Adrenal Dysfunction in Portal Hypertensive Rats with Acute Hemorrhage

Fa-Yauh Lee,Sun-Sang Wang,Han-Chieh Lin,Shou-Dong Lee,Ming-Hung Tsai,Hui-Chun Huang

doi:10.1371/journal.pone.0092093

Abstract

Nitric oxide (NO) participates in shock and poorer portal hypotensive effect to vasoconstrictors in portal hypertension with hemorrhage, the so-called splanchnic hyposensitivity. Relative adrenal insufficiency accompanies hemorrhagic shock and is found in liver disease, the ‘hepatoadrenal syndrome’, but the relevant interactions remain unsettled. Portal hypertensive rats were induced by partial portal vein ligation (PVL). Experiments were performed on the 14th day post PVL: (I) ACTH stimulation test for rats without or with hemorrhage; (II) Glypressin response (mean arterial pressure, MAP; portal pressure, PP) in rats (a) without hemorrhage or with hemorrhage, injected with (b) distilled water (DW), (c) dexamethasone 3 mg/kg; (III) To survey the dose-dependent effects of glucocorticoid without being confounded by endogenous adrenal hormone, glypressin response was surveyed in PVL rats with adrenalectomy: (a) without hemorrhage or with hemorrhage, injected with (b) DW; (c) dexamethasone 3 mg/kg; (d) dexamethasone 5 mg/kg. Plasma tumor necrosis factor-α (TNF-α) concentrations and abdominal aorta (AA), superior mesenteric artery (SMA) NO synthases (NOS) mRNA expressions were determined. The results showed that ACTH induced corticosterone release similarly in PVL rats with or without hemorrhage. In bleeding PVL rats, dexamethasone (1) down-regulated AA NOS and enhanced glypressin-induced MAP elevation; (2) did not influence glypressin-induced PP reduction; (3) reduced TNF-α. In bleeding PVL and adrenalectomized rats, high-dose dexamethasone (1) down-regulated AA/SMA NOS; (2) enhanced glypressin-induced MAP elevation and PP reduction; (3) reduced TNF-α. In conclusion, bleeding portal hypertensive rats failed to enhance corticosterone release, suggesting a relative adrenal insufficiency. High-dose dexamethasone reversed systemic hypotension and splanchnic hyporesponsiveness to glypressin in adrenalectomized PVL rats accompanied by TNF-α and NOS down-regulation, suggesting the importance of adequate adrenocorticoid supplement in portal hypertension with hemorrhage and adrenal dysfunction.

Highlights

Liver cirrhosis and portal hypertension complicated by ruptured gastroesophageal varices may lead to hemorrhagic shock, resulting in events as (i) reduction of blood pressure; (ii) endogenous vasoconstrictors release in an attempt to maintain blood pressure; (iii) vascular hyporeactivity to vasoconstrictors
portal vein ligation (PVL) rats with adrenalectomy showed lower body weight (BW), mean arterial pressure (MAP), portal pressure (PP), and heart rate (HR) as compared with those without adrenalectomy
Our data demonstrated that bleeding PVL rats, as compared with those without hemorrhage, did not exert an enhanced corticosterone response to ACTH stimulation

Summary

Introduction

Liver cirrhosis and portal hypertension complicated by ruptured gastroesophageal varices may lead to hemorrhagic shock, resulting in events as (i) reduction of blood pressure; (ii) endogenous vasoconstrictors release in an attempt to maintain blood pressure; (iii) vascular hyporeactivity to vasoconstrictors. Recent studies have shown that vasopressin administrated during hemorrhage is less effective than that used in those without hemorrhage in cirrhosis and portal hypertension (the so-called vascular hyposensitivity) [2]. It has been found that NO synthesis blockade in partial portal vein ligation (PVL)induced portal hypertensive rats with hemorrhage alleviated the glypressin hyposensitivity [3]. NO synthase (NOS) exists in either constitutive or inducible isoform. While the constitutive form (eNOS) may be activated by mechanical factors [7], the inducible form (iNOS) can be triggered by endotoxin and cytokines such as tumor necrosis factor-a(TNF-a) [8]

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