European Journal of Pharmacology, 52 (1978) 405--409

405

© Elsevier/North-Holland Biomedical Press

Short communication FACILITATION OF CARDIAC SYMPATHETIC FUNCTION BY ANGIOTENSIN II: ROLE OF PRESYNAPTIC ANGIOTENSIN RECEPTORS MUSTAFA F. LOKHANDWALA, ERIC AMELANG and JOSEPH P. BUCKLEY

Institute for Cardiovascular Studies and Department of Pharmacology, University of Houston, Houston, Texas 77004, U.S.A. Received 11 October 1978, accepted 12 October 1978

M.F. LOKHANDWALA, E. AMELANG and J.P. BUCKLEY, Facilitation of cardiac sympathetic function by angiotensin H: role of presynaptic angiotensin receptors, European J. Pharmacol. 52 (1978) 405--409. Intravenous infusion of two separate doses of angiotensin II in pentobarbital-anesthetized, desipramine-treated animals produced dose-related increases in arterial blood pressure and caused significant potentiation of the cardioacceleration observed during the stimulation of the right postganglionic cardiac sympathetic nerve fibers. Positive chronotropic effects of intravenous norepinephrine were not altered during angiotensin II infusion. Prior administration of Saralasin, an angiotensin receptor antagonist, caused significant attenuation of the pressor action of angiotensin II, and also significantly antagonized the facilitatory effect of angiotensin II on sympathetic transmission to the myocardium. These results suggest that angiotensin II can cause facilitation of sympathetic nerve function to the myocardium via an action on angiotensin receptors which may be located on sympathetic nerve terminals. Angiotensin II

Saralasin

Presynaptic receptors

1. Introduction The presence of various presynaptic receptors on postganglionic sympathetic nerves modulating the release of neurotransmitter norepinephrine is reported by several investigators (for reviews see Langer, 1977; Lokhandwala, 1978). These receptors have been demonstrated to have either an inhibitory or a facilitatory effect on the transmitter release during nerve stimulation (Starke et al., 1977). Angiotensin II is reported to have a facilitatory effect on transmitter release and it has been reported that the peptide causes an increase in the responses to sympathetic nerve stimulation in several vasculatures via a presynaptic action (Zimmerman and Gomez, 1965; Zimmerman, 1973; Johnson et al., 1974). Angiotensin II is also reported to cause an increase in the release of norepinephrine during nerve stimulation in the isolated rabbit heart (Starke, 1971) as well as produce an

Desipramine

increase in the positive chronotropic effects of sympathetic nerve stimulation in the same preparation (Thompson, 1970). The effect of angiotensin II on sympathetic nerve function to the myocardium under in vivo conditions, however, has not been reported. Therefore, the present study was undertaken to investigate the effect of angiotensin II on sympathetic nerve function to the myocardium in intact dogs and to identify the receptors involved in mediating the observed effects of angiotensin II on cardiac sympathetic function.

2. Materials and methods 2.1. General

Mongrel dogs of either sex weighing between 12--20 kg were anesthetized with sodium pentobarbital (35 mg/kg, i.v.). A femoral artery

406

was cannulated and a catheter was advanced into the abdominal aorta to measure arterial blood pressure utilizing a Statham P-23 AC pressure transducer. A femoral vein was cannulated for drug administration. Heart rate was obtained from the pressure pulse using a cardiotachograph (Grass Model 7P4F}. Blood pressure and heart rate were recorded on a Grass Model 7 polygraph recorder. All animals were bilaterally vagotomized and artificially ventilated using a Harvard respirator. A right t h o r a c o t o m y was performed at the second intercostal space and the right cardioaccelerator nerve was isolated, ligated and sectioned from the stellate ganglion. The nerve was stimulated at supramaximal voltage (8-12 V) for a period of 15 sec. with bipolar platinum electrodes using a Grass stimulator at frequencies ranging from 0.5 to 4.0 Hz and a pulse duration of 0.5 msec. A period of approximately 2--3 min was allowed to elapse between two frequencies of stimulation, at which time the heart rate had returned to the control level.

M.F. L O K H A N D W A L A E T AL.

with desipramine (1 mg/kg, i.v.). Following the evaluation of the effect of angiotensin II on cardiac sympathetic function in desipramine-treated dogs, these animals were given continuous infusion of Saralasin (10 pg/kg/ min) and responses to cardiac nerve stimulation were obtained 20 min after the start of Saralasin infusion. Finally, while continuing Saralasin infusion, angiotensin II infusion was again carried out and its influence on the positive chronotropic effect of cardioaccelerator nerve stimulation was determined in the presence of Saralasin infusion.

