L. Triner

Myocardial ischemia in untreated hypertensive patients: effect of a single small oral dose of a beta-adrenergic blocking agent

In a non-double-blind, prospective, randomized study, the intraoperative electrocardiograms of 128 mildly hypertensive surgical patients were examined in order to determine the incidence of myocardial ischemia during anesthesia. No patient had been receiving chronic antihypertensive therapy prior to the study, but a single small oral dose of a beat-adrenergic blocking agent (labetalol, atenolol, or oxprenolol) was given to 89 of them along with premedication-Forty-four per cent of the untreated control patients and 61% of the patients pretreated with a beat-adrenergic blocking agent had normal preoperative electroca rdiograms and no risk factors for coronary artery disease other than hypertension (this difference between groups was not statistically significant). During tracheal intubation and/or emergence from anesthesia, a brief, self-limited episode of myocardial ischemia was detected in 11 of 39 untreated control patients, and in two of 89 patients pretreated with a betaadrenergic blocking agent (P < 0.001). Tachycardia always accompanied the ischemic events, but a conspicuous increase in blood pressure did not. The authors conclude that mild hypertension, when untereated prior to the induction of anesthesia, is associated with a high incidence of myocardial ischemia; and that a single small oral dose of a beat-adrenergic blocking agent, given with premedication, can significantly reduce that risk.

Cyclic phosphodiesterase activity and the action of papaverine

Abstract Papaverine, a smooth muscle relaxant, inhibits phosphodiesterase activity in homogenates of rabbit aorta, rat uterus and rat diaphragm.This inhibitory effect of papaverine is about 15–30 times greater than that of theophylline. In rat diaphragm, papaverine increased glycogenolysis to the same extent as epinephrine and had a synergistic effect with epinephrine on glycogen breakdown. These results suggest that the relaxing effect of papaverine might be due to its action on phosphodiesterase and are in agreement with the postulation that cyclic 3′, 5′-AMP participates in the control of smooth muscle tone and contractility.

Adenylcyclase-phosphodiesterase system in arterial smooth muscle

Abstract Isoproterenol, epinephrine, and norepinephrine increase cyclic AMP formation in rat aorta through their stimulatory effect on adenyl cyclase. Isoproterenol, and epinephrine and norepinephrine in the presence of phentolamine, have a relaxing effect on the rat aortic strip. Propranolol prevents the rise in cyclic AMP with the three catecholamines and modifies the epinephrine-induced contraction. Inhibition of phosphodiesterase is also accompanied by relaxation of arterial smooth muscle.

The effect of catecholamines on adenyl cyclase activity in rat uterus.

Abstract Adenyl cyclase (AC) activity was assayed in uterine tissue homogenates from estrogen-pretreated rats. Epinephrine, norepinephrine and isoproterenol activate AC to the same maximum, 80–88% above control; a 20 times higher concentration of norepinephrine than of epinephrine is needed to produce the same effect. A beta adrenergic blocking agent (propranolol) antagonizes this action of catecholamines. Epinephrine in lower concentrations, unlike isoproterenol, when combined with propanolol has an inhibitory effect on AC. An alpha adrenergic blocking agent (phentolamine) does not prevent the activation of AC by catecholamines. On the contrary, the activity tends to be higher. The results show that the increase in uterine muscle AC activity is caused by the component of catecholamine action which apparently relaxes the uterus and gives some support to the possibility that another component of epinephrine action inhibits AC activity.

Effects of halothane on the cyclic 3',5'-adenosine monophosphate enzyme system in human platelets.

A study of the effects of halothane on the cyclic 3′,5′-adenosine monophosphate (cAMP) system in human platelets was undertaken since cAMP has been implicated in the regulation of the process of platelet aggregation and this anesthetic has been reported to decrease platelet aggregation and, in other tissues, to increase adenylate cyclase activity. When exposed to halothane 0.5 to 10 vol%, adenylate cyclase activity was increased in the platelet preparation in a dose-dependent manner, reaching a maximum at 5 vol% (93% increase above basal activity). Platelet aggregation was also inhibited by halothane in a dose-dependent manner, with a maximum effect at about 5 vol% halothane (a decrease of 70%). Kinetic analysis of platelet cAMP-phosphodiesterase suggested two forms of activity, neither of which was altered by halothane. The results suggest that the impairment of platelet aggregation observed with halothane may be brought about by the halothane-induced activation of platelet adenylate cyclase, which may result in a higher cAMP level, inhibiting platelet aggregation.

Acetylcholine and the cyclic AMP system in smooth muscle

Abstract The effect of acetylcholine on the cyclic AMP system and its interaction with the epinephrine effect on this system was studied in vitro in rat uterus. In the presence of acetylcholine (1–100 μMolar), epinephrine-induced cyclic AMP formation in intact tissue is decreased; this inhibitory effect of acetylcholine is more pronounced at higher concentrations of epinephrine and is reversed by atropine. In broken cell preparations, acetylcholine does not alter the activity of adenyl cyclase or phosphodiesterase, nor the stimulatory effect of epinephrine. It appears that acetylcholine has an effect on the cyclic AMP system of rat uterine smooth muscle only when the structural and functional relationships in the cell are preserved. The possible mechanisms are discussed.

