SUPPRESSED ANTI-AGGREGATING AND CGMP ELEVATING EFFECTS OF SODIUM-NITROPRUSSIDE IN PLATELETS FROM PATIENTS WITH STABLE ANGINA-PECTORIS

Platelet hyperactivity plays an important role in the pathogenesis of cardio-vascular diseases. In patients with stable angina pectoris, we have recently demonstrated that nitroglycerin suppressed the increased platelet aggregability. The anti-aggregating effect of NTG and other nitrovasodilators is mediated by platelet guanylate cyclase, which gen erates cyclic GMP (cGMP) in response to nitric oxide (NO) liberated fr om the nitrovasodilator molecule. In the current study we utilised a m ore ''direct'' NO donor, sodium nitroprusside (SNP), to examine revers al of ADP-induced platelet aggregation in comparison with intraplatele t cGMP elevation in platelets from normal subjects (n = 22) and patien ts with stable angina pectoris (n = 23). Concentrations of SNP associa ted with 50% reversal of aggregation were 2.7 +/- 0.4 x 10(-7) mol/L w ith normal subjects and 4.5 +/- 0.5 x 10(-6) mol/L with patients (P < 0.01). SNP produced a concentration-dependent elevation of intraplatel et cGMP content: with 10(-4) mol/L SNP this was 17-fold for normals an d 5-fold for patients (P < 0.01). An increase in cAMP content was seen only with 10(-4) mol/L SNP, and was 157 +/- 11% of baseline in platel ets from normal subjects and 138 +/- 14% in patients. There was a stro ng interrelationship between cGMP-stimulating and antiaggregating effe cts of SNP. The decrease in cGMP responsiveness to SNP was not related to a dysfunction of platelet guanylate cyclase; neither basal nor SNP -stimulated activity of the enzyme varied significantly between normal subjects and patients. Lipophilic derivatives of cGMP (db-cGMP) and c AMP (db-cAMP) caused reversal of aggregation; there was a nonsignifica nt trend towards decreased responsiveness of platelets from patients t o both db-cGMP and db-cAMP. The observed decrease in responsiveness of platelets from angina patients to anti-aggregating effects of the exo genous NO donor, SNP, can therefore be attributed to suppressed cGMP a ccumulation. These results imply reduced platelet sensitivity to endog enous NO (endothelium-derived relaxing factor); this might contribute to platelet hyperaggregability observed in angina pectoris.