1 Calcitonin gene-related peptide (CGRP) potently enhances mucosal blood flow in the rat stomach. The aim of this study was to examine whether CGRP also dilates extramural arteries supplying the stomach and whether the vasodilator action of CGRP involves nitric oxide (NO). 2 Rat CGRP-x (0.03-1 nmol kg-', i.v.) produced a dose-dependent increase in blood flow through the left gastric artery (LGA) as determined by an ultrasonic transit time technique in urethane-anaesthetized rats. Blockade of NO synthesis by NG-nitro-L-arginine methyl ester (L-NAME, 20 and 60 ymol kg-', i.v.) significantly reduced basal blood flow (BF) in the LGA and attenuated the hyperaemic activity of CGRP by a factor of 2.8-4. D-NAME tended to enhance basal BF in the LGA but had no influence on the dilator activity of CGRP. The ability of vasoactive intestinal polypeptide to increase left gastric arterial blood flow remained unaltered by L-NAME. 3 L-NAME (20 and 60 ymol kg-', i.v.) evoked a prompt and sustained rise of mean arterial blood pressure (MAP) and caused a slight decrease in the hypotensive activity of CGRP. In contrast, D-NAME induced a delayed and moderate increase in MAP and did not influence the hypotensive activity of CGRP. 4 Rat CGRP-o dilated the isolated perfused bed of the rat LGA precontracted with methoxamine and was 3 times more potent in this respect than rat CGRP-P. The dilator action of rat CGRP-x in this preparation was not affected by L-NAME or D-NAME (40 pM).5 L-NAME (601tmol kg-', i.v.) reduced gastric mucosal blood flow as assessed by laser Doppler flowmetry and diminished the hyperaemic activity of rat CGRP-a in the gastric mucosa by a factor of 4.5, whereas D-NAME was without effect. 6 These data show that CGRP is a potent dilator of mucosal and extramural resistance vessels in the rat stomach. Its dilator action involves both NO-dependent and NO-independent mechanisms.

1. Acid back-diffusion through a disrupted gastric mucosal barrier is known to increase gastric mucosal blood flow via a neural mechanism. The present study examined how the acid-evoked change in the gastric microcirculation compares with blood flow changes in the left gastric artery, one of the major arteries supplying the stomach, and whether the dilator mediators in the left gastric artery are identical to those in the gastric mucosa.2. The experiments were performed on rats anaesthetized with urethane. Blood flow in the left gastric artery was measured by the ultrasonic transit time shift technique, and blood flow in the gastric mucosa was assessed by the hydrogen gas clearance method. 3. Gastric acid back-diffusion evoked by perfusion of the stomach with 15% ethanol in 0-15 M HCI increased blood flow in the left gastric artery by a factor of 4 7, which was significantly larger than the 2-9-fold increase in blood flow through the gastric mucosa. Blood pressure and heart rate were not altered appreciably. 4. The acid-evoked hyperaemia in the left gastric artery was left unaltered by atropine and the substance P receptor antagonist RP-67 580. 5. The calcitonin gene-related peptide (CGRP) antagonist CGRP(8-37) had no effect on gastric blood flow but prevented the dilator action of CGRP and inhibited the acidevoked hyperaemia in the gastric mucosa to a larger degree than the hyperaemia in the left gastric artery. 6. Blockade of nitric oxide synthesis by NV-nitro-L-arginine methyl ester (L-NAME) caused constriction of the left gastric artery and the gastric mucosal microvessels. The acid-evoked vasodilatation in the gastric mucosa was blocked by L-NAME, whereas the dilator response in the left gastric artery was not significantly depressed. 7. The data show that the gastric hyperaemic response to acid back-diffusion results from dilatation of mucosal microvessels and extramural arteries. The dilator mechanisms, however, differ between the two vascular beds. CGRP and nitric oxide are important vasodilator mediators in the gastric mucosa but are of less relevance in the left gastric artery.

1 Increased production of nitric oxide (NO) has been suggested to underlie both the vascular hyporeactivity to vasoconstrictors and the splanchnic vasodilatation seen in portal hypertension. This study assessed the role of NO in the vasoconstrictor hyporeactivity of portal vein-ligated (PVL) rats in isolated and in situ perfused mesenteric arterial beds. 2 Isolated perfused mesenteric arteries of PVL rats were signi®cantly less reactive to noradrenaline (NA), methoxamine (METH), arginine vasopressin (AVP) and endothelin-1 (ET-1) than those from sham-operated (Sham) rats. 3 Blockade of NO synthesis with N G -nitro-L-arginine methyl ester (L-NAME, 100 mM) in isolated perfused mesenteric arteries from PVL rats restored the reactivity to bolus injections of AVP and ET-1, but had little e ect on the hyporeactivity to NA or METH. Cyclo-oxygenase inhibition with indomethacin (5 mM) likewise did not restore reactivity to METH of isolated perfused mesenteric arteries of PVL rats. 4 The hyporeactivity to METH seen in isolated perfused mesenteric arteries from PVL rats was reduced by low concentrations of AVP (20 nM) or ET-1 (1 nM) which per se caused only a slight increase in perfusion pressure. When L-NAME (100 mM) was combined with AVP (20 nM) or ET-1 (1 nM), respectively, reactivity to METH of isolated perfused mesenteric arteries of PVL rats was restored to the level seen in Sham rats. These e ects of AVP and ET-1 were not mimicked by precontracting the vessels with 5-hydroxytryptamine (5 mM). 5 The di erential e ects of L-NAME and AVP on the hyporesponsiveness to methoxamine and AVP were corroborated by experiments performed with the in situ perfused mesenteric vascular bed preparation. 6 These data indicate that both NO-dependent and NO-independent mechanisms are involved in the vasoconstrictor hyporesponsiveness of mesenteric arteries from portal hypertensive rats. The hyporeactivity to AVP and ET-1 is mediated by NO whereas the reduced responsiveness to adrenoceptor agonists appears to be predominantly NO-independent. AVP and ET-1, in addition, seem to inhibit the NO-independent mechanism of vascular hyporeactivity, since the hyporesponsiveness to METH was reduced in the presence of AVP or ET-1 and abolished by the combination of these peptides with L-NAME.

