l-arginine protects the mesenteric vascular circulation against cardiopulmonary bypass-induced vascular dysfunction

Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest

“…1A). In accordance with previous studies in our laboratory (1,2), this effect is related to a reduced ability of the vascular endothelium to generate NO, not to a reduced ability of the vascular smooth muscle to relax in response to NO, because the relaxant effect of the NO donor compound SNP remained unaltered (Fig. 1B).…”

“…Through the above mechanism, one can hypothesize that free radicals and oxidants injure the vascular endothelium, which reduces NO production, which then leads to neutrophil infiltration. Furthermore, leukocyte activation fuels the release of large amounts of oxygen free radicals during and after CPB (2,9), which ultimately impair the availability of NO and alter the NO-receptor interactions, thus contributing to the mesenteric endothelial injury in our control group (positive feedback cycle). PARP inhibition, by interrupting this cycle, may reduce both neutrophil infiltration and free radical generation.…”

“…Indeed, CPB is known to induce a systemic inflammatory reaction with free radical release leading to endothelial dysfunction in the mesenteric micro-and macrocirculation (1,31). Factors that are related to this damage include reduced expression and activity of the endothelial nitric oxide synthase (eNOS) and reduced L-arginine availability that results in reduced bioavailability of NO (2,15). Moreover, increased production of superoxide leads to increased degradation of NO and the formation of oxidant peroxynitrite, a potent trigger of various forms of oxidative cell injury (4,20).…”

Vasomotor dysfunction after cardiac surgery

“…In addition to these endothelial effects, eNOS also regulates tone in the vascular smooth muscle, to which the endothelium signals, and thus affects medial vasodilatory responses [20]. eNOS activity is decreased after CPB and cardioplegic arrest as a result of changes in cell membrane potential [21][22][23], substrate and cofactor depletion [5,24], alterations in the concentration or compartmentalization of intracellular calcium [25,26], and injury to cell membranes, associated regulatory enzymes, or ion pumps [19]. Following reperfusion after cardioplegic arrest, increased breakdown of bioavailable NO occurs from increased oxidative stress secondary to the generation of oxygenderived free-radicals [27], and production is further impaired by exposure of the endothelium to fragments of activated complement [28,29], activated neutrophils, and macrophages [3].…”

“…The resultant vasomotor disturbances may clinically manifest as reduced peripheral vascular resistances in the skeletal muscle bed and, conversely, increased propensity to spasm in the coronary, pulmonary, mesenteric, and cerebral circulations. Abnormal vascular permeability and secondary tissue edema may in turn contribute to malperfusion and dysfunction of the heart, lungs, brain, kidneys, gastrointestinal tract, and other organs [2][3][4][5]. These phenomena are most striking after cardiac operations for patients in cardiogenic shock [6,7] or in patients for whom CPB support of more than 80 min is needed [8][9][10].…”