Differential Regulation of Ventricular Adrenomedullin and Atrial Natriuretic Peptide Gene Expression in Pressure and Volume Overload in the Rat

Abstract

1. Adrenomedullin is a recently discovered vasodilating and natriuretic peptide whose physiological and pathophysiological roles remain to be established. Like atrial natiuretic peptide adrenomedullin is expressed in the left ventricle. Ventricular expression of atrial natriuretic peptide is known to be markedly increased by volume or pressure overload. In this study we investigated whether ventricular expression of adrenomedullin is similarly stimulated under such conditions. 2. Ventricular adrenomedullin and atrial natriuretic peptide mRNA levels as well as those of a loading control mRNA (glyceraldehyde-3-phosphate dehydrogenase) were quantified by Northern blot analysis in (a) rats with severe post-infarction heart failure induced by left coronary ligation at 30 days post-surgery and (b) in rats with pressure-related cardiac hypertrophy induced by aortic banding at several time points (0.5, 1 and 4 h, and 1, 4, 7 and 28 days) after surgery. Levels were compared with those in matched sham-operated controls. 3. The mRNA level of atrial natriuretic peptide was markedly increased (8-10-fold) in the left ventricle of animals with post-infarction heart failure. In contrast, there was only a modest (40%) increase in the level of adrenomedullin mRNA. In rats with pressure-induced cardiac hypertrophy the ventricular level of atrial natriuretic peptide mRNA was again markedly increased (maximum 10-fold). The increase was first noticeable at 24 h post-banding and persisted until 28 days. In contrast, there was no change in adrenomedullin mRNA level compared with sham-operated rats at any time point. 4. Despite having similar systemic effects, the expression of adrenomedullin and atrial natriuretic peptide in the left ventricle is differently regulated. The findings imply distinct roles for the two peptides. The results do not support an important role for ventricular adrenomedullin expression in the remodelling process that occurs during the development of cardiac hypertrophy but suggest that ventricular adrenomedullin participates in the local and/or systemic response to heart failure.

Rapid Increase in Cardiac Adrenomedullin Gene Expression Caused by Acute Pressure Overload. Effect of the Renin-Angiotensin System on Gene Expression.

“…They have suggested that mechanical wall stress is not an important regulator of cardiac AM expression, which might be due to a difference in the magnitude of POL. Although both studies used abdominal aortic-banded rat models, POL in the model of the present study was more severe than in that of Kaiser et al 7 In the present study, the ratios of LV weight corrected for body weight over 14 days after surgery were obviously higher than those in the study of Kaiser et al 7 The pressure loading in their study might have been insufficient to activate the induction of AM gene expression.…”

“…However, whether or not acute POL increases cardiac AM transcription remains controversial. [7][8][9] The results of the present study revealed that LV AM expression increased on day 1 then declined, and that it was not significant 5 or 14 days after acute aortic banding. Right ventricular AM gene expression also increased on days 1 and 5, but not on day 14.…”

“…Kaiser et al 7 have reported that VOL with post-infarction heart failure increased the expression of cardiac AM 30 days after left coronary ligation. An earlier report by Nishikimi et al has shown that VOL induced by an aortocaval shunt induced AM gene expression in the LV 21 days after shunt formation.…”

Inhibition of Angiotensin-Converting Enzyme Reduces Susceptibility of Hypertrophied Rat Myocardium to Ventricular Fibrillation.

“…To monitor the development and regression of myocardial hypertrophy at the molecular level, we measured the LV expression of atrial natriuretic factor (ANF) mRNA. 23,24 Our results indicated that short-term treatment with ramipril reduced susceptibility to reperfusion-induced ventricular fibrillation (VF) in hearts with established LV hypertrophy. Furthermore, this protection was achieved without a reduction in LV mass (but an increase in hydroxyproline content) and was accompanied by the regression of myocyte hypertrophy, as reflected by cellular and molecular indices.…”

Susceptibility to Ischemia and Reperfusion Arrhythmias in Myocardial Hypertrophy Due to Flow of Injury Current?

“…Furthermore, to monitor the development of myocardial hypertrophy at the molecular level, we measured LV expression of atrial natriuretic factor (ANF) mRNA. 11,12) …”