Cyclic nucleotide phosphodiesterase type 5 activity limits blood flow to hypoperfused myocardium during exercise

Background-Nitric oxide (NO) causes vasodilation by stimulation of guanylat e cyclase in vascular smooth muscle to produce cGMP. The resultant vasodila tor effect is regulated by a family of cGMP phosphodiesterases (PDEs). Sild enafil, a selective inhibitor of PDES used for treatment of erectile dysfun ction, has been found to cause relaxation of isolated epicardial coronary a rtery segments. The present study examined the effects of sildenafil on cor onary blood flow and hemodynamics during exercise in normal and ischemic he art. Methods and Results-In chronically instrumented normal dogs, sildenafil 2 m g/kg PO caused a slight but significant increase in left anterior descendin g (LAD) coronary blood flow during resting conditions, with a nonsignifican t trend toward increased coronary flow during treadmill exercise. Exercise in the presence of LAD stenosis that decreased distal coronary pressure to 57+/-2 mm Hg reduced LAD flow during exercise from 69+/-8 to 41+/-7 mL/min (P<0.05), with hypoperfusion most severe in the subendocardium. At the same distal coronary pressure, sildenafil increased LAD flow in the ischemic re gion to 50+/-11 mL/min (P<0.05). Increase in ischemic region blood flow pro duced by sildenafil was uniform across the LV wall, given that no change oc curred in the transmural distribution of perfusion. Conclusions-Inhibition of PDES with sildenafil caused vasodilation of coron ary resistance vessels with an increase of blood flow into an ischemic myoc ardial region during exercise in the presence of coronary artery stenosis.