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Cyclooxygenase-2 (COX-2) has been identified in renal tissues under normal conditions, with its expression enhanced during sodium restriction. To evaluate the role of COX-2-derived metabolites in the regulation of renal function, we infused a selective inhibitor (nimesulide) in anesthetized dogs with normal or low sodium intake. The renal effects elicited by nimesulide and a non-isozyme-specific inhibitor (meclofenamate) were compared during normal sodium intake. In ex vivo assays, meclofenamate, but not nimesulide, prevented the platelet aggregation elicited by arachidonic acid. During normal sodium intake, nimesulide infusion (n=6) had no effects on arterial pressure or renal hemodynamics but did reduce urinary sodium excretion, urine flow rate, and fractional lithium excretion. In contrast, nimesulide administration increased arterial pressure and decreased renal blood flow, urine flow rate, and fractional lithium excretion during low sodium intake (n=6). COX-2 inhibition reduced urinary prostaglandin E(2) excretion in both groups but did not modify plasma renin activity in dogs with low (8.1+/-1.1 ng angiotensin I. mL(-1). h(-1)) or normal (1.8+/-0.4 ng angiotensin I. mL(-1). h(-1)) sodium intake. Meclofenamate infusion in dogs with normal sodium intake (n=8) induced a greater renal hemodynamic effect than nimesulide infusion. These results suggest that COX-2-derived metabolites (1) are involved in the regulation of sodium excretion in dogs with normal sodium intake, (2) play an important role in the regulation of renal hemodynamic and excretory function in dogs with low sodium intake, and (3) are not involved in the maintenance of the high renin levels during a long-term decrease in sodium intake.

Abstract-The effects of dynamic exercise on restenosis after vascular injury are still unknown. The consequences of balloon dilation-induced injury on neointimal hyperplasia, vascular negative remodeling, and reendothelialization were assessed in sedentary and trained rats. Ex vivo eNOS vascular expression and activity were investigated in carotid arteries isolated from sedentary and exercised rats. The in vivo effects of eNOS inhibition by L-NMMA on vessel wall after balloon dilation were evaluated in sedentary and exercised rats. We also investigated the effects of exercise on neointimal formation in a rat stent model of vascular injury. Compared with sedentary group, the arteries isolated from trained rats showed higher levels of eNOS protein expression and activity 7 days after balloon dilation. A significant reduction of both neointimal hyperplasia and negative remodeling was observed 14 days after balloon injury in trained compared with sedentary rats. Moreover, we demonstrated that exercise training produced accelerated reendothelialization of the balloon injured arterial segments compared with sedentary. L-NMMA administration eliminated the benefits of physical training on vessel wall after balloon dilation. Finally, a decrease of neointimal hyperplasia as well as of platelet aggregation was observed after stent deployment in trained rats compared with sedentary. In conclusion, physical exercise could favorably affect restenosis after balloon angioplasty and stenting. Increase in eNOS expression and activity might contribute to the potential beneficial effects of exercise on the vessel wall after vascular injury. Key Words: exercise Ⅲ restenosis Ⅲ balloon angioplasty Ⅲ stent Ⅲ nitric oxide synthase R estenosis is still an unresolved issue of percutaneous coronary interventions (PCI), 1 although rapamycineeluting stents recently show considerable promise for restenosis prevention. 2 Restenosis after balloon angioplasty is primarily due to negative vascular remodeling and only partially to vascular smooth muscle cell (VSMC) proliferation. 3 On the other hand, whereas stent deployment abolished inward vascular remodeling, in-stent restenosis (ISR) is determined by VSMC proliferation generating neointimal formation. 3 The molecular pathways underlying VSMC migration and proliferation after balloon angioplasty and stenting are well known. [3][4][5][6] However, the reasons for negative remodeling after balloon angioplasty are still unclear.Endothelial damage after PCI has been associated with vascular remodeling. In fact, after balloon angioplasty and stent deployment, the vessel is almost totally endotheliumdenuded. 7,8 NO, synthesized by endothelial nitric oxide synthase (eNOS), is a key molecule preventing the detrimental consequences of arterial injury on the vascular wall 9,10 ; indeed, NO inhibits VSMC migration and proliferation, platelet adhesion to the vessel wall, and stimulates endothelial cell migration and reorganization. 9,10 All these actions lead to the inhibition of both vascular negative remo...