We recently reported that vasopressin analogues correct the in vitro vascular hyporeactivity to adrenergic vasoconstrictors in portal hypertensive rats. The aim of the present study was to determine whether vasopressin reduces splanchnic blood flow in portal vein-ligated (PVL) rats by restoring vasoconstrictor responsiveness in vivo. The ultrasonic transit time-shift technique was used for blood flow measurements. At basal conditions, blood flow through the superior mesenteric artery was elevated 1.6-fold in PVL rats as compared with sham-operated (SHAM) control rats. PVL rats also exhibited blunted mesenteric constrictor responses to the adrenoceptor agonist, phenylephrine (0.03-1 mol · min ؊1 · kg ؊1 ). Terlipressin (2-20 g · kg ؊1 ) and arginine vasopressin (3-300 pmol · min ؊1 · kg ؊1 ) dosedependently reduced, and at the highest doses, even abolished, the difference in mesenteric blood flow (MBF) between PVL and SHAM rats. When expressed as percent changes relative to baseline, mesenteric arterial responses to terlipressin and arginine vasopressin were found to be enhanced in PVL rats as compared with SHAM rats. Moreover, pretreatment with terlipressin (20 g · kg ؊1 ) reversed the mesenteric hyporesponsiveness to phenylephrine of PVL rats. These vasopressin effects were independent of the nitric oxide (NO) pathway, because they were not mimicked by inhibition of NO synthesis with N G -nitro-Larginine methyl ester (L-NAME) (0.1-10 mg · kg ؊1 ). These data indicate that pharmacological doses of vasopressin reverse the splanchnic hyperemia by restoring the responsiveness to adrenergic vasoconstrictors in portal hypertensive rats. (HEPATOLOGY 1998;28:646-654.)Portal hypertension is associated with hyperdynamic circulation, which is characterized by decreased peripheral resistance and increased cardiac output. Although vasodilation is present in most vascular beds, it is especially important in the splanchnic circulation. Blood flow to the abdominal organs in portal hypertension is about twice as high as under normal conditions, 1,2 a fact that has been shown to be responsible for the maintenance of chronically elevated portal pressure. 2,3 Several possible explanations for the splanchnic vasodilation have been raised, including circulating vasodilators, decreased reactivity of the splanchnic arteries to endogenous vasoconstrictors, and/or local overproduction of vasodilator mediators such as nitric oxide (NO), of which evidence for its involvement has increasingly accumulated. 4,5 Vasopressin analogues are currently used in the treatment of acute variceal bleeding in cirrhotic patients, because they effectively reduce splanchnic blood flow, and thus portal pressure as well. [6][7][8] In addition, ornipressin has been shown to normalize systemic and renal hemodynamics and renal function in decompensated cirrhosis. 9 We recently provided data that vasopressin analogues reverse the vascular hyporeactivity to adrenoceptor stimulation in isolated perfused mesenteric arterial beds of portal hypertensive rats. 10,11 T...

1. Acid back-diffusion through a disrupted gastric mucosal barrier increases blood flow to the stomach without any change in systemic blood pressure. This study was undertaken to examine the gastric acid-evoked changes in blood flow in a number of visceral and somatic arterial beds and to elucidate the mechanisms which lead to the regionally diverse haemodynamic responses. 2. The gastric mucosa of urethane-anaesthetized rats was challenged with acid by perfusing the stomach with ethanol (15%, to disrupt the gastric mucosal barrier) in 0 15 M HCl. Blood flow was estimated by laser Doppler flowmetry, the hydrogen clearance method or the ultrasonic transit time shift technique. 3. Gastric acid challenge increased blood flow in the gastric mucosa and left gastric artery while blood flow in the femoral artery and skin declined. antagonist) and acute ligation of the blood vessels to the adrenal glands. 7. These data show that acid challenge of the gastric mucosa elicits visceral vasodilatation and somatic vasoconstriction via divergent mechanisms. The gastric hyperaemia is brought about by extrinsic vasodilator nerves, whereas the reduction of somatic blood flow seems to be mediated by non-neural, probably humoral, vasoconstrictor messengers that remain to be identified.