Stimulation of sympathetic cardiovascular centres by RA 642, a new pyrimido-pyrimidine derivative

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Abstract
RA 642, 2,2′-[4,8-bis(diethylamino)-pyrimido[5,4-d] pyrimidine-2,6-diyl)di-(2-methoxyethyl)-imino]diethanol, has formerly been described to be hypertensive when administered systemically. In the present experiments injection of 50 μg/kg RA 642 into the vertebral artery (i.a. vert.) of the cat exerted hypertension, while the same dose given intravenously (i.v.) elicited no effect. Since the drug was still effective in cats of which the brain was removed rostrad of the myelencephalon but not in spinal animals, its site of action was concluded to be in cardiovascular centres of the medulla oblongata. An i.a. vert. injection increased total peripheral resistance of the vasculature. The electrical discharge rate in preganglionic cervical sympathetic nerve fibres increased in parallel to the arterial blood pressure following the i.v. injection of 1 mg/kg of the substance. 1 mg/kg RA 642 i.v. decreased the reflex bradycardia elicited by the i.v. injection of angiotensin in dogs pretreated with a β-adrenoceptor blocking drug to study the vagal effector reactions of the baroreceptor reflex, and treated with clonidine to facilitate the reflex. Thus, RA 642 increased sympathetic and, following clonidine treatment, decreased vagal reflex activity. RA 642 stimulated the respiration by a central action. The drug had no convulsant action.