Local regulator adrenomedullin contributes to the circulatory disturbance in cirrhotic rats

Table 1 Hemodynamic effects of chronic administration of adrenomdullin in control rats

	Vehicle (n=8)	AM (n=8)	Pvalue
Mean arterial pressure (mmHg)	132 ± 3	122 ± 4	< 0.05
Cardiac index (mL/min·100g bw)	26.0 ± 2.1	34.1 ± 2.	< 0.05
Systemic vascular resistance (mmHg·min·100g bw/mL)	5.3  ± 0.4	3.8 ± 0.4	< 0.05
Portal pressure (mmHg)	6.9 ± 0.5	7.0 ± 0.5	NS
Portal venous inflow (mL/min·100g bw)	3.5 ± 0.4	5 .0 ± 0.6	< 0.05
Portal venous system resistance (mmHg·min·100g bw/mL)	2.1 ± 0.3	1.6 ± 0.3	NS
Splanchnic arterial resistance (mmHg·min·100g bw/mL)	38.5 ± 4.1	25.7 ± 4.0	< 0.05

Control rats were chronically infused with either vehicle or human adrenomedullin (AM) (1.0 mg/h) for 14 d using mini-osmotic pump. On day 14 of chronic infusion, hemodynamic study was performed using radioactive microspheres. Values are presented as mean ± SE of 8 separate experiments.

Table 2 Effects of anti-adrenomedullin antibody on hemodynamics and aortic ring contraction of cirrhotic rats.

	Vehicle	Anti-AM antibody
Hemodynamic effects
Mean arterial pressure (mmHg)	117 ± 3	121 ± 4
Cardiac index (mL/min·100g bw)	39.5 ± 2.9	38.2 ± 3.8
Systemic vascular resistance (mmHg·min·100g bw/mL)	3.1±0.4	3.4±0.4
Portal pressure (mmHg)	13.0 ± 0.4	12.8 ± 0.5
Portal venous inflow (mL/min·100g bw)	6.8 ± 0.8	5.6 ± 1.0
Portal venous system resistance (mmHg·min·100g bw/mL)	2.2 ± 0.3	2.6 ± 0.4
Aortic ring contraction
Rmax (mg/mg tissue)	998 ± 96	1499 ± 137a
EC50 (nmol/L)	85.7 ± 11.8	53.8 ± 6.2

Cirrhotic rats with ascites were repeatedly injected either vehicle or anti-adrenomedullin (anti-AM) antibody [500 mg/(kg∙times)] via tail vein on the day of occurrence of ascites, 3 and 6 d after. Hemodynamic study was performed on the next day of the final injection. Values are presented as mean ± SE of 8 separate experiments. The contraction of aortic rings to phenylephrine was evaluated in the presence of vehicle or anti-AM antibody. Values are presented as mean ± SE of 8 rings. Rmax: maximal contraction to phenylephrine, EC₅₀: phenylephrine concentration required for 50% of Rmax,

^aP < 0.05 vs vehicle.

Table 3 Contractile response of control and cirrhotic aortic rings to adrenomedullin and/or NG-nitro-L-arginine methyl ester

	Control		Liver cirrhosis
	Rmax (mg/mg tissue)	EC50 (nmol/L)	Rmax (mg/mg tissue)	EC50 (nmol/L)
Vehicle	1860 ± 152	68.8 ± 9.4	998 ± 96a	85.7 ± 11.8
AM	1330 ± 118a	82.7 ± 12.3	698 ± 94c	91.0 ± 12.8
L-NAME	2362 ± 182a	61.8 ± 7.1	2274 ± 148c	72.1 ± 6.7
L-NAME+AM	2242 ± 91a	55.7 ± 9.5	2092 ± 219c	53.8 ± 6.2

The contraction of aortic rings to phenylephrine was evaluated in the presence of vehicle or anti-AM antibody. Values are presented as mean ± SE of 8 rings. Rmax: maximal contraction to phenylephrine, EC⁵⁰: phenylephrine concentration required for 50% of Rmax, ^aP < 0.05 vs vehicle-treated control aorta, ^cP < 0.05 vs vehicle-treated cirrhotic aorta. AM, adrenomedullin; L-NAME, N^G-nitro-L-arginine methyl ester.