Autonomic Nervous System as a Target for Cardiovascular Drugs

Clinical and Experimental Pharmacology and Physiology ( 1998) 25, 446-448

Satellite Symposium on Neural Mechanisms in Hypertension

AUTONOMIC NERVOUS SYSTEM AS A TARGET FOR CARDIOVASCULAR DRUGS P Bousquet, L Monassier and J Feldman Laboratoire de Neurobiologie et Pharmacologie Cardiavasculaire, Universite' Louis Pasteul; CNRS, Faculte' de Me'decine, Strasbourg, France

SUMMARY 1. Drugs acting within the autonomic nervous system (ANS) are of particular interest when autonomic abnormalities are implicated in the development and maintenance of various cardiovascular pathologies. For example, it has been documented that in the early stages of hypertensive disease (i.e. hyperkinetic borderline hypertension) a sympathetic hyperactivity associated with a decreased parasympathetic activity results in increased cardiac output and heart rate. 2. Several classes of drugs acting within the central, as well as the peripheral ANS, are very efficient in treating hypertensive disease. One of these classes of drugs, the second generation of centrally acting drugs, has proved beneficial in this respect because, in addition to their therapeutic efficacy, these drugs are well tolerated. 3. The central nervous system may also be the target for drugs with the potential to treat other cardiovascular diseases. Some recent experimental and clinical data supporting such new perspectives concerning idiopathic dysrhythmias, angina pectoris and congestive heart failure will be summarized. Key words: autonomic nervous system, cardiac dysrhythmias, congestive heart failure, hypertension, imidazolines, myocardial ischaemia, NMDA receptors.

INTRODUCTION One may be surprised that up until now, hypertension has been the only therapeutic indication for drugs acting within the central nervous system (CNS). Recently, a second generation of centrally acting anti-hypertensive drugs has been introduced. In this short review we will present some theoretical as well as experimental arguments supporting the view that central autonomic neurons may be interesting targets for cardiovascular drugs in the future.

Correspondence: Professor P Bousquet, Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Universitk Louis Pasteur, CNRS, Facultt de MCdecine, 11 rue Humann, 67000 Strasbourg, France. Email: Presented at the Satellite Symposium on Neural Mechanisms in Hypertension, Sydney, Australia, September 1997. Received 10 December 1997; accepted 12 December 1997.

Three different clinical problems will be discussed (i) ventricular dysrhythmias (which are quite often associated with hypertension through a sympathetic hyperactivity); (ii) myocardial ischaemia; and (iii) congestive heart failure.

ANTI-ARRHYTHMIC EFFECTS OF A CENTRALLY ACTING SECOND-GENERATION ANTI-HYPERTENSIVE DRUG Many studies have confirmed the advantages of rilmenidine and moxonidine over first-generation centrally acting drugs, such as a-methylDOPA, clonidine and its analogues.14 Among these advantages is a significantly improved patient acceptability as well as some potentially interesting therapeutic benefits. An example of an interesting additional effect of a centrally acting drug is the antiarrhythmic effect of rilmenidine, which is clearly associated with its sympathetic inhibitory actions. This effect has been described in several experimental models of ventricular dysrhythmia~.~,~ Rilmenidine is an oxazoline, a close analogue to imidazoline compounds such as clonidine. This drug was shown to be useful in treating mild to moderate hypertension; its acceptability was similar to that of the more recent classes of anti-hypertensive drugs, such as angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, or of a placebo. Among the risks associated with hypertensive diseases, ventricular dysrhythmias are observed in approximately 30% of patients; these dysrhythmias usually occur in patients with left ventricular hypertrophy and can result in sudden death.3-6 In rabbits, dysrhythmias of central origin associated with sympathetic hyperactivity were induced by central (intracisternal) injection of the GABAA receptor antagonist, bicuc~lline.~ In this animal model, we recently reported that rilmenidine reduced the occurrence of ventricular dysrhythmias in a dose-dependent manner. Bicuculline, delivered intracisternally, evoked a marked hypertensive response accompanied by ventricular ectopic beats, episodes of ventricular tachycardia evolving into a sustained tachycardia and. finally, fibrillation, which is fatal in the absence of treatment.7 Pretreatment of animals with cumulative doses (1 0 pglkg to 1 mgkg) of intravenous rilmenidine has significantly prevented the occurrence of all the aforementioned arrhythmic events in a dose-dependent manner. Rilmenidine given intracisternally (10-30 kg/kg) had very similar cardioprotective effects. It is interesting to note that, in this experimental model, rilmenidine had anti-arrhythmic effects even at doses lower than those that reduce

