DIFFERENTIAL REGULATION OF NATRIURETIC PEPTIDE RECEPTOR MESSENGER-RNAS DURING THE DEVELOPMENT OF CARDIAC-HYPERTROPHY IN THE RAT

The heart expresses the three natriuretic peptide receptors (NPR), nam ely NPR-A, NPR-B, and NPR-C. We have examined the temporal relationshi p between the expression of mRNA transcripts for atrial natriuretic pe ptide (ANP) and brain natriuretic peptide (BNP) and their receptors in the heart during the development of cardiac hypertrophy in the aortov enocaval fistula rat. Messenger RNAs were measured by cDNA amplificati on. Progressive cardiac hypertrophy was accompanied by increased ANP m RNA prevalence throughout the heart and increased BNP mRNA in the left atrium. The most striking observation was the gradual disappearance o f NPR-C transcripts (the putative ''clearance'' receptor) in all chamb ers; this was in marked contrast to the increase in mRNA levels for NP R-A and NPR-B (the guanylyl cyclase-linked receptors). Our observation s have important therapeutic implications if the transcript changes ar e mirrored at the receptor protein level because (a) the apparent down -regulation of NPR-C may enhance the local action of natriuretic pepti des on the heart, and (b) the loss of NPR-C, particularly if it is wid espread, may reduce the rate of elimination of the natriuretic peptide s, restricting the therapeutic potential of specific NPR-C ligands des igned to reduce peptide clearance.