Atrial natriuretic peptide in a rat model of cardiac failure. Atrial and ventricular mRNA, atrial content, plasma levels, and effect of volume loading.

This study examined the relation between synthesis, atrial storage, and plasma levels of atrial natriuretic peptide (ANP), and it examined plasma ANP levels and hemodynamic output in response to volume expansion in a rat model of myocardial infarction and failure. Arterial ANP concentrations did not correlate linearly with infarct size, but they did show an abrupt increase when infarct size exceeded 30% of the left ventricle, similar to the abrupt increase of left ventricular end-diastolic pressure with infarct size greater than 30%. Consequently, a close relation was found between plasma ANP levels and left ventricular end-diastolic pressure (n = 23, r = 0.89, p less than 0.001). Atrial ANP content per gram of tissue but not ANP content per pair of atria was reduced in rats with large infarcts (greater than 40%, p less than 0.05 vs. control animals). ANP mRNA level per pair of atria (related to total atrial RNA), determined by liquid hybridization (controlled by northern blot analysis), was increased by 38% in infarcted rats (p less than 0.05 vs. controls), but the ratio of atrial ANP mRNA relative to atrial beta-actin mRNA levels was not increased. Right and left ventricular ANP mRNA level increased by 90% and 380%, respectively, far exceeding the concomitant increase in beta-actin mRNA (+26% in the left ventricle). Plasma ANP increased with volume loading in controls and rats with moderate infarcts but not in rats with large infarcts despite a similar increase in right atrial pressure (compared with control animals); thus, the relation of delta ANP/delta right atrial pressure exerted by volume loading decreased in rats with large infarcts. Similarly, the response of cardiac output and renal blood flow (determined by radioactive microspheres) to volume loading was attenuated in rats with large infarcts. Thus, in this model of chronic cardiac failure, the activation of the ANP system is closely coupled with the increase in intracardiac pressures without correlating linearly to the extent of myocardial loss. Second, in severe cardiac failure, additional stimulation such as volume loading may elicit only an attenuated ANP secretion response, for example, due to saturation of the ANP receptor sensing system or to a limited transformation rate of pro-ANP. Third, the increase in atrial ANP synthesis and the increase in atrial ANP gene expression seems limited; however, substantial specific ANP gene expression occurs in the ventricles, which, in turn, may contribute to increased plasma ANP levels in chronic heart failure.