Cirrhosis decreases vasoconstrictor response to electrical field stimulation in rat mesenteric artery: role of calcitonin gene-related peptide

Abstract

Our study determines alterations in the vasoconstrictor response elicited by electric field stimulation (EFS) in mesenteric arteries from cirrhotic rats treated with CCl 4 , and how calcitonin gene-related peptide (CGRP) participates in this response. Vasoconstriction induced by EFS was analysed in the absence and presence of the CGRP receptor antagonist CGRP(8-37) in arterial segments from control and cirrhotic rats. The vasodilator response to exogenous CGRP was tested in both groups of rats, and the interference of the guanylate cyclase inhibitor ODQ or the K ATP channel blocker glibenclamide was analysed only in segments from cirrhotic rats. The vasodilator response to the K ATP channel opener pinacidil and to 8-bromo-cyclic GMP was tested. The K ATP currents were recorded using the patch-clamp technique. Expression of receptor activity-modifying protein 1 (RAMP1), calcitonin receptor-like receptor, Kir 6.1 and sulfonylurea receptor 2B (SUR2B) was also analysed. Release of CGRP and cGMP was measured. The EFS-elicited vasoconstriction was less in segments from cirrhotic rats. The presence of CGRP(8-37) increased the EFS-induced response only in segments from cirrhotic rats. The CGRP-induced vasodilatation was greater in segments from cirrhotic rats, and was inhibited by ODQ or glibenclamide. Both pinacidil and 8-bromo-cyclic GMP induced a stronger vasodilator response in segments from cirrhotic rats. Pinacidil induced greater K ATP currents in cirrhotic myocytes. Expression of RAMP1, calcitonin receptor-like receptor, Kir 6.1 and SUR2B was not modified by liver cirrhosis. Liver cirrhosis increased CGRP release, but did not modify cGMP formation. The decreased vasoconstrictor response to EFS in cirrhosis is mediated by increased vasodilator response to CGRP, as well as increased K ATP channel gating. This effect of CGRP may play a role in the splanchnic vasodilatation present in liver cirrhosis.

Effect of short- and long-term portal hypertension on adrenergic, nitrergic and sensory functioning in rat mesenteric artery

“…Additionally, an increased CGRP participation in periarterial nerve stimulation has been suggested [24]. In cirrhotic rats, we have reported a pivotal role by CGRP in the decreased vasoconstrictor response induced by EFS, mediated by an increase in CGRP release and vasodilator response [15]. In summary, few studies have analysed the function of each innervation in PH or their integrated effect on vascular tone, whereas the evolution of their participation in a situation of LT maintenance of PH is also a question of some interest.…”

“…We have previously reported that in this strain sensory innervation does not participate in vasomotor response induced by EFS in control animals, but that the participation of this innervation is increased in several pathological conditions such as hypertension, cirrhosis and diabetes [12,15,40,41]. In the present study, we observed that pre-incubation with the CGRP antagonist CGRP-(8-37) did not modify the vasoconstrictor response to EFS in mesenteric rings from SO rats, confirming CGRP non-participation in vasoconstriction in healthy Wistar rats [10,36,42].…”

“…Splenic pulp pressure, an effective indirect measurement of PP, was measured as described previously [5,15] by inserting a 23-gauge fluid-filled needle into the spleen parenchyma. The needle was joined to a PE-50 tube, and then connected to a pressure recorder (PowerLab 200 ML 201) and a transducer (Sensonor SN-844) with a Chart V4.0 computer program (AD Instruments); the recorder was re-calibrated before each experiment.…”

“…We have reported that different physiopathological situations, such as diabetes [11,12], hypertension [13,14], cirrhosis [15] or aging [16,17], can modify the participation of the different innervations in the vasomotor response to EFS (electrical field stimulation). In PH, and with regard to adrenergic innervation, both an increase and a decrease in vasoconstrictor response to NA have been reported [4,[18][19][20][21], as well as a downregulation of genes related to the adrenergic system and atrophy of mesenteric sympathetic innervation [22,23].…”

Aerobic exercise training increases neuronal nitric oxide release and bioavailability and decreases noradrenaline release in mesenteric artery from spontaneously hypertensive rats

“…The application of electrical field stimulation (EFS) produces a vasoconstrictor response which is the integrated result of the release of different neurotransmitters, mainly noradrenaline from sympathetic nerve endings, nitric oxide from nitrergic innervation and calcitonin gene-related peptide (CGRP) from sensory nerves [4][5][6][7]. Alterations of the functional role of these components in rat mesenteric artery have been associated with several experimental and pathophysiological circumstances including ageing, portal hypertension, liver cirrhosis and diabetes [8][9][10][11].…”