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The mesenteric and systemic vasodilatation that occurs in advanced liver disease leads to the development of a hyperdynamic circulatory state1 which in turn underlies many of the complications of cirrhosis.2 Studies of isolated vessel preparations from cirrhotic animal models have led to the concept that vasodilatation is linked to an intrinsic vascular hyporesponsiveness to endogenous vasoconstrictors such as noradrenaline,3 but whether the same holds true of human blood vessels in cirrhosis has not been established.
In order to study the responses of isolated human splanchnic vessels, we obtained 21 omental arteries from 10 patients undergoing orthotopic liver transplantation for advanced cirrhosis. Fifteen control arteries were obtained from six patients at the time of hepatobiliary surgery or intestinal resection. Informed consent was obtained and the study was approved by the institutional ethics committee.
A hyperdynamic circulation was confirmed by invasive measurement of haemodynamic parameters prior to surgery. Microvessels were carefully dissected free from a sample of omentum and mounted on a Mulvany-Halpern myograph in order to study isometric vascular responses. Responses were measured to potassium, noradrenaline, and the α1 adrenoceptor agonist methoxamine. Endothelium dependent vasodilatation was assessed by acetylcholine and substance P, given before and after inhibition of nitric oxide and prostanoid synthesis. Contraction responses were expressed as a percentage of the force generated by maximal potassium depolarisation. Relaxation responses were expressed as a percentage of precontraction with 30 mM KCl. Dose-response curves were fitted to a logistic equation and mean sensitivity (EC50) and maximal responses (Emax) compared between cirrhosis and control vessels by the Student’s t test. A p value <0.05 was considered significant.
Vascular responses are shown in table 1. Cirrhotic vessels demonstrated normal responses to potassium depolarisation. The sensitivity of contraction responses to noradrenaline and methoxamine was not affected by the presence of cirrhosis and in fact a greater maximal contraction to noradrenaline was observed in cirrhotic vessels compared with controls. The presence of a functional endothelium was confirmed by demonstrating vasodilatation to the endothelium dependent vasodilator substance P. Responses following inhibition of nitric oxide and prostanoid synthesis show that vasodilatation was mediated by the action of nitric oxide and vasodilator prostanoids but the contribution of the latter was greater in cirrhotic vessels.
This study is the first of its kind to directly address the question of whether intrinsic hyporeactivity to endogenous vasopressors is present in small resistance arteries from patients with cirrhosis. Previously, only large conduit branches of the hepatic artery without an intact endothelium have been studied in the organ bath. These have produced evidence for both a reduced4 or normal5 response to adrenergic agonists. Noradrenaline produces vasoconstriction via its action on α adrenoceptors. However, in high concentrations, it can mediate a vasodilator response via β adrenoceptors. It is therefore possible that the enhanced noradrenaline response observed in the present study may relate to reduced β adrenoceptor activation in cirrhosis. This concept is supported by the findings that β2 adrenoceptor density is reduced in blood lymphocytes from patients with cirrhosis,6 and that there is reduced β2 adrenoceptor mediated relaxation in human cirrhotic hepatic artery segments.4
In summary, intrinsic arterial hyporesponsiveness to vasopressors cannot be detected in isolated cirrhotic mesenteric vessels. Hyporesponsiveness of these vessels in vivo may be related to other factors, such as neurohumoral activation, or the effects of circulating vasodilators and vasoactive peptides.
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