Differential responses of circulating and tissue adrenomedullin and gene expression to volume overload

Background: Adrenomedullin (AM), which is produced by various tissues and o rgans, also circulates in the blood. Circulating AM levels increase during disease states such as essential hypertension, heart failure, and renal fai lure. However, little is known about how circulating AM or AM production re sponds to volume overload (VOL). Methods and Results: Progressive VOL was induced in rats by an aortocaval s hunt (AC) or by an aortocaval shunt with banding of the abdominal aorta dis tal to the shunt (AC + B), which created a larger shunt volume, Plasma and tissue PLM concentrations, as well as AM gene expression levels, were measu red at 1, 5, and 14 days after operation. Plasma concentrations of atrial n atriuretic peptide (ANP), aldosterone, and renin activity (PRA) were also e xamined. Pulmonary congestion, pleural effusion, and ascites rapidly progre ssed in the AC + B group, suggesting that VOL caused more rapid heart failu re under these conditions. Plasma AM concentrations in the AC + B and AC gr oups at day 1 compared with those in sham-operated rats were increased by 3 00% and 140%, respectively, and then gradually declined. The time course of plasma AM over 14 days was similar to that of plasma aldosterone and PRA, but not of plasma ANP or intracardiac filling pressure. The increase in pla sma AM was accompanied by upregulated AM gene expression in the lung and ao rta and by decreased AM concentrations in the atrium, ventricle, and adrena l gland. Cardiac AM gene expression levels were increased in the hypertroph ied ventricles of AC and AC + B rats. Conclusions: The major findings of the present study were 1) a rapid increa se in plasma AM after the imposition of VOL in association with increased p lasma aldosterone and PRA, 2) the contribution of several organs to this in crease, and 3) a late increase in the AM messenger RNA (mRNA) level in the ventricles as VOL-induced ventricular hypertrophy developed.