Antioxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation

Abstract

oxidant activity of nitro derivative of aspirin against ischemia-reperfusion in hamster cheek pouch microcirculation. Am J Physiol Gastrointest Liver Physiol 286: G437-G443, 2004. First published October 16, 2003 10.1152/ajpgi.00339.2003.-Aspirin that has been chemically combined with a nitric oxide (NO) donor (NCX-4016) has been shown to inhibit cyclooxygenase and prostaglandin generation while maintaining the inhibitory effects of aspirin. The possible role of reactive oxygen species (ROS) in the action of NCX-4016 in ischemia-reperfusion (I/R) has not been studied. Furthermore, we were interested in comparing the effects of a conventional NO donor [2,2Ј-hydroxynitrosohydrazino-bis-etanamine (DETA/NO)] and NCX-4016 at the microvascular level in the hamster cheek pouch visualized by using an intravital fluorescent microscopy technique. Microvascular injury was assessed by measuring diameter change, the perfused capillary length (PCL), and leukocyte adhesion. Animals were treated with NCX-4016 (100 mg/kg or 30 mg⅐kg Ϫ1 ⅐day Ϫ1 for 5 days po) or DETA-NO (0.5 mg/kg). Mean arterial blood pressure increased slightly but significantly after NCX-4016 treatment. During 5-and 15-min reperfusion, lipid peroxides in the systemic blood increased by 72 and 89% vs. baseline, respectively, and were still higher than in basal conditions after 30-min reperfusion in the I/R group. Pretreatment with NCX-4016 maintained ROS at normal levels; increased arteriolar diameter, blood flow, and PCL; and decreased leukocyte adhesion (P Ͻ 0.05). DETA-NO decreased ROS during 30-min reperfusion; however, later there was a significant increase during reperfusion. DETA-NO decreased leukocyte adhesion (P Ͻ 0.05) but microvascular permeability increased after 30 min of reperfusion. In conclusion, NCX-4016 attenuates oxidative stress and prevents arteriolar constriction during I/R, whereas DETA-NO increases lipid peroxides in the systemic blood and permeability after reperfusion. oxidative stress; nitric oxide-aspirin; microcirculation; lipid peroxides RECENTLY, A NEW CLASS of anti-inflammatory drugs has been developed by adding nitric oxide (NO) moiety to aspirin . NO released from these compounds has been shown to suppress prostanoid synthesis and to inhibit pathogenetic events during endotoxic shock (22,27,38,39). NCX-4016 has a more pronounced anti-thrombotic activity than aspirin (25, 37) as shown by the fact that it protected mice from pulmonary embolism, whereas in rabbits it reduced platelet accumulation induced by thrombin in the pulmonary vasculature (22, 32). NCX-4016 reduced infarct size and suppressed arrhythmias after myocardial ischemia-reperfusion (I/R) in pigs (38) and rats (40). NCX-4016, but not aspirin alone, was found to reduce brain damage induced by focal cerebral ischemia in spontaneously hypertensive rats (11).On restoration of blood flow during I/R, the production of reactive oxygen species (ROS) increases and is strongly implicated in microvascular dysfunction in experimental conditions, as well as in patients with acu...

Intermittent hypoxia modulates nitric oxide-dependent vasodilation and capillary perfusion during ischemia-reperfusion-induced damage

“…Moreover, our data showed that the eNOS inhibition caused a marked capillary perfusion loss during I/R compared with IH. This is consistent with previous findings, indicating that increases in endogenous NO levels and NO donors are beneficial in preventing the no-reflow phenomenon in I/R injury (8,11). Hence, apart from the well-established NO regulation of vascular tone, NO controls capillary perfusion during I/R injury.…”

“…The cheek pouch was spread out and fixed to a Plexiglas microscope stage (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). A thin black blade was then inserted through a small incision between the top and bottom layers of the pouch.…”

“…This response was associated with increased SS, vasoconstriction, and a small reduction in capillary perfusion. The increase in SS during IH could be explained by the increase in oxidative stress (8,31). Indeed, IH changes the susceptibility of the heart to oxidative stress, and elevated superoxide production during exposure to IH attenuates vasoconstrictor responsiveness to norepinephrine and myogenic activation in skeletal muscle resistance arteries (35,36).…”

Skeletal muscle reperfusion injury is enhanced in extracellular superoxide dismutase knockout mouse

“…Most studies suggest that increased levels of ROS enhance vasoconstriction (29,37), although exceptions do occur (40). The generation of ROS after I/R is strongly implicated in microvascular damage and dysfunction, leading to vasoconstriction and leukocyte adhesion on the endothelial surface (5). SOD and allopurinol have been shown to protect contractile function of skeletal muscle against I/R injury (39).…”

Preconditioning and Shear Stress in the Microcirculation in Ischemia-Reperfusion Injury

“…Limited dilation in face of increased flow is clinically important in arteries because this can contribute to impaired blood flow response during postischemic reperfusion. Moreover, the interaction of free radicals with membrane lipids and essential proteins, and the activities of most oxidase in the vascular cells, which in turn are subject to regulation by shear stress, influence vascular reactivity in many pathophysiologycal processes [18][19][20][21]. Recent findings show that inducing sustained blood flow during postischemic reperfusion tends to normalize shear stress, providing significant protection in postischemic reperfusion [18,22,23].…”