Naunyn-Schmiedeberg's ArchPharmacol (1984) 325:183-185

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Naunyn-Schmiedeberg's

Archives of Pharmacology �9 Springer-Verlag 1984

Chronotropic effects of pindolol Relation between ventricular effects and control resting ventricular rate values in conscious dogs with chronic A-V block

Michel Boucher, Claude Dubray, and Pierre Duch~ne-Marullaz

Department of Pharmacology, U.t95 INSERM, Faculty of Medicine, F-63001 Clermont-Ferrand C6dex, France

Summary. 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 with- drawal 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 anta- gonist endowed with a strong intrinsic sympathomimetic activity, this finding contributes to a better understanding of how pindolol affects heart rate.

Key words: Conscious A-V blocked dogs - Atrial rate - Ventricular rate - Pindolol

Introduction

Acebutolol, alprenolol, metoprolol, practolol and propra- nolol, beta-adrenoceptor antagonists either without or with a weak intrinsic sympathomimetic activity, significantly de- press ventricular automaticity in the conscious dog with chronic A-V block (Robinson et al. 1973 ; Duch~ne-Marullaz etal. 1975; Boucher and Duch~ne-Marullaz 1980), con- sequent to blockade of the ventricular chronotropic beta- adrenoceptors (Boucher and Duch~ne-Marullaz 1980). However, under the same experimental conditions, pindolol, a beta-blocker endowed with a strong intrinsic sympathomi- tactic activity (Barrett and Carter 1970), does not significantly alter, on the average, ventricular rate (Duch~ne-Marullaz et al. 1975), though analysis of the individual results obtained in this latter study has demonstrated the existence of ventri- cular chronotropic effects which vary from one animal to the next. Now, Aellig (1977) has shown that the chronotropic effects of pindolol are variable in man; when resting heart rates were low, pindolol slightly raised them and when they were high, it decreased them. The present work, carried out on the conscious dog with chronic A-V block, aimed to determine whether a similar effect could be observed on ventricular rate, so as to better define how pindolol affects ventricular rate and, more generally, heart rate.

Offprint requests to M. Boucher at the above address

Materials and methods Animals. Twenty mongrel dogs of either sex, weighing between 13 and 25kg, were used. They were housed in individual cages in a large colony room with food and water continuously available in their home cages.

Experimental procedure. In these dogs, A-V block had been produced at least two months earlier; this time lapse is sufficient for atrial and ventricular rates to become stable (Boucher etal. 1982). A-V block had been induced by crushing the bundle of His with forceps introduced through the open right atrium during temporary occlusion of the venae cavae (Fredericq's modified technique; 1911). Five of these doge were, in addition, fitted with a catheter for long- term measurement of blood pressure, inserted into the left external iliac artery and connected to a valve fixed on the dog's neck according to a technique derived from that described by Bloomberg et al. (1970).

Measurements. Electrocardiographic and blood pressure mo- nitoring was carried out with a Cardiopan III T (Massiot- Philips) instrument and a Statham P23 Db transducer con- nected to the arterial valve and linked to the recorder via a pressure module. During recording, the dogs, which were habituated to the experimentation, were placed on a table and tightly restrained. A catheter was inserted into a cephalic vein before each test to enable the experimenter to administer the drug without spurious effects due to injection stress.

Protocol. Pindolol was administered i. v. in a single injection lasting 30 s, to the 20dogs, at the dose of 0.5 mg base/kg. This relatively high dose was chosen in order to cause complete blockade of the ventricular tachycardia induced by 1 gg/kg i.v. of isoprenaline (hydrochloride), as was systematically verified throughout this study. A control series composed of eight dogs was given 0.5 ml/kg i.v. of physiological saline (0.9%w/v NaC1 solution). Atrial and ventricular rates, measured over 30s, and blood pressure, were determined before, and 2 and 5 rain after injection, and thereafter every 5 rain for 1 h.

Statistical analysis. Results were expressed as mean _+ SEM and statistical analysis of the data was carried out with analysis of variance in complete blocks without repeated measures, followed, when the F value was significant, by multiple comparisons using Student's t-test. The correlation line relating individual ventricular rate responses to their corresponding control resting ventricular rates was computed and the linear correlation coefficient determined.

184

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Fig. 1. Changes in atrial and ventricular rates and in mean arterial pressure (M.A.P.) in conscious dogs with chronic A-V block after pindolol (1------I) or saline (D n). Values are means for groups of 5-20dogs; vertical lines show SEM. ***P ~<0.001 in comparison with zero time values

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=" ' 5'0 0 40 CONTROL RESTING VENTRICULAR RATE (beats/rain)

Fig.2. Linear relationship between ventricular rate response to pindolol and control resting ventricular rate for 20 conscious dogs with chronic A-V block. The regression line equation is y = -0.79 x + 30.6 and the linear correlation coefficient 0.72 (P< 0.001)

Results

Control series

The mean basal atrial and ventricular rates, 63 + 5 and 38 + 3 beats/rain respectively, were not significantly changed after administration of physiological saline (Fig. 1).

Effect of pindolol on atrial rate

Pindolol significantly raised atrial rate (P < 0.001). This effect was observed immediately after the injection and persisted throughout the whole observation period (Fig. 1).

