Vasopressin reverses mesenteric hyperemia and vasoconstrictor hyporesponsiveness in anesthetized portal hypertensive rats

Abstract

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...

Restriction of Drinking Water Abrogates Splanchnic Vasodilation and Portal Hypertension in Portal Vein-Ligated Rats

“…This was unexpected, since portal hypertensive mesenteric arteries have been shown to be hyporeactive to vasoconstrictors both in vitro and in vivo [11,18,24] . Similar to water restriction, the mesenteric circulation of PVL rats was more sensitive to arginine-vasopressin-induced vasoconstriction than that of SHAM rats.…”

“…Therefore, our data might be taken as indirect evidence in support of the 'overfill' theory, which proposes that the hyperdynamic circulation and increased splanchnic inflow results from volume retention, with splanchnic vasodilation being a secondary event. However, splanchnic vasodilation in portal hypertension does not appear to be simply a neurogenic/ humoral reflex, since hyporeactivity to vasoconstrictors persists also in isolated vessels [11,18,19] . For this vasoconstrictor hyporesponsiveness of the vasculature in portal hypertension, local overproduction of vasodilators has been made responsible, including nitric oxide, prostaglandins, endocannabinoids, carbon monoxide or adrenomedullin [3] .…”

“…We have previously shown that vasopressin analogues correct the in vitro hyporeactivity of isolated mesenteric arterial beds of portal hypertensive rats [9,10] and terlipressin reverses the in vivo hyporesponsiveness of the mesenteric circulation to the ␣ -adrenoceptor agonist phenylephrine observed in portal hypertension [11] . Interestingly, the hyporeactivity of portal hypertensive vessels has been reported to depend on the presence of functional endothelium [26][27][28] .…”

“…Mesenteric arterial blood flow (MBF), mean arterial blood pressure (MAP) and portal pressure were recorded as previously described [11] . Rats were anesthetized by phenobarbital (200 mg/ kg body weight), placed on a heated table to maintain rectal temperature at 37 ° C and fitted with a tracheal cannula to facilitate spontaneous respiration.…”

“…Blood flow was determined by the ultrasonic transit-time shift technique with the use of a small animal flowmeter (model T206; Transonic, Ithaca, N.Y., USA) [11,15,16] . For measuring portal pressure, an ileocolic vein was cannulated with PE-50 tubing, which was advanced into the portal vein and was connected to a highly sensitive pressure transducer (Isotec).…”