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  • Title: Activation of alpha1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway.
    Author: Wang Y, Ashraf M.
    Journal: J Mol Cell Cardiol; 1998 Nov; 30(11):2423-35. PubMed ID: 9925377.
    Abstract:
    The objective was to test the hypothesis that transient activation of the alpha1-adrenergic receptor mimics the beneficial effects of Ca2+ preconditioning on the Ca2+ paradox (Ca2+ PD) injury in rat hearts, and that the protection is mediated by protein kinase C (PKC) signaling pathway. Langendorff-perfused rat hearts were subjected to the Ca2+ PD (10 min of Ca2+ depletion followed by 10 min of Ca2+ repletion). The effects of alpha1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 micromol/l phenylephrine, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca2+ PD; furthermore, peak loss of lactate dehydrogenase was significantly decreased while ATP was significantly preserved. A remarkable preservation of cell structure was observed in phenylephrine-treated hearts in contrast to non-treated Ca2+ PD hearts. However, pre-conditioning elicited by phenylephrine caused only a mild improvement in left ventricular developed pressure (LVDP) as opposed to its impressive recovery of left ventricular end-diastolic pressure (LVEDP), heart rate (HR), or coronary flow (CF). The salutary effects of phenylephrine on the Ca2+ PD injury were almost similar to those observed in hearts which underwent Ca2+ pre-conditioning (CPC) or were pretreated with 1-stearoyl-2-arachidonoyl-glycerol (SAG), a potent PKC activator. In phenylephrine pretreated hearts, PKC isoform-alpha was localized in the sarcolemma and nucleus, while PKC-delta and PKC-epsilon were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific alpha1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 micromol/l) also reversed salutary effects of CPC. Moreover, the beta-adrenergic antagonist, propranolol, had no effect on the protection provided by phenylephrine against the Ca2+ PD injury. This study suggests that the activation of the alpha1-adrenergic receptor confers protection against the lethal injury of the Ca2+ PD via PKC-mediated signaling pathways. The protection is shared by stimuli common with calcium pre-conditioning.
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