Summary Organic nitrates, including nitroglycerin, produce vascular relaxation by releasing nitric oxide in vascular tissues near the plasma member of smooth muscle cells of veins and arteries. Calcitonin gene-related peptide (CGRP), a major transmitter in capsaicin-sensitive sensory nerves, is widely distributed in cardiovascular tissues and the release of CGRP is regulated by multiple autacoids including nitric oxide (NO). CGRP exerts complex cardiovascular effects including potent vasorelaxation and protective effects on myocytes and endothelial cells. Nitroglycerin activates sensory nerves fibres to release CGRP by generating NO and increasing cGMP

Previous studies have shown that endothelial dysfunction is associated to an increase of endogenous nitric oxide synthase (NOS) inhibitor level and estrogen reduces impairment of the endothelium due to oxidized low-density lipoprotein (LDL). The purpose of the present study was to investigate the effect of estradiol on endothelial dysfunction and the increased level of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, induced by LDL. Male Sprague-Dawley rats were treated with a single injection of native LDL (4mg/kg) for 48 h. Vasodilator responses to acetylcholine in the aortic rings and serum levels of ADMA and malondialdehyde (MDA) were determined. Treatment with native LDL markedly reduced endothelium-dependent relaxation to acetylcholine in the isolated rat thoracic aortic rings and increased serum levels of ADMA and MDA (P<0.01). Pretreatment with 17h-estradiol (0.1 or 0.3mg/kg) significantly attenuated inhibition of vasodilator responses to acetylcholine and elevation of both ADMA and MDA concentration by LDL (P<0.01). These results suggest that estradiol possesses a protective effect on the endothelium and the protective effect is related to reduction of ADMA concentration by inhibition of lipid peroxidation.

Recent study has shown that monophosphoryl lipid A-induced delayed preconditioning enhanced preservation with cardioplegia and that the protective effects of monophosphoryl lipid A were related to stimulation of calcitonin gene-related peptide (CGRP) release. The purpose of the present study was to explore whether the elevated release of CGRP induced by monophosphoryl lipid A is secondary to stimulation of CGRP synthesis via the nitric oxide (NO) pathway and to characterize the isoform of CGRP. Sprague-Dawley rats were pretreated with monophosphoryl lipid A 24h before the experiment, and then the left main coronary artery of rat hearts was subjected to 1 h occlusion followed by 3 h reperfusion. Infarct size, plasma creatine kinase activity, the plasma level of CGRP, and the expression of CGRP isoforms (aand b-CGRP) mRNA in lumbar dorsal root ganglia were measured. Pretreatment with monophosphoryl lipid A (500mg/kg, i.p.) significantly reduced infarct size and creatine kinase release. Monophosphoryl lipid A caused a significant increase in the expression of a-CGRP mRNA, but not of b-CGRP mRNA, concomitantly with an increase in plasma concentrations of CGRP, and the increased level of CGRP expression happened before stimulation of CGRP release. The effect of monophosphoryl lipid A was completely abolished by pretreatment with Lnitroarginine methyl ester (L-NAME, 10 mg/kg, i.p.), an inhibitor of NO synthase or capsaicin (50 mg/kg, s.c.), which selectively depletes transmitters in capsaicin-sensitive sensory nerves. The results suggest that the delayed cardioprotection afforded by monophosphoryl lipid A involves the synthesis and release of CGRP via the NO pathway, and that the protection is mainly mediated by the a-CGRP isoform.

Previous studies have shown that the development of tolerance to nitroglycerin is related to a decrease in the release of endogenous calcitonin gene-related peptide (CGRP). In the present study, we explored whether endogenous CGRP is involved in reversal of tolerance to nitroglycerin with N-acetylcysteine or captopril in rats in vivo and vitro. Tolerance was induced by exposure to nitroglycerin (4.4

Previous investigations have demonstrated that calcitonin gene-related peptideCGRP.plays an important role in the mediation of ischemic preconditioning in rats. In the present study, we examined signal transduction pathways of CGRP-mediated ischemic preconditioning. Thirty minutes of global ischemia and 40 min of reperfusion caused a dramatic decrease in myocardial function, and a significant increase in the release of cardiac creatine kinase in the coronary effluent and in the content of tumor necrosis factor-a TNF-a.in myocardial tissues. However, ischemic preconditioninghree cycles of 5-min ischemia and 5-min reperfusion.or pretreatment with CGRP for 5 min dramatically improved the recovery of cardiac function, and reduced the release of cardiac creatine kinase and the TNF-a content. The effect of ischemic preconditioning was abolished by CGRP-8-37., the selective CGRP receptor antagonist, and by capsaicin, which depletes sensory nerve neurotransmitter content, but was unaltered by treatment with glibenclamide, a blocker of the ATP-sensitive potassiumKATP.channel. The protective effects of exogenous CGRP-induced preconditioning were also not blocked by glibenclamide. These results suggest that the cardioprotective effects afforded by CGRP-mediated ischemic preconditioning are related to inhibition of cardiac TNF-a production, but not to activation of the KATP channel.