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

Abstract

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(2α), transmural electrical stimulation caused frequency-dependent relaxations, which were blocked by propranolol and augmented by indomethacin. In superfused strips, previously incubated with [3H]norepinephrine, electrical stimulation (2 Hz) increased the overflow of tritiated neurotransmitter; indomethacin did not influence basal or evoked [3H]norepinephrine overflow. Exogenous norepinephrine caused relaxations in rings contracted with prostaglandin F(2α), 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(2α)) 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(2α) or potassium chloride were not affected by indomethacin. The augmentation of β-adrenergic responsiveness by indomethacin was abolished by exogenous prostacyclin. The prostacyclin synthetase inhibitor tranylcypromine and exogenous prostaglandin E2 depressed β-adrenergic responsiveness. Indomethacin did not affect the facilitatory action of phosphodiesterase inhibition on β-adrenergic relaxation. The data suggest that endogenous prostaglandins (most probably prostacyclin and prostaglandin E2) exert a 'braking' effect on β-adrenergic responsiveness in coronary arterial smooth muscle.