Inhibitors of prostaglandin synthesis augment beta-adrenergic responsiveness in canine coronary arteries.

Abstract

SUMMARY. The effects of inhibition of endogenous prostaglandin synthesis on the release of norepinephrine from sympathetic nerves and on postjunctional adrenergic responsiveness were studied in isolated canine left circumflex coronary arteries. In rings, suspended for isometric tension recording and contracted with prostaglandin F 2o , transmural electrical stimulation caused frequency-dependent relaxations, which were blocked by propranolol and augmented by indomethacin. In superfused strips, previously incubated with [ HJnorepinephrine, electrical stimulation (2 Hz) increased the overflow of tritiated neurotransmitter; indomethacin did not influence basal or evoked [ 3 H]norepinephrine overflow. Exogenous norepinephrine caused relaxations in rings contracted with prostaglandin F 2o , but increases in tension in potassium-depolarized tissues which could be abolished by phentolamine; isoproterenol induced relaxations in both cases. Indomethacin significantly augmented the relaxation in response to exogenous norepinephrine (during contractions with prostaglandin F 2(t ) and reversed norepinephrine-induced contractions (during potassium-depolarization) into relaxation. Other cyclooxygenase inhibitors had comparable effects. In the presence of propranolol, indomethacin did not diminish contractions evoked by norepinephrine in depolarized rings. Relaxations induced by sodium nitroprusside or acetylcholine during contractions caused by prostaglandin F 2<> or potassium chloride were not affected by indomethacin. The augmentation of ^-adrenergic responsiveness by indomethacin was abolished by exogenous prostacyclin. The prostacyclin synthetase inhibitor tranylcypromine and exogenous prostaglandin E2 depressed /3-adrenergic responsiveness. Indomethacin did not affect the facilitatory action of phosphodiesterase inhibition on /3-adrenergic relaxation. The data suggest that endogenous prostaglandins (most probably prostacyclin and prostaglandin E 2 ) exert a "braking" effect on /3-adrenergic responsiveness in coronary arterial smooth muscle. (Circ Res 56: 117-125, 1985) THE large coronary arteries of the canine heart contain adrenergic nerve terminals which release norepinephrine upon stimulation; under control conditions, the /3-adrenergic effect of the released transmitter predominates, causing relaxation (Borda et al., 1977;Rorie and Shepherd, 1980;Cohen et al., 1983). The relaxations of the canine coronary artery induced by electrical stimulation of the adrenergic nerve endings or by the indirectly acting sympathomimetic amine, tyramine, are potentiated by the inhibitor of cyclooxygenase, indomethacin (Cohen et al., 1983). These observations suggest that endogenously formed prostaglandins impair adrenergic neuroeffector interaction in this preparation by either decreasing the release of norepinephrine from the adrenergic nerve endings, by accelerating the disposition of the transmitter, by increasing a-adrenergic responsiveness of the vascular smooth muscle or by reducing /3-adrenergic relaxation. The present stud...

β-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase

“…Perhaps, by inhibiting COX, the production of prostaglandin I 2 is interrupted, thus lifting its inhibitory effect on ␤-adrenergic vasodilation. It is also possible COX products other than prostaglandin I 2 (e.g., prostaglandin E 2 ) are involved (36). Furthermore, the rise in isoproterenol-mediated dilation with ketorolac infusion may be due to an indirect effect of COX products on bioavailable NO and/or NOS.…”

Alterations of Arachidonic Acid Metabolism Modulate Adenosine Relaxation in Isolated Coronary Arteries

“…The present study demonstrates that simi lar to its effect on beta-adrenergic responsive ness [Miller et al, 1984;Rubanyi and Paul, 1984;Rubanyi and Vanhoutte, 1985a] the cyclo-oxygenase inhibitor indomethacin sig nificantly augments relaxation in response to exogenous adenosine in depolarized isolated porcine, bovine and canine coronary arteries. It is likely that the augmentation by indo methacin of the adenosine-induced relax ation is due to inhibition of prostaglandin synthesis in the coronary artery wall.…”

“…At 30-min intervals the chamber contents were exchanged with fresh Krebsbicarbonate solution and the vascular rings were re stretched to obtain 100 mN. This procedure was cho sen to yield a tissue length that was optimal for iso metric force development [Rubanyi and Paul, 1984;Rubanyi and Vanhoutte. 1985a).…”

“…Recent studies in isolated porcine, bovine [Rubanyi and Paul, 1984], canine [Rubanyi and Vanhoutte, 1985a] and sheep coronary arteries [Miller et al, 1984] demonstrated that endogenous prostaglandins modulate vascular responsiveness to beta-adrenergic agonists. Stimulation of vascular prostaglan din synthesis by hypoxia or by exogenous arachidonic acid inhibited, while indometha cin and other cyclo-oxygenase inhibitors aug mented beta-adrenergic relaxation [Rubanyi and Paul, 1984;Rubanyi and Vanhoutte, 1985a].…”

“…Stimulation of vascular prostaglan din synthesis by hypoxia or by exogenous arachidonic acid inhibited, while indometha cin and other cyclo-oxygenase inhibitors aug mented beta-adrenergic relaxation [Rubanyi and Paul, 1984;Rubanyi and Vanhoutte, 1985a]. In isolated perfused rat [Talesnik and Sunahara, 1973] and cat hearts [Sunahara and Talesnik, 1974] cyclo-oxygenase inhibi tors facilitated and exogenous prostaglandins of the E series depressed metabolically me diated coronary arterial dilatation.…”