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1. The cardiac chronotropic effects of rilmenidine (10-100 micrograms kg-1) and clonidine (1-10 micrograms kg-1) were studied in conscious dogs with chronic atrioventricular block. 2. Rilmenidine and clonidine initially (< 3 min) decreased atrial rate, although the effect was not related to dose. More lastingly, ventricular rate was decreased in a dose-related manner (ratio, 1:21). Rilmenidine lowered mean blood pressure only at 100 micrograms kg-1, while clonidine had the same effect at doses of 5 micrograms kg-1 upward (ratio, 1:15). 3. When administered after atropine and pindolol, rilmenidine (50 micrograms kg-1) produced a decrease in atrial rate, with an identical intensity but longer duration than under basal conditions. When clonidine (2.5 micrograms kg-1) was given after atropine, no chronotropic atrial effect was observed. However, when clonidine (2.5 micrograms kg-1) was given after pindolol, it produced a decrease in atrial rate that was more marked, both in intensity and duration, than under basal conditions. After phenoxybenzamine, rilmenidine decreased atrial rate with a more marked and lasting effect than observed under basal conditions. Clonidine produced a bradycardic atrial effect identical to the basal effect. After yohimbine, rilmenidine and clonidine decreased atrial rate with an intensity similar to that under basal conditions, although the time course was totally different. 4. When given after atropine, rilmenidine (50 micrograms kg-1) and clonidine (2.5 micrograms kg-1) decreased ventricular rate as under basal conditions, whereas after pindolol and phenoxybenzamine, both drugs decreased ventricular rate less markedly than under basal conditions, both in intensity and duration. After yohimbine, rilmenidine and clonidine produced no chronotropic ventricular effect. 5. These results show that (a) the initial atrial bradycardia caused by rilmenidine results from both a decrease in sympathetic tone and an increase in cholinergic activity; while the effect of clonidine is caused mainly by the enhancement of cholinergic activity. For both drugs, alpha 2-adrenoceptors are involved at least in the initiation of the effect; (b) the very short duration of atrial bradycardia may result from reflex buffering in response to ventricular bradycardia. This buffering is less effective when heart rate was high; and (c) the ventricular bradycardia caused by both drugs is mainly the result of a decrease in sympathetic tone in response to the stimulation of alpha 2-adrenoceptors. The results also suggest that negative chronotropic postsynaptic alpha 2-adrenoceptors could be involved in the ventricular bradycardia.

We studied the cardiac electrophysiologic effects of alinidine in conscious dogs. Sinus rate, corrected sinus recovery time (CSRT), and Wenckebach point (WP) were determined in 6 intact dogs. Atrial and ventricular rates, and atrial effective refractory period (AERP) were determined in 6 atrioventricular (AV)-blocked dogs. In both groups, we also measured blood pressure (BP) and plasma alinidine concentrations. Each dog received four intravenous (i.v.) injections of 0.5, 0.5, 1, and 2 mg/kg alinidine (hydrobromide) 30 min apart. At all doses, alinidine decreased sinus rate (< or = 43%) and ventricular rate (< or = 44%), but increased atrial rate (< or = 31%). It lengthened CSRT (< or = 71%) at the two highest doses and increased AERP (< or = 33%) and decreased WP (< or = 33%) at all doses. Alinidine did not modify mean BP at any dose in either group. Overall, these results indicate that alinidine exhibits electrophysiologic effects in conscious dogs that reflect antiarrhythmic potentials of this drug apart from its assumed antiischemic properties.

The chronotropic cardiac effects of neuropeptide Y (NPY) were studied in the conscious dog with chronic atrioventricular block. NPY (0.2-5 micrograms/kg i.v.) produced no effect on atrial cycle length (ACL), and increased ventricular cycle length (VCL) and mean arterial blood pressure (MBP). After atropine, NPY produced no effect on ACL and increased MBP. At 0.2 microgram/kg, it shortened VCL, whereas at 1 and 5 micrograms/kg, it lengthened this parameter. After pindolol, NPY produced no effect on ACL, shortened VCL and increased MBP. These results indicate that in the conscious dog, NPY (0.2-5 microgram/kg i.v.) does not exert any chronotropic effect on the sinoatrial node, most likely because of competition between opposite chronotropic effects and/or absence of specific NPY receptors in the sinoatrial node. They also suggest that the ventricular bradycardic effects produced by NPY result mainly from a reflex withdrawal of beta-adrenergic tone and that its ventricular tachycardic effects result from a direct action of NPY on specific receptors located in the His bundle.

