title: Negative metabolic effects of cyclic GMP are altered in renal hypertension induced cardiac hypertrophy.
abstract: We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O2 consumption and that renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change this relationship. Four groups of anesthetized open-chest New Zealand white rabbits (N = 26) were utilized. Either vehicle or 3-morpholinosydnonimine (SIN-1) (10(-4) M, a guanylate cyclase activator) was topically applied to the left ventricular surface of control or 1K1C rabbits. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption. Myocardial cyclic GMP levels were determined by radioimmunoassay. Guanylate cyclase activity was measured by conversion of GTP to cyclic GMP. 1K1C rabbits had a greater heart weight-to-body weight ratio (3.29 +/- 0.15) than controls (2.63 +/- 0.19). Systolic blood pressure was higher in 1K1C rabbits than in controls. In control rabbits, cyclic GMP levels (pmoles/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) almost double those observed in the vehicle-treated group (EPI: 6.3 +/- 0.8; ENDO: 7.7 +/- 1.1). There were no significant differences in basal or maximally stimulated guanylate cyclase activity between controls and 1K1C rabbits. Myocardial O2 consumption (ml O2/min/100 g) was significantly 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 vehicle (9.1 +/- 2.0). Myocardial O2 consumption was also significantly less 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 O2 consumption between control and 1K1C animals after treatment with SIN-1. Thus, there was a greater elevation in cyclic GMP in 1K1C rabbits, but this did not result in a corresponding greater depression in O2 consumption. This suggests that cyclic GMP plays a role in the control of myocardial metabolism, and that the sensitivity of myocardial O2 consumption to changes in cyclic GMP is reduced by renal hypertension-induced cardiac hypertrophy.
authors.affiliation: Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rabindranauth
authors.forename: K L
authors.initials: KL
authors.lastname: Naim
authors.forename: P M
authors.initials: PM
authors.lastname: Scholz
authors.forename: J
authors.initials: J
authors.lastname: Tse
authors.forename: J D
authors.initials: JD
authors.lastname: Sadoff
authors.forename: H R
authors.initials: HR
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D006332:Cardiomegaly / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006978:Hypertension, Renovascular / Q000378:metabolism*; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits
chemical_list: D004791:Enzyme Inhibitors; C002385:linsidomine; D008981:Molsidomine; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D010100:Oxygen