Effect of pindolol on ventricular rate

Overall, pindolol did not significantly change ventricular rate (Fig. 1). However, when the results were examined separately for each dog, very large individual variations in response were evident. In some dogs, ventricular cardioacceleration oc- cured, while in others cardiodeceleration was observed. These individual ventricular effects of pindolol were correlated with the corresponding basal ventricnlar rates (P < 0.001) (Fig. 2) : pindolol increased the ventricular rate when the basal ventric- ular rate was relatively low (< 36 beats/rain), and reduced it when the basal ventricular rate was relatively high (>43 beats/rain). When the basal ventricular rate was in- termediate, pindolol sometimes increased, and sometimes lowered the ventricular rate.

Effect of pindolol on arterial blood pressure

Regardless of its effect on ventricular rate, pindolol signif- icantly lowered mean arterial blood pressure ( P < 0.001), essentially through a reduction in diastolic pressure. This hypotensive effect was observed immediately after the in- jection and persisted throughout the whole observation period (Fig. 1).

Discuss ion

In these conscious dogs with chronic A-V block for more than two months, atrial rate was relatively low (73 + 7 beats/rain), consistent with the obser'~ations of Boucher etal. (1982); pindolol caused a marked increase in this atrial rate. This atrial cardioaccelerator effect results in all likelihood from the stimulation of the beta-adrenoceptors, given the strong intrinsic sympathomimetic activity of pindolol (Barrett and Carter 1970), but also from reflex withdrawal of atrial vagal tone in response to its hypotensive effect. In conscious dogs with chronic A-V block, atria are indeed under strong vagal tone (Robinson et al. 1973 ; Boucher et al. 1979).

Under these experimental conditions, pindolol did not exert any significant ventricular chronotropic effect overall; this confirms the results of Duch~ne-Marullaz et al. (1975). However, a new finding was that, in individual dogs, pindolol exerted ventricular chronotropic effects dependent on the basal ventricular rate; this agrees with the observations made by Aellig (1977) in man. The ventricular rate increases when the basal ventricular rate of the dog is low ( < 36 beats/min) and decreases when the basal ventricular rate is high (>43beats/min). In the conscious dog with chronic A-V block, there is only a very weak vagal tone at the ventricular level (Robinson et al. 1973; Boucher et al. 1979); on the other hand, there is a strong ventricular adrenergic tone (Robinson et al. 1973; Boucher and Duch~ne-Marullaz 1980). In any particular animal, the basal ventricular rate therefore essen- tially reflects the degree of adrenergic tone, and hence the degree of occupation of the ventricular chronotropic beta- adrenoceptors. In agreement with Man In' t Veld and Schalekamp (1981), it may therefore be expected that in those dogs with a low ventricular rate and thus a low occupation of the beta-adrenoceptors, a beta-adrenoceptor blocking drug with partial beta-adrenoceptor agonist activity like pindolol would act merely as an agonist and produce a ventricular tachycardiac effect. On the other hand, in those dogs with a higher ventricular rate and therefore a higher occupation of

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the beta-adrenoceptors , pindolol would act as a beta- adrenoceptor antagonist and produce a ventricular bradycar- diac effect. This result, obtained in this part icular model, contributes to a better understanding of how pindolol affects heart rate. Acknowledgements. The authors wish to express thanks to Mrs. Hosmalin and Mrs. Renoux-Nicolas for their assistance in the preparation of this manuscript.

References

Aellig WH (1977) Investigations with beta-adrenoceptor blocking drugs in healthy volunteers. Acta Med Scand [Suppl 606] 202: 71-74

Barrett AM, Carter J (1970) Comparative chronotropic activity of beta-adrenoceptive antagonists. Br J Pharmacol 40:373-381

Bloomberg ML, Bergman H, Sheiner NM (1970) A technique of chronic arterial catheterization in dogs. J Cardiovasc Surg 11:137-140

Boucher M, Duch~ne-Marullaz P (1980) Acebutolol, metoprolol and propranolol in conscious dogs with chronic heart-block: chronotropic effects and relation between depression of ventricular activity and beta-adrenoceptor blocking potency. Br J Pharmacol 70:335 - 340

Boucher M, Duch~ne-Marullaz P, Lavarenne J (1979) Catechol- amines and cardiac rhythms in the unanesthetized dog with chronic A-V block. Am J Physiol 237:H10-H17

Boucher M, Dubray C, Duch~ne-Marullaz P (1982) Long-term observation of atrial and ventricular rates in the unanesthetized dog with complete atrioventricular block. Pfltigers Arch 395: 341 - 343

Duch~ne-Marullaz P, Combre A, Lavarenne J, Lapalus P, Schaff G (1975) Comparaison des effets du propranolol, de l'alpr6nolol, du pindolol et du practolol sur les rythmes cardiaques de chiens non narcos6s en dissociation auriculo-ventriculaire chronique. J Pharmacol 6: 441 - 452

Fredericq L (1911) Dissociation par compression gradu6e des voles motrices et arrestatrices contenues darts le faisceau de His. Arch Int Physiol 11:405-417

Man In't Veld A J, Schalekamp MADH (1981) Pindolol acts as beta- adrenoceptor agonist in orthostatic hypotension:therapeutic implications. Br Med J 282:929-931

Robinson JL, Farr WC, Grupp G (1973) Atrial rate response to ventricular pacing in the unanesthetized A-V blocked dog. Am J Physiol 224: 4 0 - 45

Received September 29, 1983/Accepted November 3, 1983