Increased guanylate cyclase activity is associated with an increase in cyclic guanosine 3',5'-monophosphate in left ventricular hypertrophy.

Abstract

Left ventricular hypertrophy (LVH) produced by aortic valve plication leads to increased myocardial cyclic GMP. We tested whether this was a result of increased soluble guanylate cyclase activity or nitric oxide (NO) synthase and its functional consequences. We used the nitric oxide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibitor N G -nitro-l-arginine methyl ester (L-NAME) in 12 control and 12 LVH anesthetized open-chest mongrel dogs. L-NAME (6 mg/kg) or SIN-1 (1 g/kg per min) was infused into the left anterior descending coronary artery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43 Ϯ 0.04 to 0.28 Ϯ 0.04 mM [EC 50 ]) and maximal activity (10.1 Ϯ 2.9 to 25.5 Ϯ 6.5 pmol/mg protein per min) were significantly increased in LVH as compared with control animals in response to nitroprusside stimulation, but cyclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal cyclic GMP was significantly elevated in vivo when compared with controls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09 Ϯ 0.12 to 1.48 Ϯ 0.19 pmol/gram) and a greater increase in the LVH group (1.78 Ϯ 0.16 to 3.58 Ϯ 0.71 pmol/g). L-NAME had no effect on myocardial cyclic GMP levels in control or LVH dogs. Segment work decreased in the control group after SIN-1 (1,573 Ϯ 290 to 855 Ϯ 211 grams ϫ mm/min). LVH dogs showed no decrement in work as a result of treatment with SIN-1. L-NAME did not cause significant changes in myocardial cyclic GMP, O 2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increased cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater increased cyclic GMP in LVH dogs is not related to increased NO production, but is related to significantly higher sensitivity and maximal activity of soluble myocardial guanylate cyclase.

Pacing-Induced Cardiac Failure of Hypertrophic Hearts: Effects of Cyclic GMP Reduction

“…Many studies have shown a decreased responsiveness to catecholamines [4 -8] in the hypertrophied left ventricle. We have shown in previous work not only alterations in the ␤-adrenergic signaling pathways in hypertrophied hearts but also cyclic GMP increases, the second messenger which may also be involved in mechanisms of compensation [9]. We have also observed metabolic and functional changes associated with alterations in the cyclic GMP signal transduction system [10] in our hypertrophy model.…”

Atrial Natriuretic Peptide Has Different Effects on Contractility and Intracellular pH in Normal and Hypertrophied Myocytes From Pressure-Overloaded Hearts

“…In this study, we observed that the cGMP levels are upregulated in hypertrophied LV, which is consistent with previous observations in mechanically overloaded hypertrophied heart models. 24,25 In our previous study, we showed in hypertrophied myocytes that the direct challenge of 8-bromo-cGMP did not cause either the depression of contraction or intracellular acidification that was observed in normal myocytes. 13 Conversely, we have shown that the basal Na ϩ /H ϩ exchanger activity measured by the recovery from NH 4 Cl-induced intracellular acidosis is similar in control and hypertrophied myocytes.…”

Divergent Biological Actions of Coronary Endothelial Nitric Oxide During Progression of Cardiac Hypertrophy

“…Both impaired and enhanced NO-dependent coronary artery vasodilation has been found in LVH and heart failure, experimentally and clinically. [2][3][4][5][6][7] Likewise, other groups have reported increased, 8,9 decreased, 3,10 or unaltered 11,12 coronary eNOS expression and activity in spontaneously hypertensive rats and in compensated LVH. LVH is initially adaptive, but it is associated with a progressive decline in LV function and ultimate cardiac failure.…”