DIABETES-INDUCED ALTERATIONS IN ATRIAL-NATRIURETIC-PEPTIDE GENE-EXPRESSION IN WISTAR-KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS

We investigated the effects of streptozotocin-induced diabetes on atrial natriuretic peptide (ANP) synthesis, hemodynamic parameters, blood volume, and histopathology, as well as the reversibility of such effects with insulin therapy in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The biatrial ANP messenger RNA (mRNA) levels in the diabetic WKY rats increased by 16-17% compared with those in the age-matched WKY rats at 12 weeks after the onset of diabetes, whereas their ventricular ANP mRNA levels showed increases of 190% in left ventricles and 160% in right ventricles at 8 weeks. In the diabetic SHRs, the left atrial ANP mRNA levels increased by 36% compared with those in the age-matched SHRs, as early as 4 weeks after diabetes onset. Their ventricular ANP mRNA levels also showed 80-82% increases in left and right ventricles at 4 weeks. In proportion to changes in cardiac ANP synthesis, the biventricular end-diastolic pressures were significantly elevated at 8 weeks in the diabetic WKY rats and at 4 weeks in the diabetic SHRs. The blood volume significantly increased at 8 weeks in the diabetic WKY rats and remained higher thereafter, whereas it did not change in the diabetic SHRs throughout the experimental period. The left ventricular peak dP/dt was depressed in the 8-week diabetic SHRs, whereas in the diabetic WKY rats, its depression was observed at 12 weeks after diabetes onset. Histopathological studies showed that diabetic changes in ANP synthesis and hemodynamic parameters described above occurred before the cardiomyopathic histological changes. Cardiac ANP synthesis in the diabetic rats completely reverted to control levels after insulin therapy, accompanied by normalization of hemodynamic parameters. The present study indicates that 1) ANP synthesis is significantly augmented in the streptozotocin-induced diabetic rat compared with that in the normal rat, and the combination of diabetes and hypertension produces an earlier and greater effect in stimulating cardiac ANP synthesis than does either disease alone; 2) an elevation in the intraventricular filling pressure that occurs before observable cardiomyopathic histopathological alterations might be involved partially in the augmented ANP synthesis; and 3) the reversibility with insulin therapy suggests that the streptozotocin-induced alterations observed in cardiac ANP synthesis and hemodynamics result from insulin-deficient diabetes mellitus, not from cardiac toxicity of streptozotocin.