Prostaglandin E2, PGE2, is a potent vasodilator which paradoxically raises arterial pressure (AP) when it is infused into the common carotid artery of conscious sheep, calves, and dogs. It also raises AP when it is infused into the vertebral artery of conscious sheep, but to a lesser extent than when it is infused into a carotid artery. PGE2 also raises AP when infused into the cerebral ventricles of rats. Intracarotid infusion of PGE2 does not elicit a carotid chemoreflex, or baroreflex. It does reset the baroreflex without changing its sensitivity. The increase in AP is mediated by increased peripheral alpha-adrenergic tone and total peripheral resistance. Our hypothesis is that central administration of PGE2 raises AP by activating the brain renin-angiotensin system.
Our specific aims to test this hypothesis are to infuse PGE2 into the lateral ventricles of conscious sheep to raise AP, to infuse the angiotensin receptor and conversion blocking agents, Saralasin and Captopril, into the lateral ventricles, to attempt to block the ability of intracarotid and intraventricular PGE2 to raise AP. We also intend to produce electrolytic lesions of the anteroventral third ventricle region (AV3V) of sheep to block the rise in AP produced by central PGE2. The AV3V is an important hypothalamic locus of action of the brain renin-angiotensin system, and it must be intact for the production of both renin dependent (renal) and non-renin dependent (steroid-salt) forms of experimental hypertension. We will also conduct experiments, at least initially in rats to reduce the cost, in which PGE2 will be chronically administered into a carotid artery or the cerebral ventricular system in an attempt to produce chronic hypertension. We possess knowledge of all of the relevant technique for catheterization of vessels and ventricles and lesion production in both species, and have abundant pilot data to prove that these experiments are feasable. It is expected that PGE2 will be demonstrated to be an integral part of the activation of the brain renin-angiotensin system. Fundamental new knowledge concerning normal arterial pressure regulation and hypertension can be expected from these studies.
