CGRP release induces relaxation of smooth muscle cells due to an increase in cAMP and leads to activation of protein kinase A, which phosphorylates and opens potassium channels [
39,
40]. In blood vessels, CGRP acts as an extremely potent vasodilator when compared to several known vasodilators such as histamine, prostaglandin E2 and substance P [
41]. Even so, CGRP seems to have no pivotal role in the physiological regulation of systemic blood pressure. For instance, blocking CGRP does not affect systemic blood pressure in healthy volunteers [
42]. In the heart, CGRP is localized in sensory nerve fibers and around peripheral arteries [
9]. There are specific binding sites for CGRP linked to stimulation of adenylate cyclase activity more concentrated in the atrium [
43]. In both rats and humans, in addition to its vasodilator effect, intravenous CGRP administration has been shown to cause positive inotropic and chronotropic effects on the heart [
44‐
47]. In physiological conditions, CGRP might act on a more local level, regulating vascular responsiveness and protecting organs from injury. Thus, CGRP may have a cardiovascular protective role. In pathophysiological situations, like hypertension, conflicting observations have been made. Both decreased, increased and unchanged plasma levels of CGRP have been observed in patients with essential hypertension [
48,
49]. While CGRP does not seem to be involved in the physiological regulation of blood pressure, it has a protective role against the development of hypertension. It exerts its action mainly directly on smooth muscle cells in the vessel wall, most prominently in the microvasculature, which is responsible for the majority of the peripheral vascular resistance and thus, the blood pressure [
9,
50].
Moreover, CGRP given intravenously to patients with congestive heart failure improved myocardial contractility without any consistent change in arterial pressure or heart rate [
51]. CGRP causes beneficial effects on physiological cardiac hypertrophy helping the heart to distinguish physiological, exercise-induced from pathological stresses [
52].
In addition, CGRP may play an important role in mediation of ischemic preconditioning, the phenomenon in which a tissue is rendered resistant to the deleterious effects of prolonged ischemia. Capsaicin, which evokes CGRP release from sensory nerves, is reported to protect against myocardial injury by ischemia-reperfusion in the isolated perfused rat heart [
53]. Moreover, pretreatment with CGRP for 5 min produces a significant protective effect on the ischemic myocardium, as shown by the enhanced post-ischemic myocardial function, the reduced incidence of ventricular arrhythmia, and the attenuated release of creatine phosphate kinase [
54]. Some studies have also suggested that the protective role of CGRP against ischemia may be due to induced vasodilation [
55]. In the setting of brain ischemia, it might reduce the extent of the infarct zone [
56], while in the case of subarachnoid hemorrhage, there is evidence that CGRP is protective against cerebral vasospasm [
57‐
59]. CGRP might be protective also in the setting of chronic cerebrovascular disease (as induced by bilateral carotid stenosis) and the subsequent neuronal injury and cognitive impairment [
56].