The chronotropic cardiac effects of falipamil were studied in conscious dogs with chronic atrioventricular (AV) block. Falipamil (0.5-2 mg/kg) initially increased atrial rate dose dependently. After atropine and atropine-pindolol, falipamil (2 mg/kg) decreased atrial rate, but after pindolol, it did not modify atrial rate. After atropine-pindolol-phenoxybenzamine, atropine-pindolol-yohimbine, atropine-pindolol-verapamil, and atropine-pindolol-quinidine pretreatment, falipamil produced atrial bradycardia. Falipamil dose-relatedly decreased ventricular rate. Falipamil (2 mg/kg) decreased ventricular rate after atropine, pindolol, and atropine-pindolol more than under basal conditions. After the other four pretreatments, it also produced ventricular bradycardia. Falipamil did not affect mean blood pressure (MBP) at any dose. These results (a) show that the initial atrial cardio-acceleration produced by falipamil results from its direct vagolytic action; (b) show that absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate; (c) suggest that the falipamil ventricular bradycardia is partly buffered by the vagolytic effect, norepinephrine (NE) release, and involvement of alpha 2-adrenoceptors; (d) exclude involvement of postsynaptic muscarinic, alpha- and beta-adrenoceptors, and of the slow calcium current in the mechanism(s) by which falipamil decreases cardiac automaticity; and (e) suggest possible involvement of a quinidine-sensitive current in this (these) mechanism(s).

1. The cardiac cholinergic blockade and the chronotropic effect of the widely differing antimuscarinic drugs atropine and pirenzepine were investigated in the dog. 2. In conscious dogs, suppression of the parasympathetic system with atropine (0.2 mg kg-1 h-1) causes marked brief cardioacceleration (234 +/- 13 beats min-1) while pirenzepine (3 mg kg-1 h-1) causes moderate but persistent cardioacceleration (179 +/- 13 beats min-1). After suppression of the influence of the cardiac sympathetic system these cardioaccelerator effects are attenuated, particularly those of pirenzepine. 3. The effects of vagal stimulation are blocked completely and persistently by both agents. 4. When the cardioinhibitory action of the vagus nerve is blocked by pirenzepine the induced tachycardia can be increased by atropine, which causes an additional cardioacceleration (25 +/- 9 beats min-1). 5. These results show that the tachycardia induced by antimuscarinic agents is not only due to vagal blockade. The different mechanisms which may be involved are discussed. The results suggest that pirenzepine can suppress cholinergic influence on the heart more electively than atropine, which induced an 'excess tachycardia'. Also, intrinsic heart rate can be approached more closely when pirenzepine is used to suppress the parasympathetic system, than with atropine.

The atrial effective refractory period (AERP) and atrial and ventricular chronotropic effects of the stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious atrio-ventricular blocked dogs. Atrial beta-adrenoceptor blocking activity was assessed for all the drugs against isoprenaline. All the drugs except dextro-pindolol lengthened AERP and decreased ventricular rate dose relatedly. At comparable levels of atrial beta-adrenoceptor blockade, dextro-propranolol, dextro-metoprolol and dextro-penbutolol were more potent to induce AERP lengthening than their respective levo-isomers, whereas dextro-pindolol was less potent than levo-pindolol. In addition, levo-pindolol and levo-metoprolol were more potent to produce ventricular bradycardia than the corresponding dextro-isomers, whereas the levo- and dextro-isomers of propranolol and penbutolol were equipotent. These results confirm that the ventricular bradycardia induced by the different beta-adrenoceptor antagonists is partly due to ventricular beta-adrenoceptor blockade and to the membrane stabilizing activity of these drugs, and partly to another as yet unknown factor seen especially with the levo-isomers and particularly marked with metoprolol.

