Mesenteric Arterial Relaxation to Calcitonin Gene-Related Peptide Is Increased During Pregnancy and by Sex Steroid Hormones1

Abstract

The present study investigated whether pregnancy and circulatory ovarian hormones increase the sensitivity of the mesenteric artery to calcitonin gene-related peptide (CGRP)-induced relaxation and possible mechanisms involved in this process. Mesenteric arteries from young adult male rats or female rats (during estrous cycle, after ovariectomy, at Day 20 of gestation, or Postpartum Day 2) were isolated, and the responsiveness of the vessels to CGRP was examined with a small vessel myograph. The CGRP (10(-10) to 10(-7) M) produced a concentration-dependent relaxation of norepinephrine-induced contractions in mesenteric arteries of all groups. Arterial relaxation sensitivity to CGRP was significantly (P < 0.05) greater in female rats compared with male rats. Pregnancy increased the sensitivity to CGRP significantly (P < 0.05) compared to ovariectomized and Postpartum Day 2 rats. In pregnant rats, CGRP-receptor antagonist, CGRP(8-37), inhibited the relaxation responses produced by CGRP. The CGRP-induced relaxation was not affected by N(G)-nitro-l-arginine methyl ester (nitric oxide inhibitor, 10(-4) M) but was significantly (P < 0.05) attenuated by an inhibitor of guanylate cyclase (1H-[1 , 2 , 4 ]oxadizaolo[4 , 3 -a]quinoxalin-1-one, 10(-5) M). Relaxation responses of CGRP on mesenteric arteries were blocked (P < 0.05) by a cAMP-dependent protein kinase A inhibitor, Rp-cAMPs (10(-5) M). The CGRP-induced vasorelaxation was significantly (P < 0.05) attenuated by calcium-dependent (tetraethylammonium, 10(-3) M), but not ATP-sensitive (glybenclamide, 10(-5) M), potassium channel blocker. Therefore, the results of the present study suggest that mesenteric vascular sensitivity to CGRP is higher during pregnancy and that cAMP, cGMP, and calcium-dependent potassium channels appear to be involved. Therefore, we propose that CGRP-mediated vasodilation may be important to maintain vascular adaptations during pregnancy.

Hypertension alters the function of nitrergic and sensory innervation in mesenteric arteries from female rats

“…The presence of this antagonist did not modify the vasoconstrictor response to EFS in female WKY rats, as has also been observed in male rats [5], and this indicates that sensory innervation is not involved in this response in normotension. These results do not concur with previous studies indicating an increased sensory function in females [30,31]. The differences between our data and these studies may be because we used endothelium-denuded arteries, and the vasodilator effect of CGRP is mediated by endothelial NO [32,33] the production of which is greater in females than males [34].…”

Effects of Female Sex Hormones on Responses to CGRP, Acetylcholine, and 5‐HT in Rat Isolated Arteries

“…of CGRP is augmented. 36 It is important to highlight that the CGRP-induced relaxations are endothelium independent in the rat mesenteric 31 and caudal 32 arteries, similar to the observations in the human cerebral, 37 meningeal, 37 and coronary 38 arteries. Interestingly, unlike the mesenteric and caudal arteries, the basilar artery did not exhibit any increase in the responses to CGRP, although the potency of CGRP is in line with the previous reports in the rat basilar artery.…”

Mechanisms Leading to Increased Vasodilator Responses to Calcitonin-Gene-Related Peptide in Mesenteric Resistance Arteries of Early Pregnant Rats

“…The other mechanisms by which CGRP modulates vascular tone involve the activation of K + channels and the stimulation of adenylate cyclase resulting in an increase in cyclic AMP in arterial smooth muscle cells [20]. Both mechanisms play a role in the vasodilating response to CGRP in late pregnancy [23]. A third mechanism, the accumulation of cGMP, was also demonstrated in pregnancy [23].…”

“…Both mechanisms play a role in the vasodilating response to CGRP in late pregnancy [23]. A third mechanism, the accumulation of cGMP, was also demonstrated in pregnancy [23]. However, there is convincing evidence that the latter is an endothelium-dependent effect mediated by increased synthesis of NO [24] and therefore seems not to be responsible for the changes in pregnancy.…”