Blood platelets limit blood loss at sites of vascular injury by forming a mechanical plug. They are also involved in thrombosis, atherosclerosis, inflammation and metastasis. Platelet activation is essential for these physiological and pathological reactions and depends upon their adhesion to the vessel wall and attachment to each other in the aggregation process. The two known pathways of aggregation are mediated by the release of endoperoxides/thromboxane A2 and ADP which amplify platelet aggregation. Here we report the identification of a new pathway of aggregation which is mediated by the release of a metalloproteinase enzyme, gelatinase A.

1 The eects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA-cp rats were investigated. 2 Phenylephrine (PE; 0.1 nM ± 10 mM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA-cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium. 3 Acetylcholine (ACh; 0.1 nM ± 10 mM)-induced endothelium-dependent relaxation of rings was not signi®cantly dierent in the two genotypes. Both were inhibited to a similar extent by N G -nitro-Larginine methyl ester (L-NAME; 0.01 ± 1 mM) when administered in vitro. 4 The nitric oxide synthase (NOS) inhibitor (L-NAME; 0.3, 1 or 3 mg ml 71 , p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats. 5 L-NAME resulted in greater inhibition of ACh-induced relaxation in cp/cp rings compared with +/? rings. 6 L-NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats. 7 The NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP; 0.1 nM ± 10 mM)-induced relaxation of rings from +/? rats, an eect enhanced by the treatment with L-NAME in vivo. 8 Oral administration of L-NAME did not enhance the vasorelaxant eect of SNAP on rings of aorta from cp/cp animals. 9 Platelet aggregation and NOS activity were similar in both genotypes and were not modi®ed by oral administration of L-NAME. 10 These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exempli®ed by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.