The effects of pentobarbital and chloralose on the atrial effective refractory period (AERP), atrial and ventricular rates, and mean blood pressure and also on the effects of quinidine on the same parameters were investigated in dogs with chronic atrioventricular block and implanted atrial pacing electrodes. Pentobarbital (30 mg/kg) increased the AERP by up to 12%, atrial and ventricular rates by 39 and 40%, respectively, and after initial lowering (48%) it increased the mean blood pressure (46%). Chloralose (100 mg/kg) increased the AERP (less than 30 min) by up to 7%, the atrial rate by 49%, the ventricular rate (less than 5 min) by 18%, and the mean blood pressure by 47%. In conscious dogs, quinidine at cumulative doses of 2, 4, and 8 mg/kg, i.e., at plasma levels between 2.7 +/- 0.6 and 6.3 +/- 1.3 micrograms/ml, increased the AERP by up to 21, 28, and 46%, the atrial rate by 49, 65, and 72%, and the ventricular rate (less than or equal to 5 min) by 17, 14, and 14%, and lowered the mean blood pressure by 19, 33, and 43%, respectively. Pentobarbital increased the quinidine-induced lengthening of the AERP by up to 10, 21, and 25 ms, respectively, and reduced the corresponding atrial (38, 53, and 67 beats/min) and ventricular (4, 4, and 5 beats/min) chronotropic effects. In contrast, chloralose reduced the quinidine-induced lengthening of the AERP (5, 12, and 22 ms, respectively), but did not modify the corresponding atrial and ventricular chronotropic effects. Neither pentobarbital nor chloralose altered quinidine plasma levels or the hypotensive effects of this drug.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Adrenaline (0.25-1 microgram/kg), noradrenaline (0.125-0.5 microgram/kg) and dopamine (25-100 micrograms/kg) given in the conscious dog with chronic atrio-ventricular block after beta-adrenoceptor blockade, increased ventricular cycle length (VCL) and mean blood pressure (MBP). 2. Atropine (muscarinic receptor blocker) reduced the catecholamine-induced effects on VCL without modifying their hypertensive effects. 3. Phenoxybenzamine or phentolamine (alpha-adrenoceptor blockers) only decreased the effects of adrenaline on VCL but suppressed those of noradrenaline and dopamine. They only reduced the effects of adrenaline and noradrenaline on MBP, but reversed that of dopamine. 4. Yohimbine (alpha-adrenoceptor blocker) suppressed the catecholamine-induced effects on VCL, and reduced strongly the hypertensive effects of adrenaline and noradrenaline and reversed that of dopamine. 5. Thus, these results show the existence of negative chronotropic postsynaptic alpha-adrenoceptors in the ventricles.

1 Atrial and ventricular chronotropic effects of acebutolol, metoprolol and propranolol were studied in conscious dogs with chronic heart-block. Ventricular beta-adrenoceptor blocking activity was assessed for the three dogs against isoprenaline (1 microgram/kg) under the same experimental conditions. 2 Acebutolol and metoprolol significantly increased atrial rate. The effect was proportional to the dose for acebutolol, independent for metoprolol. Propranolol had no significant effect on atrial rate. All three drugs significantly lowered ventricular rate in proportion to the dose. 3 Ventricular beta-blocking potencies of metoprolol and acebutolol were respectively 2 and 3 times weaker than that of propranolol as indicated by ED50 values. 4 The ventricular depressor effect observed was proportional to the degree of ventricular beta-blockade present, although this may not be the only factor involved.

The effects of amiodarone, perhexiline and bepridil, which decrease effort cardioacceleration although they have no adrenergic beta blocking properties, were studied in the unanesthetized dog in chronic heart block. All three products decreased atrial rate in a durable way after an initial phase of tachycardia. Amiodarone had no depressant effect on idioventricular rate; however, this was significantly slowed by the other two compounds.

The chronotropic effects of propafenone were studied in the conscious dog with chronic atrioventricular block. Propafenone at 0.5-4 mg/kg, i.e., at plasma levels within the assumed therapeutic range, dose relatedly raises atrial rate. This effect falls off and bradycardia is even observed at 0.5 and 1 mg/kg once plasma levels have dropped below 330 +/- 31 ng/ml. After atropine, propafenone (2 mg/kg) lowers atrial rate, after propranolol it raises it, and after pindolol it does not modify it. Propafenone dose relatedly raises ventricular rate, although again this effect subsequently reverses at 4 mg/kg. After atropine, propranolol, and pindolol, propafenone (2 mg/kg) instead of initially raising ventricular rate lowers it lastingly. It initially lowers mean blood pressure according to dose. At 2 mg/kg neither this effect nor the plasma levels are modified by the antagonists. The beta-blocking potency is 1/40th that of propranolol as determined against isoproterenol-induced cardioacceleration. These results show that the atrial cardioacceleration due to propafenone results from direct and reflex vagolytic action and that the bradycardia at low plasma levels (buffered by the vagolytic effect at high levels) seems due to its membrane-stabilizing action. They also show that the initial ventricular cardioacceleration is a reflex response to its hypotensive effect, whereas the ventricular bradycardia at high doses is attributable to its membrane-stabilizing action and its albeit weak beta-blocking action.

