Frequency selective compounds and inhibition of cardiovascular reflexes

Park, K.H.; Long, J.P.; Cannon, J.G.

Journal of Pharmacology and Experimental Therapeutics 255(1): 240-247


ISSN/ISBN: 0022-3565
PMID: 2145423
Document Number: 366757
In anesthetized normotensive rats, several classes of antihypertensive agents (i.v. injection) were compared for their effects on mean arterial pressure (MAP) and reflex-induced changes in MAP produced by head-up tilt, bilateral carotid occlusion (BCO) and stimulation of the central end of sciatic nerves (SNS). Two doses which produced average MAP fall of 32 to 47 mm Hg were used for comparison. Guanethidine (1 and 3 mg/kg) depressed markedly not only the tilt responses but also responses to BCO and SNS. In contrast, clonidine (2 and 6 .mu.g/kg) or dopamine2 receptor agonists, apomorphine (100 and 300 .mu.g/kg) and VICO-81 (trans-6,9-dimethoxy-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzoquinoline, 60 and 200 .mu.g/kg), only prolonged the time required for compensation. Apomorphine inhibited BCO reflexes slightly, not affecting SNS-induced responses. However, neither the BCO nor the SNS responses were influenced by VICO-81. On the other hand, serotonin1S receptor agonists, (8-hydroxy-2-di-n-propylaminotetralin, 100 and 300 .mu.g/kg) and PM-1000 (10-methyl-11-hydroxyaporphine, 1 and 3 mg/kg), did not inhibit responses to tilt. MAP during tilt was somewhat higher than controls after the two serotoninAA receptor agonists. Although BCO or SNA was not influenced by 8-hydroxy-2-di-n-propylaminotetralin, both responses were depressed slightly by higher doses of PM-1000 (3 mg/kg). To correlate the degree of inhibition on tilt reflex with that on sympathetic neurotransmission after these hypotensive agents, plasma catecholamines, norepinephrine, epinephrine and dopamine, were measured. Results suggest a close relationship between postural hypotension liability and inhibition of norepinephrine release by these agents. It was concluded that antihypertensive agents acting by different receptor mechanisms have variable degree of inhibitory action on reflex responses to tilt, BCO and SNS; however, these reflexes are valuable test to predict the liability of postural hypotension of new agents.

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