Mechanism of methylxanthine sensitization of norepinephrine responses in a coronaryartery

Abstract

Beta-adrenergic receptor-mediated relazation to norepinephrine was enhanced by caffeine amd aminophylline in a coronary artery preparation of the beef in vitro. Augmented responses were not obtainable in the presence of known inhibitors of the extraneuronal uptake and metabolism of norepinephrine, estradiol-17beta, and the haloalkylamine GD-131, which themselves potentiate responses. In addition, the effect on the norepinephrine dose-response curve of the combination of a methyixanthine and U-0521,the latter a potent inhibitor of catechol O-methyltransferase, the major enzyme of catecholamine inactivation in vascular tissue, did not differ from that of U-0521 alone. Studies of the extraneuronal accumulation of '3H-labeled norepinephrine revealed that caffeine and aminophylline, along with the known inhibitors, materially reduced theaccumulation of label in coronary tissue. It is concluded that the methylxanthinesenhance beta-adrenergic receptor-mediated responses via a blockade of catecholamine uptake, giving rise to an increased concentration of agonist at receptors, and not by an action linked to cyclic AMP accumulation, consequent to receptor activation.

Effects of Uptake Inhibitors on Responses of Sheep Coronary Arteries to Catecholamines and Sympathetic Nerve Stimulation

“…This could be due to species differences in its potency as an inhibitor; however, in the presence of a higher concentration of caffeine (500 pM) responses to both noradrenaline and isoprenaline were enhanced while those to nerve stimulation were unaffected. Kalsner et al (1975) reported that this concentration of caffeine increased responses of coronary arteries of cattle to noradrenaline, an effect they attributed to block of extraneuronal uptake. This is unlikely to be the sole explanation for the results obtained in the present experiments since caffeine's effects are clearly different from those of the selective extraneuronal uptake inhibitor cortisol which only in- al., 1974;Kalsner et al, 1975), although in pig coronary arteries another COMT inhibitor, pyrogallol, was inactive (Nishioka, 1971).…”

“…Potentiation of amine responses have been observed in coronary arteries of cattle (Kaisner, 1974;Kalsner, Frew & Smith, 1975) but not in those from rabbits and cats (De la Lande et al, 1974;.…”

The classification of β‐adrenoceptors in isolated ring preparations of canine coronary arteries

“…In fact, potentiation, by ex-traneuronal uptake inhibitors, of responses known to be mediated exclusively by f1-adrenoceptors has not previously been described. Although extraneuronal uptake inhibitors potentiated responses of coronary arteries of sheep to isoprenaline (Brine et al, 1979) and of ox to noradrenaline (Kalsner, 1974;Kalsner et al, 1975), the absence of a minor population of 02-adrenoceptors in the preparations from these two species has not yet been experimentally established. In the present study, responses of the canine left circumflex artery to isoprenaline (mediated exclusively by 131-adrenoceptors, vide supra) were potentiated by corticosterone and by metanephrine.…”

Mechanisms of Inactivation of Noradrenaline in the Iris Sphincter, Tracheal Muscle and Facial Artery of Cattle: Implications for Β‐adrenoceptor‐mediated Responses

“…The comparison of untreated preparations with those exposed to cocaine revealed the anticipated inhibitory effect on uptake; presumably by blockade of entry into neuronal compartments (Figure 2). Additional treatment with the steroid significantly diminished uptake in the presence of cocaine, in all three preparations tested, confirmining an extraneuronal site of action for the steroid (Kalsner, 1969;Kalsner, Frew & Smith, 1975). (Furchgott, 1955;Kalsner, 1976), then termination of action is determined by the time taken for the active agonist concentration in the region of the receptors to decline towards zero.…”