Evidence for Involvement of Calcitonin Gene-Related Peptide in Nitroglycerin Response and Association With Mitochondrial Aldehyde Dehydrogenase-2 (ALDH2) Glu504Lys Polymorphism

Abstract

We found that CGRP is associated with the cardiovascular effect of GTN through an ALDH2-dependent pathway in humans.

Nitroglycerin Hits the Nerve

“…In conclusion, the findings of Guo et al (18) further strengthen the functionally relevant role of ALDH-2 in GTN bioactivation in humans. Their findings also indicate that the neuropeptide CGRP partially mediates GTN- Scheme Depicting the Mechanisms Underlying the Release of CGRP When given acutely, nitroglycerin (GTN) is bioactivated by the mitochondrial aldehyde dehydrogenase (ALDH-2), which acts as a nitrate reductase to convert the organic nitrate in a dinitrate and NO or a related compound (NO x ).…”

“…Furthermore, the platelet inhibitory effects of CGRP in response to GTN were inhibited by N Gmonomethyl-L-arginine, a NO synthase inhibitor, and by the deletion of the endothelial NO synthase gene, suggesting that GTN antiplatelet activity of CGRP is mediated primarily through the activation of eNOS (10). In this issue of the Journal, Guo et al (18) report for the first time that CGRP partially mediates nitroglycerin effects in humans through an ALDH-2-dependent mechanism. The investigators show that acute GTN challenges cause systolic blood pressure decreases and increases in heart rate that correlate well with increased CGRP levels in plasma.…”

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

“…1) Because peripheral blood mononuclear cells (PBMCs) contain large amounts of ALDH-2 protein that is highly active, endothelial progenitor cells as a subfraction of PBMCs can be analyzed by fluorescence-activated cell sorting using the expression of ALDH-2 as a marker (Povsic et al, 2007). 2) ALDH-2 activity in human PBMCs was used to characterize the role of calcitonin gene-related peptide in nitroglycerin-mediated cardiovascular effects (Guo et al, 2008). Beyond the role of ALDH-2 for organic nitrate bioactivation, a very recent publication in Science provided strong evidence that ALDH-2 activation (e.g., by ethanol and protein kinase Cε stimulation) is associated with a reduction of ischemic damage to the heart; vice versa, inhibition of ALDH-2 (e.g., by cyanamide or nitroglycerin) increases infarct size in an experimental model of myocardial infarction .…”

TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice

“…However, after a remarkable time lag (hours) from GTN exposure, migraineurs develop severe headaches that fulfil the criteria of a typical migraine attack ( Sicuteri et al , 1987 ; Iversen et al , 1989 ; Thomsen et al , 1994 ; Olesen, 2008 ). This ability of GTN to provoke migraine is temporally dissociated from the immediate and short-lived (<10 min) release of nitric oxide (NO) ( Persson et al , 1994 ) and the consequent cGMP-dependent vascular responses ( Guo et al , 2008 ). Thus, while vasodilatation by GTN/NO might account for the early dull headache experienced by most subjects ( Iversen and Olesen, 1996 ), it cannot explain the delayed headache symptoms observed in migraineurs ( Olesen, 2008 ).…”