3. Results Intravenous infusions of two separate doses of angiotensin II (100 ng/kg/min and 200 ng/ kg/min} produced significant increases in the arterial blood pressure without causing significant changes in the heart rate (fig. 1). Positive chronotropic effects of either the cardiac nerve stimulation or intravenous norepinephrine were not affected by angiotensin II in these animals. Infusion of angiotensin II in

2.2. Experimental protocol The positive chronotropic effects of cardioaccelerator nerve stimulation were obtained at different frequencies and then angiotensin II infusion was carried out using a Sage pump {Model 341) at a rate o f 0.16 ml/min in varying doses for a period of 20--30 min. During the infusion period, when the blood pressure response had stabilized to peak level, responses to cardiac nerve stimulation were again obtained at different frequencies. A suitable time period was allowed to elapse after termination of angiotensin II infusion, following which responses to cardiac nerve stimulation were obtained. Similarly, positive chronotropic effect of intravenous norepinephrine was also determined before and during angiotensin II infusion. The second part of the experimental protocol consisted o f conducting the similar experiment as described above in the same animals after treatment

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ANGIOTENSIN II AND CARDIAC SYMPATHETIC FUNCTION

the same animals after the administration of desipramine resulted in a significant potentiation of the positive chronotropic effect of cardiac nerve stimulation (fig. 2). However, increase in heart rate observed following intravenous administration of norepinephrine were not affected during angiotensin II infusion (table 1). The pressor effects of both the doses of angiotensin II were also significantly potentiated in desipramine-treated animals (fig. 1). It is important to note that the dose of desipramine used in the present study has been shown to be effective in blocking neuronal reuptake of catecholamines (Lokhandwala and Buckley, 1977). In order to identify the receptors involved in mediating the facilitatory effect of angiotensin II on the myocardial sympathetic function, the peptide was administered following the blockade of angiotensin receptors with Saralasin. Saralasin infusion, while significantly antagonizing the pressor effects of both the

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407

TABLE 1 Positive chronotopic effects of norepinephrine prior to and during the infusion of angiotensin-II in pen_~obarbital-anesthetized, desipramine-treated dogs (X + S.E.M.). Norepinephrine ~g/kg

Increase in heart rate (beats/rain) Control

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doses of angiotensin II (fig. 1) also prevented the facilitatory effect of angiotensin II on the responses to cardiac nerve stimulation (fig. 2). Saralasin infusion itself did not cause any alterations in the positive chronotropic effect of cardioaccelerator nerve stimulation.

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408

4. Discussion The present study has demonstrated that angiotensin II can facilitate sympathetic nerve function to the myocardium as evidenced in the potentiation of the cardioacceleration elicited b y cardiac nerve stimulation. The observation that positive chronotropic effects of nerve stimulation were potentiated, whereas increases in heart rate produced by exogenously administered norepinephrine were unchanged during angiotensin II infusion indicates that the peptide can influence neurogenic function via a presynaptic action. Angiotensin II has been shown to cause facilitation of sympathetic nerve function in several experimental preparations and this action of the peptide has been attributed to its ability in either increasing the release and/or preventing the reuptake of norepinephrine (Khairallah, 1972; Zimmerman et al., 1972). In the present experiment, angiotensin II-induced facilitation of sympathetic nerve function was observed only after the blockade of neuronal reuptake of catecholamines with desipramine. Therefore, theae results indicate that at least under our experimental conditions, facilitation of sympathetic function produced by angiotensin II was n o t due to the blockade of reuptake b u t was probably the result of an increased release of the neurotransmitter, norepinephrine. In the presen t experiment, it was necessary to block neuronal reuptake with desipramine in order to observe the facilitatory effect of angiotensin II on sympathetic nerve function to the myocardium. Although no definite hypothesis can be advanced to explain this observation at the present time, it is possible that in the animal with intact neuronal reuptake mechanism, any effect of angiotensin II in increasing the release of norepinephrine m a y have been masked or negated b y an increased reuptake or accumulation of the neurotransmitter into sympathetic nerve terminals. It should be noted that Peach and Ford (1968) have also reported that the ability of angiotensin II to cause an increased release of norepinephrine was significantly

