NEGATIVE METABOLIC EFFECTS OF CYCLIC-GMP ARE ALTERED IN RENAL-HYPERTENSION INDUCED CARDIAC-HYPERTROPHY

We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O-2 consumption and that renal hypertension (O ne Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change thi s relationship. Four groups of anesthetized open-chest New Zealand whi te rabbits (N = 26) were utilized. Either vehicle or 3-morpholinosydno nimine (SIN-1) (10(-4) M, a guanylate cyclase activator) was topically applied to the left ventricular surface of control or 1K1C rabbits. C oronary blood flow (radioactive microspheres) and O-2 extraction (micr ospectrophotometry) were used to determine O-2 consumption. Myocardial cyclic GMP levels were determined by radioimmunoassay. Guanylate cycl ase activity was measured by conversion of GTP to cyclic GMP. 1K1C rab bits had a greater heart weight-to-body weight ratio (3.29 +/- 0.15) t han controls (2.63 +/- 0.19). Systolic blood pressure was higher in 1K 1C rabbits than in controls. In control rabbits, cyclic GMP levels (pm oles/g) were higher in SIN-1-treated (EPI: 7.5 +/- 1.6; ENDO: 8.1 +/- 1.5) than in vehicle-treated animals (EPI: 5.4 +/- 0.4; ENDO: 5.6 +/- 0.6). This effect was enhanced in 1K1C rabbits, with cyclic GMP levels in the SIN-1-treated group (EPI: 11.9 +/- 1.3; ENDO: 13.0 +/- 1.5) al most double those observed in the vehicle treated group (EPI: 6.3 +/- 0.8; ENDO: 7.7 +/- 1.1). There were no significant differences in basa l or maximally stimulated guanylate cyclase activity between controls and 1K1C rabbits. Myocardial O-2 consumption (ml O-2/min/100 g) was si gnificantly less in the EPI region of control animals treated with SIN -1 (7.2 +/- 1.2) than in the same region of controls treated with vehi cle (9.1 +/- 2.0). Myocardial O-2 consumption was also significantly l ess in SIN-1-than vehicle-treated 1K1C animals (SIN-1-treated: EPI: 6. 9 +/- 0.8; ENDO: 6.2 +/- 0.7; vehicle-treated: EPI: 10.0 +/- 0.8; ENDO : 12.5 +/- 3.0). There was no significant difference in O-2 consumptio n between control and 1K1C animals after treatment with SIN-1. Thus, t here was a greater elevation in cyclic GMP in 1K1C rabbits, but this d id not result in a corresponding greater depression in O-2 consumption . This suggests that cyclic GMP plays a role in the control of myocard ial metabolism, and that the sensitivity of myocardial O-2 consumption to changes in cyclic GMP is reduced by renal hypertension-induced car diac hypertrophy.