Beta-adrenergic antagonists are widely used in the treatment of hypertension and coronary artery disease. While a number of antihypertensive mechanisms have been suggested, they fail to completely explain the blood pressure lowering with these drugs. We have recently found that the beta-blocker propranolol in therapeutically relevant doses inhibits the action of subpressor doses of angiotensin II to enhance the release of norepinephrine from the adrenergic neuron. This action was unrelated to beta-blockade, membrane stabilization or neuronal blockade but appears to be mediated by prostaglandins (PG) since it is inhibited by indomethacin; PGE2 produces an identical effect, propranolol increases PGE2 release from the mesentery and kidney, and indomethacin blocks the antihypertensive activity of propranolol. We plan to further examine the effect of the beta-blockers on PG release and the mechanism by which this occurs in an attempt to explain their antihypertensive activity. These studies will characterize the role of PG's in the inhibition of angiotensin II-potentiation of norepinephrine release by beta-blockers and the adrenergic neuronal blocking action of these drugs. These studies will be conducted both in vitro and in vivo in tissue cultures, isolated vascular strips, perfused tissues, experimental hypertension, and patients with essential hypertension. Additionally, the effect of the beta-blockers on the urinary PG excretion and the renal functional consequences of this PG release will be studied. Since propranolol inhibits platelet aggregation and PG's play a pivitol role in this process, the possibility that beta-blockers inhibit aggregation through a prostaglandin mechanism will also be examined. The effect of the beta-blockers on platelet aggregation and thromboxane and PG synthesis will be studied in vitro and in vivo as well as the effect of beta-blockers on the release of antiaggregatory PG's from cultured endothelial cells. These findings will provide insights into the pharmacologic actions and the side effects of these drugs and provide new directions for therapy and drug design.