Vascular responses to 8‐nitro‐cyclic GMP in non‐diabetic and diabetic mice

BACKGROUND AND PURPOSE 8‐Nitroguanosine 3′,5′‐cyclic monophosphate (8‐nitro‐cGMP), formed nitric oxide (NO)‐dependently, is a physiological second messenger, yet little is known about its role in the pathophysiology of vascular diseases. To study the pharmacological activity of 8‐nitro‐cGMP in diabetic mice, we compared its effects on vascular reactivity of aortas from non‐diabetic and diabetic mice. EXPERIMENTAL APPROACH Vascular tension recording was performed in thoracic aortic rings from wild‐type (C57BL/6), non‐diabetic db/+ and obese/diabetic db/db mice. Endothelial NO synthase (eNOS) uncoupling and superoxide were tested by Western blot and dihydroethidium fluorescence respectively. KEY RESULTS 8‐Nitro‐cGMP, at concentrations up to 10 µM, enhanced phenylephrine‐induced contractions in aortas from C57BL/6 and db/+ mice, but not from db/db mice. This enhancement was not observed with 8‐bromo‐cGMP. Pretreatment of aortas from C57BL/6 and db/+ mice with l‐NAME (100 µM), superoxide dismutase (100 U·mL−1) or tiron (1 mM), abolished 8‐nitro‐cGMP‐induced enhancement of the phenylephrine contraction. In 8‐nitro‐cGMP (10 µM)‐treated C57BL/6 aortas, eNOS dimer/monomer ratio was significantly decreased and vascular superoxide production increased, suggesting that 8‐nitro‐cGMP‐induced superoxide production via eNOS uncoupling may mediate the enhancement of the phenylephrine contraction. At higher concentrations (>10 µM), 8‐nitro‐cGMP produced relaxation of the phenylephrine‐contracted aortas from C57BL/6, db/+ and db/db mice. The 8‐nitro‐cGMP‐induced relaxation in db/db mouse aortas was found to be resistant to a phosphodiesterase 5 inhibitor, zaprinast (1 µM). CONCLUSIONS AND IMPLICATIONS The vasodilator effect of 8‐nitro‐cGMP may contribute to amelioration of the vascular endothelial dysfunction in diabetic mice, representing a novel pharmacological approach to prevent the complications associated with diabetes.