Pathway‐specific effects of calcitonin gene‐related peptide on irideal arterioles of the rat

Abstract

), vasodilatory effects of CGRP are mediated via the endothelium and are due to the production of nitric oxide. In the majority of vessels studied to date, however, CGRP causes vasodilatation through an endothelium-independent process, not involving nitric oxide. These vessels include the rat mesenteric, gastric, splenic and renal arteries Li & Duckles, 1992;Amerini, Mantelli & Ledda, 1993;Holzer, Lippe, Jocic, Wachter, Erb & Heinemann, 1993;Gao, Nishimura, Suzuki & Yoshida, 1994), rabbit jejunal (La & Rand, 1993), rat and rabbit hepatic artery Brizzolara & Burnstock, 1991), skin and skeletal muscle microcirculations (Persson, Hedqvist & Gustafsson, 1991;Ralevic, Khalil, Dusting & Helme, 1992;Brain, Hughes, Cambridge & O'Driscoll, 1993) dog basilar (Oyama et al. 1993), cat cerebral (Saito, Masaki, Uchiyama, Lee & Goto, 1989), dog lingual (Kobayashi, Todoki, Ozono & Okabe, 1995) and human uterine arteries (Bodelsson & Stjernquist, 1992 1. Arteriolar diameter and membrane voltage have been measured to investigate the actions of calcitonin gene-related peptide (CGRP) in rat irideal arterioles. 2. Activation of sensory nerves inhibited sympathetic vasoconstriction, reduced the accompanying 40-50 mV depolarization by 90 % and caused a 4 mV hyperpolarization. 3. The inhibition of vasoconstriction was prevented by either preincubation in ¬_NAME (10 ìÒ), to inhibit nitric oxide production, by preincubation in the cell-permeant adenylate cyclase inhibitor dideoxyadenosine (1 mÒ) or by preincubation in the ATP-sensitive potassium channel blocker glibenclamide (10 ìÒ). The subsequent addition of a nitric oxide donor to the glibenclamide solution inhibited nerve-mediated vasoconstriction, suggesting that the potassium channel involvement preceded the production of nitric oxide. The small hyperpolarization was not affected by ¬_NAME. 4. Nerve-mediated vasodilatation persisted in the presence of ¬_NAME (10 ìÒ) but was abolished with the CGRPÔ receptor antagonist CGRP8-37. 5. In arterioles preconstricted with the áµ-adrenoceptor agonist UK-14304 (100 nÒ), exogenous CGRP caused a hyperpolarization and a dose-dependent vasodilatation, neither of which was affected by ¬_NAME (10 ìÒ). 6. In arterioles preconstricted with 30 mÒ KCl, CGRP (10 nÒ) caused vasodilatation but not hyperpolarization, suggesting that the hyperpolarization was not causal to the vasodilatation. 7. Forskolin (30 nÒ), in the presence of ¬_NAME to prevent effects due to nitric oxide, caused vasodilatation. 8. These results suggest that CGRP inhibits sympathetic nerve-mediated vasoconstriction through sequential increases in cyclic AMP and nitric oxide, while vasodilatation results from increases in cyclic AMP alone. The production of nitric oxide, but not its mechanism of action, appears to be dependent on the activation of ATP-sensitive potassium channels. The possible sites of action of these two pathways are discussed.

Calcitonin gene-related peptide activates different signaling pathways in mesenteric lymphatics of guinea pigs

“…It has been shown to be causal in the dilation observed in mesenteric arteries of the rabbit, the lingual artery of the dog, and the basilar artery of the rat (32,33,38). In contrast to this, it has been shown to be of little if any consequence in the ophthalmic artery of the rabbit (62), the small mesenteric and renal arteries of the rat (20), and in rat irideal arterioles (26). In some vessels, CGRP released from sensory nerves has been shown to inhibit sympathetic nerve-induced vasoconstriction (5,26).…”

“…Thus, whereas ACh is known to induce synthesis of NO by increasing endothelial synthesis of inositol 1,4,5-trisphosphate and intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) (8, 9), CGRP has been reported to enhance endothelial production of PKA and/or PKB, causing increased synthesis of NO independent of increases in [Ca 2ϩ ] i (15,19,23,24,61). Further to this, studies on the downstream actions of CGRP-induced NO indicate enhancement of both cGMP and cAMP in the smooth muscle of some blood vessels (17,23,61).CGRP has been shown to produce hyperpolarization in cat cerebral arteries, rabbit mesenteric and ophthalmic arteries, and in iris arterioles (26,38,48,62). This hyperpolarization is due to the activation of K ATP ϩ channels (26, 62) and is considered to be a consequence of receptor-activated increases in cAMP and PKA activation (37, 41).…”

“…This hyperpolarization is due to the activation of K ATP ϩ channels (26,62) and is considered to be a consequence of receptor-activated increases in cAMP and PKA activation (37,41). However, the role of this hyperpolarization in the vasodilatory effect of CGRP varies between vascular beds.…”

“…CGRP has been shown to produce hyperpolarization in cat cerebral arteries, rabbit mesenteric and ophthalmic arteries, and in iris arterioles (26,38,48,62). This hyperpolarization is due to the activation of K ATP ϩ channels (26, 62) and is considered to be a consequence of receptor-activated increases in cAMP and PKA activation (37, 41).…”

“…In contrast to this, it has been shown to be of little if any consequence in the ophthalmic artery of the rabbit (62), the small mesenteric and renal arteries of the rat (20), and in rat irideal arterioles (26). In some vessels, CGRP released from sensory nerves has been shown to inhibit sympathetic nerve-induced vasoconstriction (5,26).…”