Antihypertensive activity of LY141865, a selective presynaptic dopamine receptor agonist
Hahn, R.A.; MacDonald, B.R.; Martin, M.A.
Journal of Pharmacology and Experimental Therapeutics 224(1): 206-214
1983
ISSN/ISBN: 0022-3565 PMID: 6848744 Document Number: 210866
Oral (0.3-3 mg/kg) and i.v. (1-1000 .mu.g/kg) administration of LY14865 lowered mean arterial blood pressure and cardiac rate in anesthetized and conscious spontaneously hypertensive rats (SHR). These effects were dose-related, rapid in onset and sustained. For example, LY141865 (1-3 mg/kg p.o. ) produced statistically significant arterial hypotension in conscious SHR for a period in excess of 6 h. The hypotension and bradycardia produced by LY141865 (1-1000 .mu.g/kg i.v.) in anesthetized SHR were inhibited by surgical and pharmacological sympathectomy, sulpiride and domperidone, but were unaffected by yohimbine or the combination of cervical vagotomy plus atropine. Administration of LY141865 (100-1000 .mu.g/kg i.v.) to pithed SHR shifted the frequency-response curve for vasoconstriction induced by peripheral sympathetic nerve stimulation to the right. This effect was dose-dependent and prevented by sulpiride pretreatment. The antagonism of neurogenic vasoconstriction was selective since LY141865 had no concomitant inhibitory action on vascular or cardiac responses to exogenous norepinephrine, pressor responses to tyramine or neurogenic bradycardia induced by vagal nerve stimulation. LY141865 (1-1000 .mu.g/kg i.v.) did not increase diastolic blood pressure or cardiac rate in pithed SHR and its hypotensive activity in anesthetized SHR was not attenuated by propranolol. In anesthetized dogs, the hypotensive activity of LY141865 (20 .mu.g/kg i.v.) was abolished by sulpiride pretreatment. Hemodynamic analysis indicated that LY141865 (20-100 .mu.g/kg i.v.) lowered arterial blood pressure, without reflex tachycardia, solely by dilating the systemic vasculature; aortic blood flow was unchanged and supported by increments in stroke volume. LY141865 reduced myocardial minute work and stroke work as a consequence of its hypotensive activity. LY141865 apparently is a highly selective agonist at presynaptic dopamine receptors which mediate inhibition of peripheral adrenergic neurotransmission. The proposed use of dopamine receptor agonists in the treatment of arterial hypertension is supported. An additional potential use in congestive heart failure is suggested by data indicating that LY141865 maintained systemic perfusion at reduced levels of myocardial work.