SUMMARY The effects of propranolol on angiotensin II (AH) enhancement of sympathetic nerve transmission were investigated in the in situ blood-perfused mesenteric vascular bed of the rat. Angiotensin II in subpressor concentrations (3 ng/ml) potentiated the vasoconstrictor responses to both sympathetic nerve stimulation (NS) and exogenous norepinephrine (NE). The dl-propranolol had no effect on the basal vasoconstrictor responses to NS and NE, yet inhibited the All-enhanced vasoconstrictor responses to NS by 47% (p< 0.0S) and 81% (p< 0.001) at 100 and 300 ng/ml respectively. In contrast, the potentiation of NE responses by AH was unaffected by propranolol. A similar blockade of All enhancement of NS was observed with the d-isomer of propranolol. Dibucaine (300 ng/ml), a local anesthetic, failed to alter the basal or AH-enhanced responses to either NS or NE. Indomethacin, a prostaglandin synthetase inhibitor (5 mg/kg, s.c), abolished the inhibitory effect of dl-propranolol on AH enhancement of NS. Prostaglandin Ej (PGE,), but not prostaglandin Ii. (3 ng/ml) inhibited AH enhancement of NS without altering the basal response to NS or NE in indomethacin-pretreated animals. Intraarterial infusions of dl-propranolol, d-propranolol, AH, and dlpropranolol-plus-AII into the superior mesenteric artery increased mesenteric venous PGE, concentrations from 216 ± 33 to 355 i 33 (p< 0.01), 328 ± 44 (p< 0.05), 325 ± 27 (p< 0.02), and 407 ± 44 pg/ml (p< 0.01) respectively. We conclude that propranolol antagonizes AH enhancement of NS by increasing prostaglandin levels in vascular tissue. Furthermore, these findings suggest that propranolol may exert its antihypertensive effect through the release of prostaglandins when used in therapeutic doses in excess of those required for beta-adrenergic blockade.