Vascular hyporeactivity persists despite increased contractility after long-term administration of isosorbide dinitrate in portal hypertensive rats

Abstract

Background/Aims: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamics. Isosorbide dinitrate is an effective portal hypotensive drug. The present study aimed to investigate whether chronic administration of isosorbide dinitrate could affect vascular responsiveness in portal hypertensive rats. Methods: Portal hypertension was induced by partial portal vein ligation. Sham-operated (Sham) rats served as controls. There were four animal groups for this study: portal vein ligation-isosorbide dinitrate groups, portal vein ligation-vehicle (Veh) group, Sham-isosorbide dinitrate group and Sham-Veh group. Isosorbide dinitrate (5 mg · kg −1 · 12 h −1 was given by gavage for 8 days starting 1 day before ligation and continuing thereafter. Mesenteric arteries were removed for contractile study after hemodynamic measurement. Results: Contractile responses to KCl (15–90 mM) and phenylephrine (10 −9−10 −4 M) were recorded. Both vascular reactivity and sensitivity were significantly reduced in portal vein ligation rats as compared to Sham rats. Chronic isosorbide dinitrate treatment reduced portal venous pressure in portal vein ligation rats. Moreover, the maximal contractile responses to KCl and phenylephrine were significantly enhanced in both portal vein ligation and Sham rats after isosorbide dinitrate treatment, but relative hyporeactivity persisted in portal vein ligation rats. In contrast, a single dose of isosorbide dinitrate did not alter the contractile sensitivity or reactivity to KCl or phenylephrine in either portal vein ligation or Sham rats. Conclusion: Our results show that long-term administration of isosorbide dinitrate enhanced vascular contractility in both portal vein ligation and Sham rats, but relative hyporeactivity persisted in portal vein ligation rats.