Adrenal dysfunction in portal hypertensive rats with acute hemorrhage

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.

Figure 1. Experimental design.

G: glypressin; DW: distilled water (vehicle); Dexa: dexamethasone (3 or 5 mg/kg).

Figure 2. ACTH-induced corticosterone changes in PVL rats without- (H(-), n = 21) or with-hemorrhage (H(+), n = 19).

There was no significant difference (P>0.05).

Figure 3. Glypressin-induced hemodynamic changes in PVL rats.

(A) Chronological changes of MAP in PVL rats without-(PHN, n = 8) or with-hemorrhage treated with vehicle (PHV, n = 6) or dexamethasone 3 mg/kg (PHD, n = 7). MAP1: baseline; MAP2: 45 minutes after hemorrhage-transfusion; MAP3: 10 minutes after glypressin. PHN group had significantly higher MAP2 (P<0.05 vs. PHV or PHD) and PHV group had lower MAP3 (P<0.05 vs. PHN or PHD). (B) PHD group had higher glypressin-induced MAP change (MAP3-MAP2) (P<0.05 vs. PHN or PHV). (C) Chronological changes of PP. PHN group had higher PP2 (P<0.05 vs. PHV or PHD) and lower PP3 (P<0.05 vs. PHD). (D) PHN group had a more prominent PP reduction (PP3-PP2, P<0.05 vs. PHV or PHD).

Figure 4. TNF-α concentrations in (A) PVL (PHN, PHV, PHD) and (B) adrenalectomized PVL (PAHV, PAHV, PAHD3, PAHD5) groups.

(A): TNF-α level was significantly higher in PHV group (P<0.05 vs. PHN) and was reduced by dexamethasone (P<0.05 PHV vs. PHD). (B): PAHV group had significantly higher TNF-α level (P<0.05 vs. all groups).

Figure 5. The vascular NOS mRNA expressions in PVL rats.

AA: abdominal aorta; SMA: superior mesenteric artery; iNOS: inducible nitric oxide synthase; eNOS: endothelial NOS. PHV group had higher AA and SMA iNOS, eNOS expressions (P<0.05 vs. PHN), which were down-regulated by dexamethasone in AA (P<0.05 vs. PHD), but not in SMA.

Figure 6. Glypressin-induced hemodynamic changes in adrenalectomized PVL rats.

(A) Chronological MAP changes in adrenalectomized PVL rats without-(PAHN, n = 7) or with-hemorrhage treated with vehicle (PAHV, n = 9), dexamethasone 3 (PAHD3, n = 7), or 5 mg/kg (PAHD5, n = 11). PAHD5 group had higher MAP2 than PAHD3 group and higher MAP3 than all groups (P<0.05); (B) PAHD5 group had higher MAP change (P<0.05 vs. all groups). (C) Chronological changes of PP. PAHN group had higher PP2 (P<0.05 vs. PAHD3 or PAHD5) and PAHD5 group had lower PP3 (P<0.05 vs. PAHV); (D) PAHN group had more prominent PP reduction (P<0.05 vs. PAHV or PAHD3).

Figure 7. The vascular NOS mRNA expressions in adrenalectomized PVL rats.

PAHV group had higher AA iNOS, eNOS expressions (P<0.001 vs. PAHN), in which iNOS was down-regulated by dexamethasone, especially 5 mg/kg (P<0.05, PAHD5 vs. PAHD3). PAHV group had higher SMA iNOS expression (P<0.001 vs. PAHN), which was down-regulated by dexamethasone, especially 5 mg/kg. PAHV group had higher SMA eNOS expression (P<0.05 vs. PAHN), which was down-regulated by dexamethasone (P<0.05 vs. PAHD3 or PAHD5).