REDUCED EFFECT OF cGMP PHOSPHODIESTERASE ON O2 CONSUMPTION IN RENAL HYPERTENSION-INDUCED CARDIAC HYPERTROPHY IN RABBITS

Abstract

S518 Introduction: Cyclic GMP (cGMP), has been shown to exert negative metabolic and functional effects on the heart [1]. It has also been demonstrated that changes in cGMP levels lead to inverse changes in myocardial O2 consumption (O2 Cons) [2]. However, the importance and actions of cGMP in cardiac hypertrophy have been little studied. We studied the effect of topically applied zaprinast, a specific inhibitor of cGMP phosphodiesterase (PDE), on myocardial O2 Cons in renal hypertension-induced cardiac hypertrophy. Methods: Renal hypertension (HTN) was induced in rabbits using the surgical procedure of one-kidney-one clip (1K1C). The animals were allowed to recover for 35 days. Four groups of anesthetized open-chest New Zealand rabbits (N=26) were utilized. An intra-atrial cannula was inserted to allow injection of radioactive microspheres for coronary blood flow measurements, and a catheter-tip transducer was introduced into left ventricle (LV). A data acquisition system was employed to record HR, aortic BP, LV BP and dP/dt. Either vehicle or zaprinast (3 mM) were topically applied to LV surface of control or 1K1C rabbits for 15 min. Coronary flow and O2 extraction (microspetrophotometry) were used to determine O2 Cons. Myocardial cGMP levels were determined by radioimmunoassay. Data were presented as Mean +/- S.E.M. ANOVA was used. Results: 1K1C rabbits had a greater heart wt-to-body wt ratios (2.94 +/- 0.08) than controls (2.58 +/- 0.17). Systolic BP was higher in 1K1C (102 +/- 9 mm Hg) than controls (86 +/- 3 mm Hg). Zaprinast significantly and similarly increased cGMP level (pmol/g) in both control subepicardium (EPI) (3.90 +/- 0.47 to 4.66 +/- 0.89) and subendocardium (ENDO) (5.08 +/- 0.69 to 7.06 +/- 1.36) and 1K1C hearts (5.53 +/- 0.61 to 7.48 +/- 1.51 for EPI and 6.48 +/- 0.42 to 8.88 +/- 1.08 for ENDO). Myocardial O2 Cons (ml O2/min/100 g) was significantly lower in the controls treated with zaprinast (EPI: 8.8 +/- 0.1; ENDO: 9.5 +/- 1.9) compared to controls treated with vehicle (EPI: 13.6 +/- 1.3; ENDO: 16.2 +/- 2.9). This effect was diminished in 1K1C rabbits treated with zaprinast (EPI: 10.3 +/- 2.4; ENDO: 11.2 +/- 2.6) compared to the vehicle treated 1K1C group (EPI: 13.3 +/- 1.2; ENDO: 14.5 +/- 2.4). Discussion: There was a similar increase in myocardial cGMP after treatment with zaprinast, but a greater depression of myocardial O2 consumption in the control animals compared to 1K1C after treatment with zaprinast. This suggested that the sensitivity of myocardial O2 consumption to increases in cGMP caused by inhibition of cGMP PDE was blunted by 1K1C cardiac hypertrophy.