In the conscious dog, after intravenous injection of 0.2 mg/kg 3H-labelled atropine the progressive decrease of the heart rate was well correlated with the disappearance of atropine from the blood. But, with atropine infusion (0.2 mg/kg/h) the tachycardia decreased progressively in spite of an increase in the blood concentration of atropine. Differences appeared between the normal animals or those pretreated with propranolol or reserpine, and the animals which had undergone bilateral thoracic sympathectomy. In the stellectomized animals atropine induced a smaller but much more lasting cardiac acceleration than under the other experimental conditions. It seems that only peripheral factors are involved in the complex interactions between the adrenergic and cholinergic nervous systems at the sinus node level.

The intrinsic sympathomimetic activity (ISA) of the adrenergic beta-blocker pindolol was studied by comparing its effects with those of propranolol in two experimental models: In the non-anesthetized dog with atrio-ventricular block created at least two months previously, propranolol at 0.078, 0.156 and 0.312 mg/kg depressed idioventricular automaticity without affecting atrial rate. Pindolol at 0.5 mg/kg raised atrial rate but left idioventricular rate unchanged. Beta-blockers depress the ventricular adrenergic tone which is strong in this model. With pindolol, this effect is offset by its ISA. Two successive injections of Thallium-201 enable variations in blood mass distribution caused by an agent administered between them to be studied. Isoprenaline increased blood flow in heart and skeletal muscles at the expense of lungs and kidneys. Pindolol (0.1 and 0.2 mg/kg) did not modify coronary blood flow, but increased muscular blood flow.

The beta-adrenoreceptor populations mediating atrial and ventricular chronotropic responses were studied comparatively in the unanaesthetized dog with chronic atrio-ventricular block. With this aim, we first compared the increases in atrial and ventricular rate induced by isoprenaline. We then compared the reductions of this isoprenaline-induced atrial and ventricular cardio-acceleration, observed after administration of cumulative doses of propranolol and alprenolol, both non-selective beta-adrenoreceptor blocking agents, and metoprolol, a blocking agent selective for beta 1-adrenoreceptors. Isoprenaline induced a much more intense stimulation of atrial chronotropic beta-adrenoreceptors than of ventricular chronotropic beta-adrenoreceptors, whether or not the cholinoreceptors were blocked. Similarly, all three beta-blocking agents induced a more intense blockade of atrial chronotropic beta-adrenoreceptors than of ventricular chronotropic beta-adrenoreceptors, whatever the dose of isoprenaline considered and whether or not the cholinoreceptors were blocked. These results cannot be readily explained by quantitative differences in the distribution of beta 1- and beta 2-adrenoreceptors in the heart, given the identical effects obtained with metoprolol, propranolol and alprenolol. Therefore, beta-adrenoreceptor populations are not identical throughout the nodal tissue, and in particular, differences occur between beta-adrenoreceptors in the sinus node mediating atrial chronotropic responses and those in the His bundle mediating ventricular chronotropic responses, which might be linked to differing sensitivities of these beta-adrenoreceptor populations.

Extension to the unanesthetized dog with chronic A-V block of the method of determination of the atrial effective refractory period described in vitro by Dawes provides a useful model for the study in atria of potential antiarrhythmic agents. This model, which comes fairly close to physiological conditions, is capable of furnishing reproducible results which correlate well with those obtained by other techniques, as shown by a study of quinidine chosen as reference. It also makes possible long-term studies of the effects of prolonged administration of antiarrhythmic agents on atrial effective refractory period, under conditions close to those of therapeutic practice, and so is likely to have predictive value.

The chronotropic effects of pindolol were studied in the conscious dog with chronic A-V block. Pindolol significantly increased atrial rate, probably through both its strong intrinsic sympathomimetic activity and reflex withdrawal of atrial vagal tone in response to its hypotensive effect. Pindolol did not alter ventricular rate overall. However, in individual dogs, pindolol caused ventricular chronotropic effects that were inversely related to resting ventricular rate: it increased ventricular rate when the resting ventricular rate was low and reduced it when it was high. In view of the fact that pindolol is a beta-adrenoceptor antagonist endowed with a strong intrinsic sympathomimetic activity, this finding contributes to a better understanding of how pindolol affects heart rate.

The evolution of atrial and ventricular rates was studied in unanesthetized dogs with complete A-V block over a three-year period. During the first 40 days after A-V block, atrial rate far exceeded the sinus rate recorded before surgery, but had fallen progressively back to this level by the 41st day, and remained there until the end of the three-year period. Ventricular rate had settled down to a plateau by the 31st day. These findings explain certain differences among previously reported results, and have led us to use such animals for drug studies only after the beginning of the third month after creation of the complete A-V block.

