The purpose of this study was to investigate sex differences in the functional response of isolated rat heart ventricular myocytes to beta-adrenergic stimulation and in isoproterenol-stimulated signal transduction. Fractional shortening was measured using a video edge-detection system in control- and isoproterenol-stimulated myocytes that had been isolated from weight-matched rats. Number and affinity of the beta-adrenergic receptors and the L-type Ca(2+) channel were measured in ventricular cardiac membranes by radioligand binding studies. Control- and isoproterenol-mediated alteration in Ca(2+) current density (I(Ca)) was determined by patch clamping and cellular cAMP content was determined by radioimmunoassay. Study results demonstrate that female myocytes have higher Ca(2+) channel density and greater I(Ca) than male myocytes. However, isoproterenol elicits a greater beta-adrenergic receptor-mediated increase cell shortening, I(Ca) and cAMP production in male myocytes. Male myocytes were also found to have a higher beta-adrenergic receptor density. These results suggest that cardiac myocytes from male rats have an enhanced response to beta-adrenergic stimulation due to augmented beta-adrenergic signaling that results in a greater transsarcolemmal Ca(2+) influx.
Accumulation of lipid metabolites, such as palmitoylcarnitine and lysophosphatidylcholine, is thought to be a major contributor to the development of cardiac arrhythmias during myocardial ischemia. This arrhythmogenicity is likely due to the effects of these metabolites on various ion channels. Diabetic hearts have been shown to accumulate much higher concentrations of these lipid metabolites during ischemia, which may be an important factor in the enhanced incidence of arrhythmias in diabetic hearts. However, it is not known whether these metabolites have similar effects on the ion channels of diabetic hearts as in non-diabetic hearts. Previous studies on myocytes from non-diabetic hearts have reported either enhancement or inhibition of L-type calcium current (I(Ca)) by these lipid metabolites. Thus, it is not clear whether the effects of palmitoylcarnitine and/or lysophosphatidlycholine on I(Ca) contribute to the enhanced arrhythmogenicity of diabetic hearts or protect against arrhythmias. We determined the effect of exogenous palmitoylcarnitine and lysophosphatidylcholine on the (I(Ca)) in ventricular myocytes from streptozotocin-diabetic and non-diabetic rat hearts under identical conditions. We found that palmitoylcarnitine and lysophosphatidylcholine exhibited a dose-dependent inhibition of I(Ca), which was virtually identical in diabetic and non-diabetic cardiac myocytes. Thus, we conclude that these arrhythmogenic lipid metabolites have similar actions on calcium channels in diabetic and non-diabetic hearts. Therefore, the greater susceptibility of diabetic hearts to arrhythmias during myocardial ischemia is not due to an altered sensitivity of the L-type calcium channels to lipid metabolites, but may be explained, in large part, by the greater accumulation of these metabolites during ischemia.
The contractile hyporesponsiveness of the streptozotocin diabetic rat heart in vitro to beta-adrenergic agonists is eliminated when the heart is perfused with N(G)-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of nitric oxide synthase (NOS). The following study evaluated the hypothesis that an increased production of NO/cGMP within the diabetic myocyte inhibits the beta-adrenergic-stimulated increase in calcium current and contractile response. Male Sprague-Dawley rats were given an intravenous injection of streptozotocin (60 mg/kg). After 8 weeks, L-type calcium currents were recorded in ventricular myocytes using the whole cell voltage-clamp method. Shortening of isolated myocytes was determined using a video edge detection system. cAMP and cGMP were measured using radioimmunoassay. Nitric oxide production was determined using the Griess assay kit. Basal cGMP levels and nitric oxide production were elevated in diabetic myocytes. Shortening of the diabetic myocytes in response to isoproterenol (1 microM) was markedly diminished. However, there was no detectable difference in the isoproterenol-stimulated L-type calcium current or cAMP levels between control and diabetic myocytes. Acute superfusion of the diabetic myocyte with L-NAME (1 mM) decreased basal cGMP and markedly enhanced the shortening response to isoproterenol but did not alter isoproterenol-stimulated calcium current. These data suggest that increased production of NO/cGMP within the diabetic myocyte suppressed beta-adrenergic stimulated shortening of the myocyte. However, NO/cGMP apparently does not suppress shortening of the myocyte by inhibition of the beta-stimulated calcium current.
During pregnancy, the uterus undergoes several modifications under the influence of hormonal and mechanical stimuli. We hypothesize that while most of these modifications are reverted during involution, some of the physiological properties of the uterus are permanently altered. To investigate this hypothesis, we conducted motility experiments to evaluate the contractility response of uterine tissue samples from non-pregnant virgin and proven breeder female rats to oxytocin (10−10 to 10−5 M). We found that the virgin tissue contracts more robustly than proven breeder tissue in the absence of oxytocin, yet with oxytocin, proven breeder samples displayed a significantly higher increase in activity. These results could depend on a more elevated expression of oxytocin receptor and/or on an alteration in the intracellular pathways affected by the activation of the oxytocin receptors. Here, we explored the impact of some structures involved in the management of intracellular calcium on the dose response to oxytocin recorded from virgin and proven breeder uterine strips. Specifically, we replicated the dose response experiments in low extracellular calcium (10 μM), in the presence of the intracellular calcium channel blocker ruthenium red (10 μM), and in the presence of the sarcoplasmic-endoplasmic reticulum calcium ATP-ase pump inhibitor, cyclopiazonic acid (10 μM). The results of these experiments suggest that also the expression of proteins that control intracellular calcium availability is affected by the experience of pregnancy. Molecular biology experiments will give us more detail on the magnitude of these expression changes.
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