A possible antihypertensive mechanism of propranolol: antagonism of angiotensin II enhancement of sympathetic nerve transmission through prostaglandins.
The effects of propranolol on angiotensin II (AII) 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 AII-enhanced vasoconstrictor responses to NS by 47% (p less than 0.05) and 81% (p less than 0.001) at 100 and 300 ng/ml respectively. In contrast, the potentiation of NE responses by AII was unaffected by propranolol. A similar blockade of AII enhancement of NS was observed with the d-isomer of propranolol. Dibucaine (300 ng/ml), a local anesthetic, failed to alter the basal or AII-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 AII enhancement of NS. Prostaglandin E2 (PGE2), but not prostaglandin I2, (3 ng/ml) inhibited AII enhancement of NS without altering the basal response to NS or NE in indomethacin-pretreated animals. Intraarterial infusions of dl-propranolol, d-propranolol, AII, and dl-propranolol-plus-AII into the superior mesenteric artery increased mesenteric venous PGE2 concentrations from 216 +/- 33 to 355 +/- 33 (p less than 0.01), 328 +/- 44 (p less than 0.05), 325 +/- 27 (p less than 0.02), and 407 +/- 44 pg/ml (p less than 0.01) respectively. We conclude that propranolol antagonizes AII 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.
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001769:Blood; D006973:Hypertension / Q000188:drug therapy*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008642:Mesenteric Veins / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011458:Prostaglandins E / Q000097:blood; D051381:Rats; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D011458:Prostaglandins E; D000804:Angiotensin II; D011433:Propranolol; D011451:Prostaglandin-Endoperoxide Synthases; D009638:Norepinephrine; D007213:Indomethacin