Effects of remifentanil on intracellular Ca(2+) and its transients induced by electrical stimulation and caffeine in rat ventricular myocytes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Preconditioning with remifentanil confers cardioprotection. Since Ca(2+) overload is a precipitating factor of injury, we determined the effects of remefentanil on intracellular Ca(2+) ([Ca(2+)](i)) and its transients induced by electrical stimulation and caffeine, which reflects Ca(2+) handling by Ca(2+) handling proteins, in rat ventricular myocytes.</p><p><b>METHODS</b>Freshly isolated adult male Sprague-Dawley rat myocytes were loaded with Fura-2/AM and [Ca](i) was determined by spectrofluorometry. Remifentanil at 0.1 - 1000 microg/L was administered. Ten minutes after administration, either 0.2 Hz electrical stimulation was applied or 10 mmol/L caffeine was added. The [Ca(2+)](i), and the amplitude, time resting and 50% decay (t(50)) of both transients induced by electrical stimulation (E [Ca(2+)](i)) and caffeine (C [Ca(2+)](i)) were determined.</p><p><b>RESULTS</b>Remifentanil (0.1 - 1000.0 microg/L) decreased the [Ca(2+)](i) in a dose-dependent manner. It also decreased the amplitude of both transients dose-dependently. Furthermore, it increased the time to peak and t(50) of both transients dose-dependently.</p><p><b>CONCLUSION</b>Remifentanil reduced the [Ca(2+)](i) and suppressed the transients induced by electrical stimulation and caffeine in rat ventricular myocytes.</p>

Cardioprotection by the female sex hormone -- interaction with the beta₁-adrenoceptor and its signaling pathways / 生理学报

Estrogen is a steroid and the predominant female sex hormone in the body. Ovariectomised (OVX) adult female rats exhibit greater myocardial injury compared to the sham rats following ischemic insult in the presence of beta-adrenoceptor stimulation. Estrogen replacement restores the response of OVX female rats to ischemic/beta-adrenoceptor stimulation to that of normal female rats, providing evidence for a cardioprotective role of estrogen during ischemic insult. The protective effect is due to down-regulation of the beta(1)-adrenoceptor. There is also evidence that estrogen suppresses the expression and activity of protein kinase A (PKA), a second messenger of the G(s) protein/adenylyl cyclase/cAMP/PKA pathway which ultimately influences contractile function. There is also preliminary evidence that estrogen may suppress the activity of Ca(2+)/calmodulin kinase II deltac isoform (CaMKII-deltac), another downstream second messenger of the beta(1)-adrenoceptor pathway, which is involved in PKA-independent cell apoptosis. Acute administration of estrogen at physiological level could inhibit myocardial beta(1)-adrenoceptor and attenuate Ca(2+) influx independent of the estrogen receptor. In addition, brain studies also show estrogen inhibits the activities activated by the beta-adrenoceptor in brain regions responsible for the regulation of arterial blood pressure. Thus, it can be appreciated that the interaction between estrogen and the beta(1)-adrenoceptor and its signaling pathways is a complex one. Estrogen plays an important role not only in reproduction but also in other regulatory functions such as cardioprotection.

Roles of kappa opioid receptors in cardioprotection against ischemia: the signaling mechanisms / 生理学报

There is evidence that the myocytes produce dynorphin and dynorphin-like peptides, which are kappa opioid receptor (kappa-OR) agonists. Activation of kappa-OR, a dominant opioid receptor in the heart, alters the cardiac function in vivo and in vitro. The observations suggest that the endogenous kappa-opioid peptides may act as autocrines or paracrine in regulation of cardiac functions. Myocardial ischemia is a common cause of heart disorders, which is manifested in decreased myocardial performance, arrhythmia and infarct. When myocardial ischemia occurs, the sympathetic discharge increases, which in turn increases the work-load and oxygen consumption. This exacerbates the situation induced by ischemia. One of the mechanisms with which the body protects against ischemia-induced injury/arrhythmia is inhibition of stimulation of beta-adrenoceptor (beta-AR), the receptor mediating the actions of sympathetic stimulation. kappa-Opioids inhibit the beta-AR activation. The inhibition of the beta-AR activation is due to inhibition of Gs-protein and to a lesser extent the adenylyl cyclase of the signaling pathway mediating beta-AR stimulation by a pertussis sensitive G-protein that mediates kappa-OR activation. Another mechanism against ischemia-induced injury is preconditioning, which is defined as prior exposures to ischemia or other insults make the heart more tolerant to subsequent and more severe insults. Protection occurs immediately or 1-3 days after preconditioning. kappa-OR mediates protection of preconditioning with ischemia or metabolic inhibition, one of the consequences of ischemia, in the heart. Activation of kappa-OR by U50488H, a selective kappa-OR agonist (pharmacological preconditioning with U50488H, UP), activates protein kinase C (PKC), opens K(ATP) channels and increases the production of heat shock proteins. Blockade of PKC, or closing of the K(ATP) channels or inhibition of the synthesis of the heat shock protein abolishes the cardioprotection of UP. The findings indicate the important roles of PKC, the K(ATP) channels and the heat shock protein in cardioprotection of UP. In addition, UP also attenuates the Ca(2+) overload, a precipitating cause of cardiac injury, induced by ischemic insults, indicating that UP may confer cardioprotection via at least partly attenuating the Ca(2+) overload. Most interestingly, blockade of the K(ATP) channels with channel blockers, that abolishes the delayed cardioprotection of UP, also attenuates the inhibitory effect of UP on Ca(2+) overload, suggesting that the cardioprotective effect of opening of the K(ATP) channels may be due at least partly to the prevention/attenuation of Ca(2+) overload.