Modulation of hepatic protein kinase activity by indomethacin

We previously demonstrated that treatment with indomethacin in vivo significantly blunted the glucagon-induced glycemic response in the rat. This prostaglandin synthetase (cyclo-oxygenase) inhibitor also accentuated the evanescent effect of glucagon on hepatic glucose output in the intact, anesthetized rat. In this report, we present evidence that impairment of glucagon action in the rat liver by indomethacin is mediated through its inhibitory effect on both cAMP-dependent and cAMP-independent hepatic protein kinase. Indomethacin treatment did not have a measurable effect on any of the other components of the glucagon transducer system. Furthermore, infusion with glucagon for two hours that maintained plasma glucagon values at high physiological levels significantly reduced hepatic cAMP-dependent protein kinase activity without altering its Km. Glucagon infusion also down-regulated its own hepatic receptors and glucagon-stimulated cAMP production; prostaglandin E1-stimulated cAMP production was not affected. We concluded that prostaglandins may play a role in the regulation of hepatic protein kinases involved in the glucagon-stimulated glycogenolytic response and that glucagon-induced down-regulation extends at least to the hepatic protein kinases. However, a direct effect of indomethacin or protein kinase and the adenylate cyclase complex cannot be ruled out.     

Effects of morphine and pethidine on coronary vascular resistance, blood pressure, and myocardial infarction-induced cardiac arrhythmias

In the present study, the effects of morphine and pethidine on coronary vessel resistance (CPP), blood pressure (BP), and experimental myocardial infarction-induced cardiac arrhythmia were investigated. Both morphine and pethidine induced a fall in CPP and BP and inhibited the cardiac arrhythmia. The morphine effects on CPP and BP were largely blocked by mepyramine. The effects of pethidine, on the other hand, were not blocked by mepyramine, propranolol, or atropine. An interesting dose dependent inhibition of cardiac arrhythmia was observed with pethidine.