Beta adrenergic receptor antagonists are widely used to treat hypertension and coronary artery disease, yet the mechanisms responsible for their beneficial effects remain uncertain. We have found that chronic, but not acute, blockade of beta adrenergic receptors decreases neurovascular transmission, lowers arterial pressure and enhances synthesis of the vasodilator prostaglandins, PGI2 and PGE2, in response to norepinephrine (NE), angiotensin II (AII) and bradykinin (Bk). Consequently, the goal of this proposal is to define the cellular and molecular basis for beta adrenergic receptor-mediated regulation of arachidonic acid metabolism in peripheral blood vessels. The working hypothesis is that beta adrenergic receptors tonically modulate vascular prostaglandin synthesis through regulation of arachidonic acid release by phospholipases. Studies will be performed with isolated aorta. Experiments are proposed to: 1) Determine t e effects of acute and chronic beta adrenergic receptor stimulation and blockade on agonist-induced (NE, AII, Bk) synthesis of PGI, and PGE, in vit o and b) on in vivo eicosanoid synthesis as assessed by urinary metabolites (2,3-dinor 6-keto PGF1 alpha and 13,14-dihydro-15-keto tetranor PGE2) which reflect systemic prostaglandin production; 2) Determine the relative contribution of vascular endothelial and smooth muscle cells to beta receptor-induced changes in vascular arachidonic acid metabolism; and 3) Determine the mechanism of beta receptor-induced changes in the storage and release of vascular arachidonic acid. The effects of chronic beta receptor blockade on activation of phospholipases A2 and C and phospho-inositide metabolism will be examined in aorta prelabeled with [3H] arachidonic acid or [3H] myoinositol. Complementary studies will be performed with vascular endothelial and smooth muscle cells in culture wherein the mechanisms of be a receptor control of arachidonic acid metabolism can be directly approached. The long-term objective is to determine the importance of beta receptor regulation of arachidonic acid metabolism to the control of arterial blood pressure. These studies should further the understanding of mechanisms responsible for the therapeutic benefits of beta receptor blocking drugs in cardiovascular diseases and reveal new information on the relationship between beta adrenergic receptors and eicosanoids in vascular homeostasis.
| Kubalak, S W; Webb, J G (1993) Angiotensin II enhancement of hormone-stimulated cAMP formation in cultured vascular smooth muscle cells. Am J Physiol 264:H86-96 |
