Abstract
Ischemic stroke remains the fifth cause of death, as reported worldwide annually. Endothelial dysfunction (ED) manifesting with lower nitric oxide (NO) bioavailability leads to increased vascular tone, inflammation, and platelet activation and remains among the major contributors to cardiovascular diseases (CVD). Moreover, temporal fluctuations in the NO bioavailability during ischemic stroke point to its key role in the cerebral blood flow (CBF) regulation, and some data suggest that they may be responsible for the maintenance of CBF within the ischemic penumbra in order to reduce infarct size. Several years ago, the inhibitory role of the platelet NO production on a thrombus formation has been discovered, which initiated the era of extensive studies on the platelet-derived nitric oxide (PDNO) as a platelet negative feedback regulator. Very recently, Radziwon-Balicka et al. discovered two subpopulations of human platelets, based on the expression of the endothelial nitric oxide synthase (eNOS-positive or eNOS-negative platelets, respectively). The e-NOS-negative ones fail to produce NO, which attenuates their cyclic guanosine monophosphate (cGMP) signaling pathway and—as result—promotes adhesion and aggregation while the e-NOS-positive ones limit thrombus formation. Asymmetric dimethylarginine (ADMA), a competitive NOS inhibitor, is an independent cardiovascular risk factor, and its expression alongside with the enzymes responsible for its synthesis and degradation was recently shown also in platelets. Overproduction of ADMA in this compartment may increase platelet activation and cause endothelial damage, additionally to that induced by its plasma pool. All the recent discoveries of diverse eNOS expression in platelets and its role in regulation of thrombus formation together with studies on the NOS inhibitors have opened a new chapter in translational medicine investigating the onset of acute cardiovascular events of ischemic origin. This translative review briefly summarizes the role of platelets and NO biotransformation in the pathogenesis and clinical course of ischemic stroke.
Highlights
Ischemic stroke remains the fifth cause of death, as reported worldwide annually
These results, accompanied with the study by Dougherty et al suggesting that acetylsalicylic acid (ASA) and dipyridamole treatment have no effect on platelet hyperreactivity to adenosine diphosphate (ADP), suggest that the lower threshold of platelet activation in ischemic stroke patients may be predominantly associated with the presence of plasmatic factors rather than with platelet functional disturbances [19, 31]
Different iNOS inhibitors were studied by Armengou et al, in which N-(3-(aminomethyl)benzyl) acetamidine (1400W) administrated at the onset of ischemia and at 8-hour intervals for 3 days after middle cerebral artery occlusion (MCAO) resulted in a 55% reduction of infarct size, as measured 72 hours after induction of cerebral ischemia [65]
Summary
Cardiovascular disease (CVD) remains the main cause of morbidity and mortality, as reported worldwide annually. Tration between stroke patients and controls returned to normal after 90 days of observation or gradually with implementation of antiplatelet treatment (stronger correlation with clopidogrel than with acetylsalicylic acid (ASA), but no association with warfarin treatment) Such treatment had no effect on normalization of the circulating platelet-leukocyte aggregate level in those patients [18, 19]. Cross-incubation of control platelets with plasma from stroke patients resulted in activation of platelets measured by the raised basal platelet calcium level and release of serotonin from platelets These results, accompanied with the study by Dougherty et al suggesting that ASA and dipyridamole treatment have no effect on platelet hyperreactivity to ADP, suggest that the lower threshold of platelet activation in ischemic stroke patients may be predominantly associated with the presence of plasmatic factors rather than with platelet functional disturbances [19, 31]. An increasing number of studies suggest that nitric oxide deficiency and nitric oxide synthase inhibitors can be one of the factors responsible for greater platelet aggregation in ischemic stroke patients
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