Chronotropic effects of histamine and dimaprit were studied in the conscious dog with chronic atrioventricular block. Histamine at 0.2-5 micrograms/kg and dimaprit at equimolar doses (i.e. 0.25-6.25 micrograms/kg) increased atrial rate dose-relatedly. Blockade of muscarinic receptors reduced these effects and simultaneous blockade of muscarinic and beta-adrenergic receptors abolished them. Histamine and dimaprit moderately increased ventricular rate. Blockade of muscarinic receptors did not modify these effects, but blockade of beta-adrenoceptors with or without simultaneous blockade of muscarinic receptors suppressed them. After blockade of beta-adrenoceptors, histamine and more rarely dimaprit sometimes decreased atrial and ventricular rates. These effects were prevented by additional muscarinic blockade. Histamine and dimaprit lowered mean blood pressure to the same degree before and after each antagonist. The positive chronotropic effects of histamine and dimaprit, at these doses, are probably reflex responses to their hypotensive effects. The negative chronotropic effects of histamine after pindolol are due to muscarinic receptor activation. No evidence was found to implicate histamine-specific receptors in any of the chronotropic effects of histamine and dimaprit.

The chronotropic cardiac effects of alinidine were studied in the conscious dog with chronic atrioventricular block. Alinidine at 0.5 - 4 mg/kg, i.e., at plasma concentrations between 42 +/- 2 and 1625 +/- 371 ng/ml, initially increased atrial rate dose-dependently. This effect fell off rapidly, but atrial bradycardia was never observed. After atropine and pindolol, which raised basal atrial rate, alinidine (2 mg/kg) decreased atrial rate, whereas after phenoxy-benzamine, yohimbine or phentolamine, it produced atrial effects identical to those observed under basal conditions, i.e., initial tachycardia and no bradycardia. Alinidine dose-relatedly decreased ventricular rate. None of the pretreatments modified the maximal ventricular bradycardia, but interestingly after pindolol or yohimbine this effect developed more rapidly (maximal bradycardia between 3 and 5 against 30 min) and then declined progressively. Alinidine did not modify mean blood pressure at any dose. After atropine, phenoxybenzamine or phentolamine, alinidine remained without effect on mean blood pressure, but after pindolol or yohimbine, a hypotensive effect appeared concomitantly with the reduction of the ventricular bradycardia. These results show that the initial atrial cardioacceleration due to alinidine results from a direct vagolytic action of this drug and that the absence of atrial bradycardia results from buffering by the vagolytic effect and/or a relatively low basal atrial rate. They also suggest that the ventricular bradycardia does not involve either the muscarinic cholinoceptors or the alpha- or beta-adrenoceptors, though the results obtained after pindolol or yohimbine suggest possible involvement of a fall in sympathetic tone by stimulation of presynaptic or central alpha2-adrenoceptors, particularly in the persistence of the bradycardic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

The chronotropic effects of dopamine were studied in the conscious dog with chronic A-V block. Dopamine at 12.5-200 micrograms/kg and 12.5-50 micrograms/kg/min lowered atrial rate independently of dose. After blockade of muscarine receptors or alpha-adrenoceptors, it raised atrial rate. After blockade of dopamine receptors, dopamine still lowered atrial rate, and did so dose-relatedly after blockade of beta-adrenoceptors. It raised ventricular rate, and at high doses also induced ventricular rhythm disorders. Blockade of muscarine receptors enhanced the ventricular cardioaccelerator effect of dopamine (P less than 0.025) at 100 micrograms/kg, while blockade of alpha-adrenoceptors reduced it (P less than 0.05). Blockade of dopamine receptors did not modify this effect, but blockade of beta-adrenoceptors reversed it. Dopamine at 25-200 micrograms/kg raised mean blood pressure. This effect was enhanced by blockade of muscarine receptors, reversed by blockade of alpha-adrenoceptors, and was unaffected by blockade of beta-adrenoceptors or dopamine receptors. These results show that the atrial cardiomoderator effect of dopamine is a vagal reflex response to its hypertensive action, and that it is limited by its direct beta-adrenergic stimulating action. They also show that the ventricular cardioaccelerator effect of dopamine is attenuated by a reflex vagal depressor effect consequent to the induced hypertension. No evidence was found for the existence of positive chronotropic dopamine receptors in either atria or ventricles.