Halothane Effect on cGMP and Control of Motor Activity in Mouse Cerebellum

The effect of halothane on cerebellar control of motor activity and on cerebellar cyclic 3′,5′-guanosine monophosphate (cGMP) content was studied in mice. Isoniazide and picrotoxin were used to increase motor activity and induce seizures associated with an increase in cerebellar cGMP content. Halothane markedly decreased the cerebellar cGMP content (by 60 per cent at 0.61 per cent, the concentration at which 50 per cent of mice lost righting reflex) and prevented the isoniazide-induced increase in cGMP content. Halothane, 0.61 per cent, significantly reduced both isoniazide- and picrotoxin-induced motor activity; the ED50 convulsive dose of isoniazide (137.7 ± 7.04) and of picrotoxin (1.9 ± 0.2 mg·kg−1, sc) was about three times higher (402.2 ± 17.9 and 5.8 ± 0.6 mg·kg−1, sc, respectively) in mice exposed to halothane. In contrast, halothane did not alter the ED50 convulsive dose of strychnine, which has a different site and mechanism of action, blockade of glycine receptors, a mechanism not involving the cerebellar system. These results indicate that halothane has a significant effect on the cerebellar control of motor activity and that cGMP plays an important role in the alteration of cerebellar function by halothane.

Halothane Effect on Beta-adrenergic Receptors in Canine Myocardium

Halothane depresses the inotropic state of the heart, possibly by decreasing the rate of formation of cyclic 3′, 5′-adenosine monophosphate (cAMP) through depression of the activity of adenylate cyclase, the cAMP-generating enzyme. As catecholamines regulate the inotropic state and adenylate cyclase activity by binding to myocardial beta-adrenergic receptors, the effect of halothane on binding to these receptors was studied to determine whether this was a site of halothane effect. Beta-adrenergic binding was measured at binding equilibrium in vitro in a canine myocardial membrane preparation in the absence and presence of halothane, 3 to 5 vol%, using as the radioligand 3H-dihydroalprenolol (3H-DHA), a beta-adrenergic antagonist with high affinity and radioactivity. In addition, the effect of halothane on the binding of /-isoproterenol, a beta-adrenergic agonist, was measured by displacement of 3H-DHA. The results indicate that halothane has no effect on either the affinity of canine myocardial beta-adrenergic receptors for 3H-DHA or /-isoproterenol, nor does it alter the number of available receptors at binding equilibrium.

Action of Halothane on Myocardial Adenylate Cyclase of Rat and Cat

Summary The effect of halothane on myocardial adenylate cyclase was studied since cAMP is thought to participate in the regulation of myocardial contractility and since halothane has been shown to alter the activity of the cAMP-generating enzyme in other organs. Halothane significantly decreased the stimulatory effect of catecholamines on myocardial adenylate cyclase without altering the basal or the sodium fluoride-induced adenylate cyclase activity. In the presence of halothane (2%, vol/vol) the effect of 5 μM norepinephrine on adenylate cyclase in rat myocardium, 74.0 ± 3.0, was reduced to 53.0 ± 3.0 pmol/mg protein/5 min (P < 0.001) (control adenylate cyclase activity, 140.0 ± 1.0 pmol/mg protein/5 min). The activation of adenylate cyclase by isoproterenol was also significantly decreased by halothane in rat and cat myocardium. The maximum stimulatory effect of isoproterenol (2.5 μM) on adenylate cyclase in rat myocardium, 71.0 ± 8.0, was decreased to 26.0 ± 6.0 pmol/mg protein/5 min (P < 0.001) in the presence of halothane (2%, vol/vol). Furthermore, halothane diminished the effects of 5-guanylyl imidodiphosphate, which is thought to act at a site linking the regulatory and catalytic units of adenylate cyclase. The results suggest possible sites of halothane action on myocardial adenylate cyclase and raise the possibility that this inhibitory action of halothane and the decreased positive inotropic action of catecholamines in the presence of halothane may be related.

Effects of Ouabain on Insulin Secretion in the Dog

The mechanism of the previously reported hypoglycemic effect of ouabain was studied in dogs. Ouabain (1.0 μg/kg/min infused intravenously for 60 minutes) combined with insulin or propranolol caused a greater and more prolonged decrease in blood glucose than either of the drugs administered separately. In intact dogs, ouabain changed significantly portohepatic venous differences in plasma glucose from +6.6 to −13.6 mg/100 ml and in K+ from −0.03 to −0.4 mEq/liter. In pancreatectomized animals, ouabain did not cause any significant decrease in peripheral glucose level, and the portohepatic differences in plasma glucose changed from +5.3 to +30.2 mg/100 ml and the differences in K+ from −0.01 to +0.2 mEq/liter. These changes, indicating an increased release of glucose and K+ by the liver in the pancreatectomized dog, were also observed in isolated rat liver perfused with ouabain 10-6M. Glucose uptake of the hindlimb increased significantly during the infusion of ouabain in normal dogs, but did not change in pancreatectomized dogs. Ouabain caused a significant increase in plasma insulin in portal blood (+155%). These results demonstrate that the observed metabolic effects of ouabain in the dog are mainly mediated by insulin and that ouabain increases the secretion of insulin in intact dogs.