Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway

Yigang Wang, Muhammad Ashraf

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The objective was to test the hypothesis that transient activation of the α1-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 α1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 μmol/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-α was localized in the sarcolemma and nucleus, while PKC-δ and PKC-ε were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific α1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 μmol/l) also reversed salutary effects of CPC. Moreover, the β-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 α1-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.

Original languageEnglish (US)
Pages (from-to)2423-2435
Number of pages13
JournalJournal of molecular and cellular cardiology
Volume30
Issue number11
DOIs
StatePublished - Jan 1 1998
Externally publishedYes

Fingerprint

Phenylephrine
Adrenergic Receptors
Protein Kinase C
Wounds and Injuries
Adrenergic Antagonists
Prazosin
Protein Isoforms
Blood Pressure
Sarcolemma
Ventricular Pressure
L-Lactate Dehydrogenase
Propranolol
Adenosine Triphosphate
Heart Rate
Cell Membrane
Calcium

Keywords

  • Ca paradox
  • Ca pre-conditioning
  • Phenylephrine
  • Protein kinase C
  • α-adrenergic receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway",
abstract = "The objective was to test the hypothesis that transient activation of the α1-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 α1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 μmol/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-α was localized in the sarcolemma and nucleus, while PKC-δ and PKC-ε were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific α1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 μmol/l) also reversed salutary effects of CPC. Moreover, the β-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 α1-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.",
keywords = "Ca paradox, Ca pre-conditioning, Phenylephrine, Protein kinase C, α-adrenergic receptor",
author = "Yigang Wang and Muhammad Ashraf",
year = "1998",
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T1 - Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway

AU - Wang, Yigang

AU - Ashraf, Muhammad

PY - 1998/1/1

Y1 - 1998/1/1

N2 - The objective was to test the hypothesis that transient activation of the α1-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 α1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 μmol/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-α was localized in the sarcolemma and nucleus, while PKC-δ and PKC-ε were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific α1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 μmol/l) also reversed salutary effects of CPC. Moreover, the β-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 α1-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.

AB - The objective was to test the hypothesis that transient activation of the α1-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 α1-adrenergic receptor activation and other interventions on functional, biochemical and pathological changes were assessed. In hearts pretreated with 50 μmol/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-α was localized in the sarcolemma and nucleus, while PKC-δ and PKC-ε were localized in the cell membrane, and intercalated disk respectively. Prazosin, a specific α1-adrenergic receptor antagonist completely abolished the beneficial effects of phenylephrine on the Ca2+ PD and blocked translocation of PKC isoforms. In addition, prazosin (1 μmol/l) also reversed salutary effects of CPC. Moreover, the β-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 α1-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.

KW - Ca paradox

KW - Ca pre-conditioning

KW - Phenylephrine

KW - Protein kinase C

KW - α-adrenergic receptor

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