Enhanced external counterpulsation (EECP) is a noninvasive, pneumatic technique that provides favorable effects in patients with coronary artery disease and heart failure. The mechanisms by which EECP exerts its beneficial effects remain poorly understood. Cyclic GMP (cGMP) regulates vascular smooth muscle tone that may improve arterial function. We investigated the effect of a single session of EECP on plasma and platelet cGMP in asymptomatic subjects with cardiovascular risk factors (HCVR) and in patients with coronary artery disease (CAD).Fifty-five subjects were included (25 HCVR and 30 CAD) and randomized into two groups to receive either sham (control) or active EECP during 1 h. Plasma and platelet cGMP were measured immediately before and after EECP by radioimmunoassay.One hour of EECP increased cGMP plasma concentration by 52% +/- 66% (SD) (P < .001) and platelet content by 19% +/- 28% (P < .01). The increase in plasma cGMP was particularly marked in CAD patients receiving active EECP (P < .01), mainly in those with low LDL-cholesterol. Platelets, inhibition of nitric oxide synthesis by N(G)-monomethyl-l-arginine (L-NMMA) reduced cGMP by 23% +/- 31% (P < .001), whereas presence of superoxide dismutase and inhibition of phosphodiesterase-5 increased cGMP by 46% +/- 49% and 70% +/- 77%, respectively (P < .001). In all of the cases EECP increased additional platelet cGMP content, which suggests nitric oxide synthase activation.Acute external counterpulsation showed that very early treatment increases the cGMP production that may participate in the mechanism by which EECP exerts its clinical benefit. Analysis of the modulation of platelet cGMP content suggests that EECP activated the nitric oxide-dependent pathways.