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The role of adenosine 3’, 5’-monophosphate in the cardiac actions of glucagon

University of British Columbia

The biochemical and mechanical effects of glucagon were investigated in the isolated, perfused rat heart. Glucagon produced time and dose-dependent alteractions in myocardial force of contractions, glycogen phosphorylase activation and cyclic AMP accumulation. The positive inotropic effect was maximal following a 4.0 μg dose, after which systolic tension increased 77.1 ± 7.9 % (N=6) relative to pre-injection systolic tension. This dose was also found to produce the maximal phosphorylase activation (38.8 ± 3.5 % in the "a" form). The cyclic AMP content was 0.73 ± 0.01 pmol/mg wet weight following 8.0 μg glucagon. Since higher doses were not investigated the saturating glucagon dose for cyclic AMP accumulation remains undetermined. The minimum effective glucagon dose for increasing contractile force and % phosphorylase "a" was 0.5 μg, whereas only 0.25 μg was required to significantly elevate the ventricular cyclic AMP content over basal level. The temporal sequence of these cardiac events was determined following 2.0 μg glucagon. Cyclic AMP increased significantly at 15 seconds. The positive inotropic effect was detectable 25 seconds after injection and % phosphorylase "a" elevation at 30 seconds. All three parameters remained significantly greater than control at least 120 seconds after glucagon administration. The observed time course is consistent with the proposal that cyclic AMP mediates the glucagon-elicited alterations in force and glycogen phosphorylase activity. Propranolol 10⁻⁸M was found not to significantly influence glucagon-induced changes in force of contraction, % phosphorylase "a" or tissue cyclic AMP content, although this concentration readily blocked the positive inotropic response to norepinephrine. It is therefore unlikely that the cardiac actions of glucagon are a result of endogenous catecholamine release or an interaction with the catecholamine β receptor. To further elucidate the role of cyclic AMP in the cardiac mechanical and metabolic responses to glucagon, the influence of 1 mM theophylline on these parameters was also investigated. In the presence of the methylxanthine, glucagon produced dose-dependent changes in % phosphorylase "a", contractile force and cyclic AMP accumulation which were considerably greater than in buffer-perfused hearts. Systolic tension was increased 116.3 ± 7.4 % over pre-injection level with 4.0 μg glucagon, and % phosphorylase "a" was augmented to the maximum theoretical value of 72.2 % (N=1) with 8.0 μg glucagon. The most dramatic influence of theophylline was on ventricular cyclic AMP accumulation, for glucagon 8.0 μg elevated tissue nucleotide content to 1.64 ± 0.02 pmol/mg wet weight. The sequence of events noted in buffer-perfused hearts was maintained in the presence of theophylline 1 mM. The data obtained in the present study strongly implicate an association between myocardial cyclic AMP content and the metabolic and mechanical actions of glucagon. However, the mechanism by which theophylline potentiated the glucagon responses is not clear. One mM theophylline possessed intrinsic ability to alter force of contraction, phosphorylase activation and cyclic AMP accumulation in a manner inconsistent with the widely-accepted theory of phosphodiesterase inhibition. Control levels of cyclic AMP were approximately 30 % greater than in buffer-perfused hearts yet the % active phosphorylase was not significantly elevated. Furthermore, 1 mM theophylline was cardiodepressant in many animals. These observations indicate that data with theophylline must be cautiously interpreted with respect to cyclic AMP involvement in the theophylline cardiac responses, and in the theophylline- glucagon interaction. Other possible mechanisms of action, such as an influence on calcium, should be given equal consideration.

Text

2010-01-27

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http://hdl.handle.net/2429/19192

Pharmacology

University of British Columbia

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