INCREASED CYCLIC GUANOSINE-MONOPHOSPHATE PRODUCTION AND OVEREXPRESSION OF ATRIAL-NATRIURETIC-PEPTIDE A-RECEPTOR MESSENGER-RNA IN SPONTANEOUSLY HYPERTENSIVE RATS

Atrial natriuretic peptide (ANP) specifically stimulates particulate g uanylate cyclase, and cyclic guanosine monophosphate (cGMP) has been r ecognized as its second messenger. Spontaneously hypertensive rats (SH R) have elevated plasma ANP levels, but manifest an exaggerated natriu retic and diuretic response to exogenous ANP when compared to normoten sive strains. In isolated glomeruli, the maximal cGMP response to ANP corresponds to a 12- to 14-fold increase over basal levels in normoten sive strains (Wistar 13+/-2; Wistar-Kyoto 12+/-2; Sprague-Dawley 14+/- 2) while a maximal 33+/-3-fold elevation occurs in SHR (P < 0.001). Th is hyperresponsiveness of cGMP is reproducible in intact glomeruli fro m SHR from various commercial sources. Furthermore, this abnormality d evelops early in life, even before hypertension is clearly established , and persists despite pharmacological modulation of blood pressure, i ndicating that it is a primary event in hypertension. In vitro studies have revealed a higher particulate guanylate cyclase activity in memb ranes from glomeruli and other tissues from SHR. This increase is not accounted for by different patterns of ANP binding to its receptor sub types between normotensive and hypertensive strains, as assessed by co mpetitive displacement with C-ANP102-121, an analog which selectively binds to one ANP receptor subtype. The hyperactivity of particulate gu anylate cyclase in SHR and its behavior under basal, ligand (ANP), and detergent-enhanced conditions could be attributed either to increased expression or augmented sensitivity of the enzyme. Radiation-inactiva tion analysis does not evoke a disturbance in the size of regulatory e lements normally repressing enzymatic activity, while the expression o f particulate guanylate cyclase gene using mutated standard of A- and B-receptors partial cDNAs, quantified by polymerase chain reaction (PC R) transcript titration assay, manifests a selective increase of one g uanylate cyclase subtype. Our data suggest that in hypertension, genet ic overexpression of the ANP A-receptor subtype is related to the exag gerated biological response to ANP in this disease.