Abstract
α-Calcitonin gene-related peptide (α-CGRP) is a regulatory neuropeptide of 37 amino acids. It is widely distributed in the central and peripheral nervous system, predominantly in cell bodies of the dorsal root ganglion (DRG). It is the most potent vasodilator known to date and has inotropic and chronotropic effects. Using pharmacological and genetic approaches, our laboratory and other research groups established the protective role of α-CGRP in various cardiovascular diseases such as heart failure, experimental hypertension, myocardial infarction, and myocardial ischemia/reperfusion injury (I/R injury). α-CGRP acts as a depressor to attenuate the rise in blood pressure in three different models of experimental hypertension: (1) DOC-salt, (2) subtotal nephrectomy-salt, and (3) L-NAME-induced hypertension during pregnancy. Subcutaneous administration of α-CGRP lowers the blood pressure in hypertensive and normotensive humans and rodents. Recent studies also demonstrated that an α-CGRP analog, acylated α-CGRP, with extended half-life (~7 h) reduces blood pressure in Ang-II-induced hypertensive mouse, and protects against abdominal aortic constriction (AAC)-induced heart failure. Together, these studies suggest that α-CGRP, native or a modified form, may be a potential therapeutic agent to treat patients suffering from cardiac diseases.
Highlights
Reviewed by: Claudia Penna, University of Turin, Italy Luciana Venturini Rossoni, University of São Paulo, Brazil
Α-Calcitonin gene-related peptide (α-calcitonin gene-related peptide (CGRP)) is a regulatory neuropeptide that belongs to the calcitonin/CGRP peptide family that includes adrenomedullin (ADM), amylin, and calcitonin (Breimer et al, 1988). α-Calcitonin gene-related peptide (α-CGRP) is generated from the tissue-specific alternative splicing of the primary transcript of the calcitonin gene CALC-I (Amara et al, 1982; Rosenfeld et al, 1983)
In comparison, decreased levels of immunoreactive CGRP were observed in laminae I and II of the spinal cord, and CGRP mRNA was observed in the dorsal root ganglion (DRG) in the spontaneously hypertensive rats (SHRs) (Supowit et al, 1993). These results suggest that the lower level of α-CGRP expression in the SHR might contribute to the high blood pressure observed by the relative reduction of vasodilator activity, whereas higher α-CGRP levels in the DOC-salt hypertension animal attenuate the elevated blood pressure by the compensatory vasodilator activity
Summary
Reviewed by: Claudia Penna, University of Turin, Italy Luciana Venturini Rossoni, University of São Paulo, Brazil. Several lines of evidence suggest that binding of α-CGRP to its receptor CLR activates a variety of signaling pathways (Figure 5). In most instances, binding of α-CGRP to the CLR/ RAMP1 receptor activates adenylate cyclase through the G-protein Gαs that in turn elevates intracellular cAMP level.
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