Adrenoceptors Within the Central Nervous System Concerned in the Modification of Arterial Blood Pressure and Heart Rate

Abstract

Initial experiments using hypertensive rats indicated that the antihypertensive effect of α-methyldopa given either systemically or intracerebroventricularly (icv) was mediated by the formation of α-methylnoradrenaline in the central nervous system. Blood pressure and heart rate responses were recorded after icv infusions of α- and β-adrenoceptor agonists and antagonists in conscious, unrestrained, normotensive cats, rabbits and rats. In the majority of cats used, icv infusions of α-adrenoceptor agonists (noradrenaline, adrenaline in the presence of propranolol, phenylephrine, α-methylnoradrenaline, methoxamine and clonidine) produced hypotension and bradycardia which were abolished by icv phentolamine. The α-adrenoceptor antagonist itself generally induced hypertension and tachycardia. It was found that the clinically used antihypertensive agents, α-methyldopa and clonidine, produced hypotension and bradycardia by stimulating central α-adrenoceptors. A comparison was made between the central effects of noradrenaline and α-methylnoradrenaline in the cat with respect to the false transmitter theory. Icv α-methylnoradrenaline induced similar sized responses but of a longer duration than those of icv noradrenaline. α-Adrenoceptor stimulation by clonidine led to bradycardia resulting from a decreased efferent sympathetic and increased efferent vagal outflow to the heart. In 4 cats, icv noradrenaline produced hypertension and bradycardia, these effects also being abolished by icv phentolamine. Although both blood pressure responses of noradrenaline were inhibited by icv phentolamine, the receptors involved may be slightly different as clonidine always produced hypotension in the cats that responded with hypertension to noradrenaline. Opposite effects to the α-agonists were generally observed to icv administrations of β-adrenoceptor agonists (isoprenaline, adrenaline given after phentolamine, salbutamol and isoetharine) in conscious cats, rabbits and rats. Tachycardia was always obtained and was usually accompanied by hypertension, although hypotension, biphasic responses and an absence of blood pressure effects were occasionally observed. All these responses were inhibited by icv infusions of β-adrenoceptor blocking agents. Peripheral adrenergic neuron blockade with bethanidine completely blocked the icv effects of β-adrenoceptor agonists, indicating that a change in efferent vagal tone played no part in the tachycardia and adrenal catecholamine secretion no part in the 'pressor' responses. Icv dopamine always induced large pressor effects with small tachycardias which were inhibited by central α-adrenoceptor or dopamine receptor blockade. In 4 cats, the initial stimulant effects were followed by hypotension and bradycardia. These latter effects were due to α-adrenoceptor stimulation as they were absent after icv phentolamine and were probably caused by noradrenaline formation since disulfiram, a dopamine β-hydroxylase inhibitor, prevented the depressant effects of dopamine. In a large number of conscious cats and rabbits, 7 clinically useful β-blocking agents infused icv induced potent hypotensive effects with bradycardias. Results were obtained which indicated that these depressant effects were produced by central β-adrenoceptor blockade. Thus, it was demonstrated that it was possible for these compounds to exert centrally mediated cardiovascular depressant effects once introduced into the brain and that the central nervous system may provide a site of action, in part at least, for the mediation of their antihypertensive effects. All the β-blockers with the exception of ICI 66082 produced initial rises in blood pressure and heart rate. These effects were investigated and found to be due to either local anaesthetic or intrinsic β-adrenergic stimulant activity or both and were blocked by central β-adrenoceptor antagonism. The central effects of parasympathetic agonists were investigated. Icv carbachol was the most potent agonist and produced pronounced pressor effects and tachycardias which were inhibited by both nicotinic and muscarinic blocking agents and also β-blocking and adrenergic neuron blocking agents given icv. The possibility of a link between central cholinergic and sympathetic mechanisms involved in cardiovascular control is discussed. It was concluded that the experimental model used in this project (i.e. the conscious cat) would be an excellent one in the screening of future antihypertensive agents (e.g. β-blockers), especially those which act centrally. The results of the putative central neurotransmitters given icv to conscious cats are discussed in the light of their possible roles in central cardiovascular control. The mechanisms by which α-methyldopa, clonidine and α-adrenoceptor blockers produced their centrally mediated effects are also discussed.