ANS and cardiovascular drugs blood p r e ~ s u r e In . ~ addition, treatment with idazoxan, a selective imidazoline antagonist, confirmed that the anti-arrhythmic effect of rilmenidine involved imidazoline-specific receptor^.^ Our results were consistent with those of Mammoto et al., who reported that rilmenidine prevented the occurrence of ventricular dysrhythmias induced by a mixture of halothane and adrenaline.* Additional beneficial effects that control risk factors associated with hypertension may be an added impetus to the development of new anti-hypertensive drugs. In this respect, the anti-arrhythmic effect of second-generation centrally acting anti-hypertensive drugs may be taken into account during the further development of this new class of drugs. Of course, the same reasoning may apply for other additional effects, such as myocardial anti-ischaemic effects or improvement of glucose tolerance. Our results7 also indicate that centrally acting drugs may be useful as anti-arrhythmics at doses devoid of any hypotensive action. Thus, a novel class of anti-arrhythmic drugs acting centrally could be proposed. As most available anti-arrhythmic drugs have a bad press because of their adverse effects, in particular their occasional paradoxical pro-arrhythmic actions, a new class of anti-arrhythmic drugs that lacked this risk would be extremely valuable.

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We observed similar results with antagonists to any site on the NMDA receptor. For example, ifenprodil, an antagonist of the polyamine site, administered intravenously inhibited all cardiovascular responses induced by electrical stimulation of the hypothalamic PVN.I6 Ifenprodil, as well as baclofen, failed to alter basal cardiovascular parameters. It is also interesting to note that ifenprodil did not modify baroreflex f ~ n c t i o n . 'Blockers ~ of the glutamate binding site, such as 2,5-aminophosphonovaleric acid (APV), as well as blockers of the channel site, such as dizocilpine (MK801), or even an antagonist of the glycine site, 5,7dichlorokynurenic acid, all had similar effects on myocardial oxygen consumption." The channel site blockers were much more potent than the others, even to the extent that some of them elicited a cardiodepression. Of course, it is now necessary to extend this research and to confirm the potential benefit of such drugs in experimental models of myocardial ischaemia. Studies on this subject are in progress. If confirmed, one could propose that glutamatergic synapses that are involved in the sympathetic drive to the heart may be interesting targets for therapeutic drugs modulating myocardial oxygen consumption.

CONGESTIVE HEART FAILURE MYOCARDIAL ISCHAEMIA As far as myocardial ischaemia is concerned, many efficacious drugs are available for the treatment of this common disease. Nevertheless, all the available drugs have a restricted use due to their numerous side effects and contraindications. The negative inotropic effects of the beta-blockers or the controversy regarding the use of some calcium antagonists in the treatment of cardiac ischaemia illustrate this particular point well.9 The sympathetic drive to the heart could be an interesting target for drugs by reducing myocardial oxygen consumption during physical exercise or stress situations, which can trigger angina pectoris. We are particularly interested in glutamatergic relays in the CNS, the presence of which have been described at various levels of the sympathetic nervous system.10-'' In anaesthetized rabbits, we developed a model of activation of sympathetic activity by electrically stimulating the hypothalamic paraventricular nucleus (PVN).'* This nucleus plays a role as an integrative centre in numerous activities, including cardiovascular control. l 3 Electrical stimulation of this area evoked haemodynamic responses similar to those observed when angina pectoris is triggered; in particular, there is a rise in blood pressure and a significant increase in myocardial contractile force, the latter measured by the dP/dt,,,,, index. The oxygen consumption indices, the double product of the systolic pressure by the heart rate and the triple product of the systolic pressure by the heart rate by dP/dt were markedly increased as a result of the haemodynamic responses. This elevation was dependent on the current intensity." We showed that drugs inhibiting glutamatergic synapses prevented this response. Thus, baclofen, a lipophilic analogue of GABA, inhibits glutamate release because it selectively acts on presynaptic GABAB receptors. We have reported that baclofen administered either systemically or directly within the brain reduced blood pressure and positive inotropic responses." As a consequence, of course, this drug also reduced myocardial oxygen consumption in a dose-dependent manr~er.'~-'~

