Two NO synthase (NOS) isoforms have been described in vessels, an endothelial constitutive NOS (eNOS) and an inducible NOS (iNOS). The purpose of the present study was to examine the endothelium-dependent and endothelium-independent hypotensive response in aging rats, analyzing the ability of their vessels to produce NO. The studies were performed in 2 groups of euvolemic, conscious, male Wistar rats: aging rats (n=20, 18 months old) and young rats (n=20, 5 months old). The hypotensive responses to acetylcholine, bradykinin, and sodium nitroprusside were determined. Furthermore, the expression of the NOS isoforms by Western blot and the eNOS and iNOS activities, defined as Ca2+-dependent and Ca2+-independent conversion of [14C]L-arginine into [14C]L-citrulline, respectively, were also determined. In the aging rats, we found an impaired hypotensive response to acetylcholine and bradykinin (2 NO- and endothelium-dependent hypotensive agents) that was accompanied by a preserved hypotensive response to sodium nitroprusside. Aging rats also demonstrated an enhanced sensitivity response to the pressor effect of the L-arginine antagonist L-Nomega-nitro-L-arginine and a reduced vasoconstrictor response to angiotensin II. The inhibition of NO synthesis normalized the pressor effect of angiotensin II in the aging animals. Nitrite plus nitrate plasma levels were increased in aging rats. Furthermore, cGMP content was also higher in the aging vessels. In the aging aortas, the expression of both eNOS and iNOS isoforms was enhanced. However, in aging rats, the activity of the eNOS isoform was markedly reduced, a finding that was accompanied by the presence of iNOS activity. The vessel wall of aging rats showed an enhanced expression of eNOS and iNOS isoforms. However, eNOS activity was reduced in the aging animals. These findings could explain the impaired endothelium-dependent hypotensive response associated with aging.
Endothelin-1 stimulates neutrophil adhesion to endothelial cells by an effect on the expression of adhesive molecules on the neutrophil surface. Endothelin-1 stimulates neutrophil accumulation in vivo and in vitro in the heart. Antibodies against the integrin complex block the endothelin-1-dependent neutrophil adhesion. These findings have potential importance in the pathophysiology of endothelin-1-increased states.
The present study addressed the effect of interventions aimed to increase NO in the setting of acute renal ischemia/reperfusion (I/R) in uninephrectomized rabbits. In the 60-minute post-I/R period, L-arginine+superoxide (O2.-) dismutase (SOD) synergistically improved the renal functional (69.4% versus 10.4% of the pre-I/R glomerular filtration rate with or without L-arginine+SOD, respectively; p < .01) and histological parameters (82.9% decrease of medullary congestion in L-arginine+SOD, P < .01 versus vehicle) and blocked the I/R-dependent neutrophil accumulation (89.3% reduction). In spite of these results over the short term, a second set of experiments disclosed that the protection by L-arginine+SOD was no longer present at 24 and 48 hours (plasma creatinine in vehicle-treated versus L-arginine+SOD-treated animals [mg/100 mL]: 24 hours after I/R, 9.4 +/- 1.9 versus 8.07 +/- 0.65; 48 hours after I/R, 11.6 +/- 3.6 versus 9.7 +/- 0.9; P = NS in all the cases). Additional experiments were conducted using a milder 30-minute ischemic model, which showed no significant functional or histological protection by using L-arginine+SOD. In conclusion, our experiments disclosed the following: (1) the critical importance of the interaction between NO and O2.- in the acute protective effect of L-arginine (this effect not only improved renal function and histology but also reduced neutrophil accumulation) and (2) the discordance existing between the immediate protection afforded by L-arginine+SOD and the lack of protection observed at 24 and 48 hours. This finding suggests that a punctual intervention on the NO system at the time of I/R is not sufficient to reduce renal damage over the long term.
Our results show that myocardial ischemia/reperfusion stimulates production of NO by circulating neutrophils, an effect that was enhanced in the presence of aspirin. These results suggest a novel interpretation of the protective effect of aspirin on myocardial ischemia damage.
The present study addressed the acute effects of endothelin-1 on renal function and neutrophils accumulation in the setting of in vivo severe (60 min) acute ischemia/reperfusion. Ischemia/reperfusion decreased renal functional parameters and increased renal neutrophil accumulation and medullary congestion. All these parameters markedly improved with the intrarenal administration of anti-endothelin-1 antiserum. Comparatively, the intrarenal infusion of endothelin-1 decreased renal function and increased neutrophil accumulation. Abnormalities in renal histology were, however, less pronounced than with ischemia/ reperfusion. In experiments using rabbit isolated perfused kidneys, endothelin-1 induced the accumulation of labeled neutrophils. This accumulation was similar to that observed in kidneys obtained after 60 minutes of ischemia plus 60 minutes of reperfusion. Both endothelin and ischemia/ reperfusion effects were counteracted by an anti-endothelin antibody. In further in vitro studies, we found that endothelin-1-induced the expression of the CD18 antigens on the neutrophil surface. In subsequent experiments based on this effect of ET-1 on CD18 antigens, a blockade of both ischemia/reperfusion-induced and endothelin-1-induced neutrophil accumulation was obtained by infusion an anti-CD18 antibody. In conclusion, our experiments disclosed the critical role of endothelin-1 as a major promoter of early neutrophil accumulation after ischemia/reperfusion, which occurred through an integrin-mediated mechanism.
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