Influence of the diabetic state on isoproterenol-induced cardiac necrosis.

Isoproterenol-induced myocardial necrosis was examined in male mice with alloxan-induced and genetically transmitted diabetes. Ten days after alloxan treatment, mice exhibited an elevation in blood glucose concentrations, weight loss, polyuria and decreased heart rates (510 +/- 15 v. 675 +/- 11 beats/min) compared with matched control mice. Similarly, genetically diabetic mice exhibited lower heart rates than the corresponding age-matched controls (383 +/- 30 v. 603 +/- 30 beats/min). In comparison to matched controls, both groups of diabetic mice had a significant decrease in the severity of the cardiac necrosis which was induced by the administration of isoproterenol. The reduction in isoproterenol-induced cardiac lesions was similar in mice with chemically induced diabetics and mice with genetically transmitted diabetes. Biochemical studies of ventricular slices revealed no change in basal cAMP levels and no differences in isoproterenol-induced changes in cAMP levels in mouse hearts from both models of diabetes. Insulin treatment corrected the chemically induced diabetic state and restored the cardiotoxic potential of isoproterenol.

Ventricular fibrillation threshold and myocardial cyclic AMP production in rats sensitive or resistant to isoproterenol.

Beta-Adrenoceptor agonists, such as isoproterenol, produce ventricular fibrillation and myocardial necrosis in rats. After the initial insult, a resistance develops to the lesion-inducing effects of subsequent doses of the drug. Cyclic AMP has been considered to play a major role in beta-adrenergic amine-induced myocardial necrosis as well as in the genesis of ventricular fibrillation. In the present studies, we investigated the ventricular fibrillation threshold and the responsiveness of myocardium to cAMP formation in isoproterenol-sensitive and resistant rats. Myocardial necrosis was induced in male Sprague-Dawley rats by subcutaneous injection of isoproterenol at 50 micrograms/kg for 2 consecutive days to make them resistant to subsequent challenges. Control rats received saline. Both groups were challenged 10 days later with graded doses of isoproterenol and ECGs were recorded. In another experiment, hearts from rats similarly treated were used for histopathology and cAMP determinations. The incidence of ventricular fibrillation and death was significantly lower in resistant rats compared with isoproterenol-sensitive rats. All rats pretreated with isoproterenol showed healed myocardial necrosis. The basal myocardial cAMP levels and the levels after in vitro isoproterenol stimulation were not significantly different between isoproterenol- and saline-pretreated rats. Moreover, no significant differences in the responsiveness of myocardium to cAMP formation were noted between the more sensitive apical and less sensitive ventricular regions in resistant or sensitive rats. These data indicate that the altered myocardial sensitivity or the mechanism for the increased ventricular fibrillation threshold in isoproterenol resistance appears to involve factors other than cAMP.

Induction of estrogen and progesterone receptors and decidualization in the hamster uterus by cholera toxin.

Cholera toxin (CT) injected ip on day 1 (day of ovulation) of the 4-day hamster estrous cycle, when circulatory progesterone is high and estrogen low, induced a massive uterine decidual reaction, a progesterone-dependent growth normally triggered by the implanting blastocyst. However, CT injected ip on day 3, when circulatory estrogen is high and progesterone low, did not induce a decidual reaction but, instead, intensified the effects of estrogen (stromal edema and stimulation of the mucosa). These cycle day effects were reproduced in one uterine horn injected intraluminally with CT, but not in the other horn of the same animal given solvent alone as a control. The intrauterine injection of CT had no effect on the concentration of serum estrogen or progesterone. The decidual reaction resulting from intrauterine injection of CT on day 1 was accompanied by increases in estrogen receptor (femtomoles per mg DNA) in both cytoplasm and nucleus. In long term ovariectomized hamsters, an ip or intrauterine injection of CT induced only histological effects of estrogen (stromal edema and mucosal mitosis) without affecting circulatory estrogen. These estrogenic effects were accompanied by increases in receptors for estrogen and progesterone in both cytoplasm and nucleus. CT injected ip into ovariectomized hamsters primed with estrogen intensified the stromal edema and mucosal mitosis and resulted in progesterone and estrogen receptor levels equal to or greater than those after the administration of CT or estrogen alone. When progesterone was included in the priming (estrogen + progesterone + CT), all receptor levels were decreased, and a massive decidual reaction resulted. Thus, the induction of estrogen receptor by CT may have been the primary event that triggered the decidual reaction. Whether CT-induced estrogen receptor is mediated by cAMP, a known mediator of CT, remains to be determined.