At the present time there is an interesting debate concerning the treatment of congestive heart failure (CHF). Our approach to this subject is based on the observation that sympathetic activation is associated with severe left ventricular failure. Although this sympathetic hyperactivity is a compensatory process, it also accelerates the progression of the disease and increases the morbidity and mortality due to CHF. The plasma level of noradrenaline is a predictive index of the evolution of this cardiac pathology." During CHF, the reduction of the left ventricular ejection fraction (LVEF) is associated with sympathetic hyperactivity. The latter, in turn, elicits a down-regulation of P-adrenoceptors, which aggravates the functional consequence of the activation of the a-adrenoceptors by circulating catecholamines.2"The overall result of these alterations is, in fact, an elevation of systemic vascular resistance, which is still further aggravated by activation of the renin-angiotensinaldosterone system (RAAS) as a result of the sympathetic stimulation. As far as the LVEF is concerned, this functional cascade is critical. In the same way, destruction of the sympathetic nerve terminals, which has been shown to occur in the myocardium, will worsen the reduction of the LVEF and, therefore, the disease itself. All the available drugs used to treat CHF have their own restrictions,*' which we can summarize as follows: 1. Beta-blockers have a limited beneficial effect because of the aforementioned down-regulation of the P-adrenoceptors, which facilitates the elevation of the peripheral vascular resistances due to activation of a-adrenoceptors.2" 2. Carvedilol is assumed to associate P- and a-adrenoceptor blocking properties with anti-oxidant properties." Whether this drug is really efficacious in the treatment of CHF is still debatable; little is known about its tolerability. 3. Thiazides are capable of inducing hypovolaemia and hypokalaemia. 4. Digitalis has a positive inotropic effect and a tendency to inhibit sympi-thetic hyperactivity and to increase the vagal activity, but its therapeutic hdex is unfavourable and it is arrhythmogenic.

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5. Angiotensin-converting enzyme inhibitors and angiotensin 11 receptor antagonists are certainly effective in treating CHF, as they reduce systemic vascular resistances and have an anti-proliferative action. However, they still have some contraindications, in particular in relation to potassium homeostasis and the state of renal arteries. 6. Part of the interest in anti-aldosterone diuretics lies in the prevention of myocardial fibrosis. However, these drugs can produce hyperkalaemia. Theoretically, the potential interest in using centrally acting drugs to treat CHF is quite obvious. Drugs specifically inhibiting sympathetic activity would reduce the release of noradrenaline and adrenaline from the adrenal gland. As a result of their inhibitory action on global sympathetic tone, such drugs would diminish systemic vascular resistances and prevent activation of the RAAS. All these effects would lead to improvements in diastolic function and restoration of the LVEEZ3In addition, centrally acting drugs that not only inhibit sympathetic activity but can also facilitate vagal activity would contribute to normalization of the heart rate variability. There are already some clinical data obtained with clonidine and a-methylDOPA confirming the potential interest of centrally acting drugs in the treatment of heart Based on our experience with the second generation of centrally acting anti-hypertensive drugs, we know that drugs with such a profile may have very few side effects; in particular, they do not affect lipid and glucose metabolism. Whether such drugs may be useful in the treatment of CHF at non-hypotensive doses still remains to be demonstrated. In conclusion, theoretical reasons, as well as experimental and clinical data, strongly suggest that the autonomic nervous system may be an interesting target for novel cardiovascular drugs. In fact, the role of the CNS has not yet been explored extensively in cardiovascular pathologies, such as ventricular dysrhythmias, angina pectoris and CHF.

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