus node recovery time. In isolated left atria bunaphtine prolonged the effective refractory period and decreased atrial excitability. Bunaphtine did not block positive chronotropic and inotropic responses to isoprenaline and did not reduce the positive inotropic effect of raised calcium concentrations. These results support the hypothesis that bunaphtine exerted on isolated atria a direct cardiodepressant effect similar to that of quinidine, and that it may be classified as a class 1 antiarrhythmic according to the classification of Vaughan Williams.

Cardiac drugs known to affect sinus function mostly exhibit negative chronotropic activity. However, impulse conduction within the sinus node can also be influenced. Recently we studied the direct effects of bepridil on rabbit sinus function. It appeared that sinoatrial impulse conduction was depressed markedly with drug concentrations that did not affect sinus automaticity. In the present study the direct effects of verapamil, diltiazem and disopyramide on rabbit sinus function and atrial conduction properties were studied. Verapamil (8.8 x 10(-8) M) reduced the sinoatrial impulse conduction velocity by 35% and prolonged sinoatrial refractoriness by 36%. On the other hand, the sinus rate and atrial conduction parameters were hardly affected. Diltiazem (5 x 10(-6) M) exerted similar actions on the sinoatrial impulse conduction velocity and caused a simultaneous reduction in the sinus rate of 48%. Atrial conduction remained unaffected. Disopyramide (5 x 10(-5) M) depressed both the atrial and nodal conduction properties markedly, whereas the sinus rate was reduced moderately, by almost 20%. Thus, verapamil, diltiazem and disopyramide act differently on sinus function and atrial conduction, whereby the predominant effect of verapamil and diltiazem on sinoatrial conduction properties favours the occurrence of a sinus exit block.

The electrophysiological effects of trimebutine maleate were studied on rabbit sinus node cells with the two-microelectrode voltage clamp method. Trimebutine (above 10 microM) produced a negative chronotropic effect accompanied by decreases in the maximum upstroke velocity at phase 0, slope of phase 4 depolarization and action potential amplitude. The effects on the current systems were depression of the slow inward current and a decrease in the current oscillations induced by elevating [Ca]0. It is concluded that trimebutine exerts a Ca2+ channel blocking effect on the sinus node pacemaker cells.