M.F. LOKHANDWALA ET AL.

enhanced after desipramine and as observed in the present study, this also resulted in the enhancement of pressor responses produced by angiotensin II. Although several investigators have demonstrated a facilitatory effect of angiotensin II on cardiac sympathetic nerve function in isolated rabbit hearts (Thompson, 1970; Starke, 1971) as well as in the pithed rat (Finch and Leach, 1969), no attempt was made to identify the receptors mediating this effect of the peptide. In the present study, while extending these observations to the intact system, we have further attempted to identify the nature of the receptors mediating the facilitatory effect of angiotensin II on the responses to cardioaccelerator nerve stimulation. The fact that Saralasin, a competitive angiotensin receptor antagonist, prevented the facilitatory effect of the peptide on neurogenic function indicates that the observed facilitation was mediated via the activation of angiotensin receptors located on sympathetic nerve terminals. The ability of Saralasin to antagonize the potentiating action of angiotensin II on sympathetic nerve function has also been reported by Zimmerman (1973) for the perfused hindpaw of the dog. In summary, the results of the present study have demonstrated that angiotensin II can produce facilitation of sympathetic nerve function to the myocardium in intact dogs, probably by causing an increased release of the neurotransmitter and that this effect of the peptide is mediated via the activation of angiotensin II receptors located on sympathetic nerve terminals.

Acknowledgements This work was s u p p o r t e d in part by HL-22868 from NHLBI. The authors wish to t h a n k Ms. Barbara Lewis for t h e p r e p a r a t i o n of this manuscript.

References

Finch, L. and G.D.H. Leach, 1969, The role of sympathetic nervous s y s t e m in t h e cardiovascular

ANGIOTENSIN II AND CARDIAC SYMPATHETIC FUNCTION responses to angiotensin in the pithed rat, Brit. J. Pharmacol. 36, 481. Johnson, E.M., G.R. Marshall and P. Needleman, 1974, Modification of responses to sympathetic nerve stimulation by the renin--angiotensin system in rats, Brit. J. Pharmacol. 51, 541. Khairallah, P.A., 1972, Action of angiotensin on adrenergic nerve endings: Inhibition of norepinephfine uptake, Federation Proc. 31, 1351. Langer, S.Z., 1977, Presynaptic receptors and their role in the regulation of transmitter release, Brit. J. Pharmacol. 60,481. Lokhandwala, M.F., 1978, Presynaptic receptor systems on cardiac sympathetic nerves, Life Sci. (in press). Lokhandwala, M.F. and J.P. Buckley, 1977, Analysis of presynaptic inhibitory actions of various dopamine analogs on sympathetic neurotransmission in mongrel dogs, Life Sci. 20, 507. Peach, M.J. and G.D. Ford, 1968, The actions of angiotensin II on canine myocardial and plasma catecholamines, J. Pharmacol. Exptl. Therap. 162, 92.

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Starke, K., 1971, Action of angiotensin on uptake, release and metabolism of 14C-noradrenaline by isolated rabbit hearts, European J. Pharmacol. 14, 112. Starke, K., H.D. Taube and E. Borowski, 1977, Presynaptic receptor systems in catecholaminergic transmission, Biochem. Pharmacol. 26, 259. Thompson, J.L., 1970, Effect of angiotensin on the cardioaccelerator response to sympathetic nerve stimulation in the isolated rabbit hearts, Proc. Soc. Exptl. Biol. Med. 135,825. Zimmerman, B.G., 1973, Blockade of adrenergic potentiating effect of angiotensin by 1-Sar-8-Alaangiotensin If, J. Pharmacol. Exptl. Therap. 185, 486. Zimmerman, B.G., S.K. Gomer and J.C. Liao, 1972, Action of angiotensin on vascular adrenergic nerve endings: facilitation of norepinephrine release, Federation Proc. 31, 1344. Zimmerman, B.G. and J. Gomez, 1965, Increased response to sympathetic stimulation in the cutaneous vasculature in presence of angiotensin, Intern. J. Neuropharmacol. 4, 185.

Facilitation of cardiac sympathetic function by angiotensin II: role of presynaptic angiotensin receptors.

European Journal of Pharmacology, 52 (1978) 405--409 405 © Elsevier/North-Holland Biomedical Press Short communication FACILITATION OF CARDIAC SYMP...
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