INCREASED GUANYLATE-CYCLASE ACTIVITY IS ASSOCIATED WITH AN INCREASE IN CYCLIC GUANOSINE 3',5'-MONOPHOSPHATE IN LEFT-VENTRICULAR HYPERTROPHY

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 oxid e (NO) synthase and its functional consequences. We used the nitric ox ide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibito r N-G-nitro-1-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 mu g/kg per min) was infused into the left anterior descending coronary a rtery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43+/-0.04 to 0.2 8+/-0.04 mM [EC(50)]) and maximal activity (10.1+/-2.9 to 25.5+/-6.5 p mol/mg protein per min) were significantly increased in LVH as compare d with control animals in response to nitroprusside stimulation, but c yclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal c yclic GMP was significantly elevated in vivo when compared with contro ls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09+/-0.12 to 1.48+/-0.19 pmol/gram) and a gr eater increase in the LVH group (1.78+/-0.16 to 3.58+/-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+/ -290 to 855+/-211 grams x mm/min). LVH dogs showed no decrement in wor k as a result of treatment with SIN-1. L-NAME did not cause significan t changes in myocardial cyclic GMP, O-2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increas ed cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater incr eased cyclic GMP in LVH dogs is not related to increased NO production , but is related to significantly higher sensitivity and maximal activ ity of soluble myocardial guanylate cyclase.