Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction

Abstract

Background Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved. Methods All experiments were performed in CCl 4 -induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to a 1 -adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries. Results NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries. Conclusions NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.

International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

“…We did not find any SNPs reaching genome-wide significance with DBP or with either SBP-or DBP-measured postpuberty, but when we reduced our statistical significance threshold to P≤5×10 −3 , there were several additional variants in gene clusters relating to SBP or DBP across the 3 epochs. At this more liberal P value threshold, we found some evidence of overlap in novel SNPs across childhood/adolescent age epochs within our study and some overlap with those that have been found by previous GWAS to be associated with adult BP.ITGA11 was genome-wide associated with SBP during the prepubertal epoch and has been shown to be associated with hypertrophic cardiomyopathy 43 and coronary artery disease. 44 An SNP in close proximity to the SMARCA and VLDLR genes (rs872256) was genome-wide associated with SBP during the pubertal epoch.…”

Dysbalance in sympathetic neurotransmitter release and action in cirrhotic rats: Impact of exogenous neuropeptide Y

“…This substantiates the clinical significance of the observed lack of splanchnic NPY release. Furthermore, NPY deficiency could explain our previous findings, namely why the following effects of external NPY were more markedly pronounced in portal hypertension: NPY (i) inhibited eNOS-and nNOS-mediated NO production and its vasodilating effect [16,38], (ii) enhanced vasoconstrictive Rho-A kinase expression and activity [38], and (iii) reduced portal pressure and portal blood flow [38]. Here exogenous NPY not only corrected mesenteric PNS-induced pressure response in portal hypertension, but markedly slowed the desensitization process, restoring vascular sensitivity to PNS-induced endogenous NA.…”

“…NPY-induced potentiation of a 1 -adrenergic vasoconstriction via postsynaptic Y 1 receptors is well known [13,14,38]. Besides, prejunctional NPY effects have been studied in healthy rats.…”

Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms

“…For example, decreased orexigenic response to NPY has been shown in cholestatic rats (29). Amelioration of portal hypertension and the hyperdynamic circulatory syndrome has been observed in cirrhotic rats by NPY via pronounced splanchnic vasoaction (25).…”