The Cardioprotection of Rutaecarpine is Mediated by Endogenous Calcitonin Related-Gene Peptide Through Activation of Vanilloid Receptors in Guinea-Pig Hearts

Abstract

Previous investigations have shown that calcitonin gene-related peptide (CGRP) protects against myocardial ischemia-reperfusion injury and that rutaecarpine activates vanilloid receptors to evoke CGRP release. In the present study, we examined whether rutaecarpine enhances preservation with cardioplegia in guinea-pig hearts, and whether the protective effects of rutaecarpine are related to stimulation of endogenous CGRP release via activating vanilloid receptors. The isolated guinea-pig heart was arrested using St. Thomas Hospital solution, and then reperfused with normothermic Krebs-Henseleit solution for 30 min after a 4-h hypothermic ischemic period. Hypothermic ischemia caused a decline in cardiac function (left ventricular pressure, ±dp/dt_max, heart rate and coronary flow) and an increased release of creatine kinase during reperfusion. Rutaecarpine at the concentration of 1.0 μM significantly improved the recovery of cardiac function and reduced the release of creatine kinase during reperfusion after hypothermic ischemia. Rutaecarpine at the concentration of 3.0 μM significantly reduced the release of creatine kinase and increased the coronary flow, but only caused a slight improvement of left ventricular pressure, ±dp/dt_max, heart rate during reperfusion. The cardioprotective effects of rutaecarpine were abolished by capsazepine, a competitive vanilloid receptor antagonist, or by CGRP (8-37), a selective CGRP receptor antagonist. Rutaecarpine at the concentration of 1.0 or 3.0 μM significantly increased the release of CGRP, which was also abolished by capsazepine. These results suggest that rutaecarpine enhances preservation with cardioplegia in guinea-pig hearts and that the protective effects of rutaecarpine are due to stimulation of endogenous CGRP release via activating vanilloid receptors.

Evodia rutaecarpa - Rutaceae - rutaecarpine - calcitonin gene-related peptide - vanilloid receptor - capsaicin - guinea-pig isolated heart

References

• 1 Wang G J, Wu X C, Chen C F, Lin L C, Huang Y T, Shan J, Pang P K. Vasorelaxing action of rutaecarpine: effects of rutaecarpine on calcium channel activities in vascular endothelial and smooth muscle cells.  J Pharmacol Exp Ther. 1999;  289 1237-44
• 2 Sheu J R, Hung W C, Wu C H, Lee Y M, Yen M H. Antithrombotic effect of rutaecarpine, an alkaloid isolated from Evodia rutaecarpa, on platelet plug formation in in vivo experiments.  Br J Haematol. 2000;  110 110-5
• 3 Franco-Cereceda A. Calcitonin gene-related peptide and tachykinins in relation to local sensory control of cardiac contractility and coronary vascular tone.  Acta Physiol Scand. 1988 (Suppl 596);  133 3-63
• 4 Ren Y S, Ma T G, Wang H B, Yu S Q. Protective effects of calcitonin gene-related peptide (CGRP) on myocardial cell injury and calcium and magnesium contents following severe hypoxia and simulated reperfusion.  Med Sci Res. 1993;  21 177-8
• 5 Li Y J, Peng C F, Li N S, You T M, Deng H W. Calcitonin gene-related peptide protects against endothelial cell damage due to oxidised low-density lipoprotein.  Med Sci Res. 1993;  23 253-4
• 6 Li Y J, Xiao Z S, Peng C F, Deng H W. Calcitonin gene-related peptide-induced preconditioning protects against ischemia-reperfusion injury in isolated rat hearts.  Eur J Pharmacol. 1996;  311 163-7
• 7 Lu E X, Peng C F, Li Y J, Cheng S X. Calcitonin gene-related peptide-induced preconditioning improves preservation with cardioplegia.  Ann Thorac Surg. 1996;  62 1748-51
• 8 Kobayashi Y, Hoshikuma K, Nakano Y, Yokoo Y, Kamiya T. The positive inotropic and chronotropic effects of evodiamine and rutaecarpine, indoloquinazoline alkaloids isolated from the fruits of Evodia rutaecarpa, on the guinea-pig isolated right atria: possible involvement of vanilloid receptors.  Planta Med. 2001;  67 244-8
• 9 Lu R, Hu C P, Deng H W, Li Y J. Calcitonin gene-related peptide-mediated ischemic preconditioning in the rat heart: influence of age.  Regul Pept. 2001;  99 183-9
• 10 Kallner G, Franco-Cereceda A. Aggravation of myocardial infarction in the porcine heart by capsaicin-induced depletion of calcitonin gene-related peptide (CGRP).  J Cardiovasc Pharmacol. 1998;  32 500-4
• 11 Lechleitner P, Genser N, Mair J, Dienstl A, Haring C, Wiedermann C J, Puschendorf B, Saria A, Dienstl F. Calcitonin gene-related peptide in patients with and without early reperfusion after acute myocardial infarction.  Am Heart J. 1992;  124 1433-9
• 12 Kallner G, Owall A, Franco-Cereceda A. Myocardial outflow of calcitonin gene-related peptide in relation to metabolic stress during coronary artery bypass grafting without cardiopulmonary bypass.  J Thorac Cardiovasc Surg. 1999;  117 447-53