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.

Altered relationship between cyclic GMP and myocardial O2 consumption in renal hypertension-induced cardiac hypertrophy

“…The basal myocardial level of cyclic GMP has been reported to be elevated in some types of pressure-load hypertrophy [20,23]. In this and a previous study [22], basal cyclic GMP levels were not shown to be significantly elevated in the renal hypertensive induced hypertrophied rabbits. This has also been demonstrated previously in hypertrophied hearts from T 4 -treated rabbits [31].…”

“…Previous studies from our laboratory provide further evidence that raising myocardial cyclic GMP by various means lowers O 2 consumption in both control and in renal hypertensive rabbit hearts [22,30]. In this study, we examined whether reducing cyclic GMP degradation through inhibition of the cyclic GMP phosphodiesterase would have differential negative metabolic effects in normal and hypertrophic hearts.…”

“…Blocking cyclic GMP-phosphodiesterase with zaprinast has been shown to lead to a significant increase in myocardial cyclic GMP levels [30]. Increases in cyclic GMP lead to negative functional and metabolic effects in the heart [13,22,25,27,30]. There have been reports that cyclic GMP may also have positive functional effects on the myocardium [17].…”

“…Cyclic GMP levels can be altered in the heart through changes in its production or degradation. In the rabbit heart, previous work has demonstrated that changes in cyclic GMP levels lead to inverse changes in myocardial O 2 consumption [22,30,31]. Some positive functional effects of lowering cyclic GMP by inhibition of guanylate cyclase have also been reported in isolated papillary muscle [3] and in the intact dog heart [6].…”

“…Sensitivity to other second messengers has been reported to be altered in renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy in the rabbit [2]. Previous studies in rabbits have shown that, while basal cyclic GMP levels were not altered, alteration of cyclic GMP levels with various drugs had different effects on myocardial oxygen consumption in hypertrophic as compared to control hearts [22,31].…”