The cardioprotection of calcitonin gene-related peptide-mediated preconditioning

doi:10.1016/S0014-2999(02)01538-8

European Journal of Pharmacology

Volume 442, Issue 3, 10 May 2002, Pages 173-177

https://doi.org/10.1016/S0014-2999(02)01538-8 Get rights and content

Abstract

Preconditioning induced by brief ischemia or hyperthermia or some drugs shows two phases, early and delayed protection. The cardioprotection afforded by preconditioning is related to stimulation of endogenous mediators release. Calcitonin gene-related peptide (CGRP), a major transmitter of capsaicin-sensitive sensory nerves, has recently been shown to play an important role in mediation of the preconditioning induced by brief ischemia or hyperthermia or by some drugs, and α-CGRP seems to play a major role in the mediation of delayed preconditioning. It has been shown that the cardioprotection afforded by CGRP-mediated preconditioning is due to inhibition of cardiac tumor necrosis factor-α (TNF-α) production, but not to the activation of the K_ATP channel.

Introduction

Since the term ischemic preconditioning was originally recognized by Murry et al. (1986), considerable progress has been made in understanding this phenomenon. Ischemic preconditioning shows two phases: an early phase of protection termed “classic preconditioning”, which occurs within minutes and disappears within 2 to 4 h. Subsequently, a delayed phase of protection termed “second window of protection” appears 24 h after initial ischemic preconditioning and lasts for 48 to 72 h. Preconditioning of the heart has been exploited from ischemic stimulus to heat stress and some drugs Pagliaro et al., 2001, Bolli, 2000.

The mechanisms underlying preconditioning have not yet been elucidated but one suggestion is that the protective effect is mediated by endogenous active substances, including neurotransmitters and autocoids (Parratt, 1994). We and others have shown that endogenous calcitonin gene-related peptide (CGRP) plays an important role in mediation of preconditioning (Li et al., 2000).

Section snippets

The biology characteristic of CGRP

CGRP is a major transmitter in capsaicin-sensitive sensory nerves and has two isoforms named CGRP_α and CGRP_β. CGRP_α was cloned in the early 1980s from the gene encoding calcitonin (Amara et al., 1982). In the thyroid, calcitonin is the main product of this gene, whereas, in neural tissues, a novel neuropeptide, CGRP_α, is generated. A second CGRP homologue, CGRP_β, was later characterized, bearing high sequence homologies with the α-form but that was not derived from the calcitonin gene (Amara et

CGRP and ischemic preconditioning

The release of CGRP is regulated by multiple factors, such as transient ischemia, hyperthermia or autocoids, and the elevated level of CGRP during ischemia probably constitutes a compensatory response Kallner, 1998, Franco-Cereceda, 1988, Kress and Zeilhofer, 1999. Administration of exogenous CGRP has been shown to alleviate the incidence of reperfusion-induced ventricular arrhythmia and to protect the cultured myocyte against hypoxygen injury Zhang et al., 1994, Ren et al., 1993. It has been

CGRP and heat stress-induced cardioprotection

It has been documented that sublethal hyperthermia is also capable of inducing preconditioning-like protection, including classical or early preconditioning and delayed preconditioning or “second window” protection Gowda et al., 1998, Yamashita et al., 1998. The mechanism responsible for the beneficial effect of heat stress is still not fully understood. Early studies have found that a stress, cold or heat, is also capable of activating capsaicin-sensitive sensory nerves and stimulating the

CGRP and pharmacological preconditioning

Substitution of some drugs for ischemic stimulus is also capable of inducing a protection similar to that with ischemic preconditioning and this is described as pharmacological preconditioning. The protective effects of some drug-induced preconditioning have been suggested to be related to stimulation of endogenous active substances. For example, angiotensin-converting enzyme inhibitors or monophospheryl lipid A-induced preconditioning protects the myocardium against damages due to

Mechanisms of CGRP-mediated cardioprotection

The exact mechanisms responsible for the protective effects of CGRP remain unclear. Endogenous mediators including neurotransmitters bind to specific receptors and then activate the endogenous protective mechanisms via complex signal pathways, which are related to the activation of protein kinase C or ATP-sensitive K+ (K_ATP) channels. There is evidence to suggest that CGRP enhances the activity of protein kinase C and activates K_ATP channels in vascular smooth muscle Bell et al., 1995, Wellman

Summary

The results from animal experiments and clinical studies have shown that CGRP plays an important role in the mediation of ischemic preconditioning. Endogenous CGRP is also involved in mediation of the preconditioning of the heart induced by heat stress or some drugs. It is likely that CGRP-mediated early preconditioning only involves the release of CGRP, while the development of CGRP-mediated delayed preconditioning is related to the upregulation of α- but not β-CGRP gene expression via NO

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ReviewThe cardioprotection of calcitonin gene-related peptide-mediated preconditioning

Abstract

Introduction

Section snippets

The biology characteristic of CGRP

CGRP and ischemic preconditioning

CGRP and heat stress-induced cardioprotection

CGRP and pharmacological preconditioning

Mechanisms of CGRP-mediated cardioprotection

Summary

J. Biol. Chem.

FEBS Lett.

J. Mol. Cell. Cardiol.

Neurosci. Lett.

Eur. J. Pharmacol.

Biochem. Biophys. Res. Commun.

Ann. Thorac. Surg.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

J. Thorac. Cardiovasc. Surg.

Trends Pharmacol. Sci.

Am. Heart J.

Eur. J. Pharmacol.

Ann. Thorac. Surg.

Ann. Thorac. Surg.

Regul. Pept.

Life Sci.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Regul. Pept.

Neuropeptides

Regul. Pept.

Neuropeptides

Toxicology

Eur. J. Pharmacol.

Ann. Thorac. Surg.

J. Mol. Cell Cardiol.

Review
The cardioprotection of calcitonin gene-related peptide-mediated preconditioning