Hyperdynamic Circulation of Cirrhotic Rats: Role of Substance P and Its Relationship to Nitric Oxide

Abstract

Background: It has been suggested that excessive formation of nitric oxide (NO) is responsible for the hyperdynamic circulation observed in portal hypertension. Substance P is a neuropeptide partly cleared by the liver and causes vasodilatation through the activation of the endothelial NO pathway. However, there are no previously published data concerning the plasma level of substance P in cirrhotic rats and its relationship to NO. Methods: Plasma concentrations of substance P and nitrate/nitrite (an index of NO production) were determined in control rats and cirrhotic rats with or without ascites using an enzyme-linked immununosorbent assay and a colorimetric assay, respectively. In addition, systemic and portal hemodynamics were evaluated by a thermodilution technique and catheterization. Results: Cirrhotic rats with and without ascites had a lower systemic vascular resistance (2.6 ± 0.2 and 3.9 ±0.4 mmHg-ml-¹ min 100 g body weight, respectively) and higher portal pressure (14.6 ± 0.6 and 11.3 ± 1.8 mmHg) than control rats (6.5 ± 0.3 mmHg mP¹ min 100 g BW and 6.8 ± 0.2 mmHg, respectively, P < 0.05), and cirrhotic rats with ascites had the lowest systemic vascular resistance. Plasma levels of nitrate/nitrite progressively increased in relation to the severity of liver dysfunction (control rats, 2.7 ± 0.5 nmol/ml; cirrhotic rats without ascites, 5.6 ±1.3 nmol/ml; cirrhotic rats with ascites, 8.3 ± 2.2 nmol/ml; P < 0.05). Cirrhotic rats with ascites displayed higher plasma values of substance P (57.7 ± 5.9 pg/ml) than cirrhotic rats without ascites (37.9 ± 3.1 pg/ml, P < 0.05) and control rats (30.1 ± 1.0 pg/ml, P < 0.05). There was no significant difference in plasma substance P values between control rats and cirrhotic rats without ascites (P ± 0.05). No correlation was found between plasma levels of substance P and nitrate/nitrite (r = 0.318, P ± 0.05). Conclusions: Excessive formation of NO may be responsible, at least partly, for the hemodynamic derangements in cirrhosis. Although substance P may not participate in the initiation of a hyperdynamic circulation in cirrhosis, it may contribute to the maintenance of the hyperdynamic circulation observed in cirrhotic rats with ascites.

Key Words:

• Cirrhosis
• hyperdynamic circulation
• nitric oxide
• substance P