We studied the effects of the heme oxygenase (HO) inhibitor stannous mesoporphyrin (SnMP; 40 micromol/kg i.v.) on renal hemodynamics in anesthetized rats with and without 48-h pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis. SnMP decreased renal blood flow (RBF) and increased renal vascular resistance (RVR) in both groups. The SnMP-induced reduction of RBF in L-NAME-pretreated rats was more prominent than in rats without pretreatment (43 +/- 7 vs. 13 +/- 3%) as was the SnMP-induced elevation of RVR (87 +/- 31 vs. 14 +/- 5%). The renal vasoconstrictor effect of SnMP is linked, in part, to amplification of prevailing neurohormonal constrictor mechanisms, since in L-NAME-pretreated rats it was prevented by concurrent administration of prazosin or losartan. However, SnMP (15 micromol/l) also elicits vasoconstriction in isolated, pressurized renal interlobular arteries and the response is more intense in vessels obtained from L-NAME-pretreated rats than from rats without pretreatment. These data indicate that the status of NO synthesis conditions the vascular response to HO inhibition in the rat kidney.

Although the lesions, clinical signs and biochemical alterations observed in the course of canine leishmaniasis have been amply described a thorough definition and characterisation of the affected populations is important in order to detect relationships between parameters which may be involved in the development of this disease and to correctly assess further studies. This study included 61 dogs diagnosed with naturally acquired canine leishmaniasis by means of indirect immunofluorescence assay (IFA). At diagnosis, dogs were classified according to the following qualitative and quantitative variables: gender, breed, age, clinical picture, antibody titre, serum protein electrophoretogram, haemogram (CBC), urea, creatinine and ALT. Our population included dogs of 24 breeds, both sexes and different ages indicating no sex, age or breed predilection. In relation to the clinical picture, eight dogs were asymptomatic, 16 displayed mainly cutaneous signs, 18 presented primarily visceral signs and 19 displayed both cutaneous and visceral signs. Our results indicate that the clinical picture is significantly related to electrophoretogram and to RBC, PCV and haemoglobin. Dogs with mainly cutaneous signs showed the highest eosinophil mean values and those with mainly visceral signs showed the highest alpha-globulin mean values. This study confirms that the antibody titre is highly correlated with electrophoretogram and with RBC, PCV and haemoglobin. Lymphocytes were not associated or correlated with any other variable considered. PMNC, monocytes and eosinophils, as well as WBC, showed a significant correlation with beta-globulins, which is difficult to interpret.

The present study evaluated the effects of heme oxygenase-1 (HO-1) induction on the changes in renal outer medullary nitric oxide (NO) and peroxynitrite levels during 45-min renal ischemia and 30-min reperfusion in anesthetized rats. Glomerular filtration rate (GFR), outer medullary blood flow (OMBF), HO and nitric oxide synthase (NOS) isoform expression, and renal low-molecular-weight thiols (-SH) were also determined. During ischemia significant increases in NO levels and peroxynitrite signal were observed (from 832.1 +/- 129.3 to 2,928.6 +/- 502.0 nM and from 3.8 +/- 0.7 to 9.0 +/- 1.6 nA before and during ischemia, respectively) that dropped to preischemic levels during reperfusion. OMBF and -SH significantly decreased after 30 min of reperfusion. Twenty-four hours later, an acute renal failure was observed (GFR 923.0 +/- 66.0 and 253.6 +/- 55.3 microl.min(-1).g kidney wt(-1) in sham-operated and ischemic kidneys, respectively; P < 0.05). The induction of HO-1 (CoCl(2) 60 mg/kg sc, 24 h before ischemia) decreased basal NO concentration (99.7 +/- 41.0 nM), although endothelial and neuronal NOS expression were slightly increased. CoCl(2) administration also blunted the ischemic increase in NO and peroxynitrite (maximum values of 1,315.6 +/- 445.6 nM and 6.3 +/- 0.5 nA, respectively; P < 0.05), preserving postischemic OMBF and GFR (686.4 +/- 45.2 microl.min(-1).g kidney wt(-1)). These beneficial effects of CoCl(2) on ischemic acute renal failure seem to be due to HO-1 induction, because they were abolished by stannous mesoporphyrin, a HO inhibitor. In conclusion, HO-1 induction has a protective effect on ischemic renal failure that seems to be partially mediated by decreasing the excessive production of NO with the subsequent reduction in peroxynitrite formation observed during ischemia.

Abstract-We tested the hypothesis that the status of NO synthesis influences the renal heme-heme oxygenase system.Studies were conducted in untreated rats and rats treated with the NO synthesis inhibitor N G -nitro-L-arginine methyl ester for 2 days. Treated and untreated rats were contrasted in terms of renal expression of heme oxygenase-1 and -2, renal carbon monoxide (CO)-generating activity, and urinary CO concentration and excretion rate. Heme oxygenase-1 and -2 proteins were similarly expressed in the kidneys of untreated and treated rats. In contrast, the NADPH-dependent component of the CO-generating activity of renal homogenates incubated with heme (a measure of heme oxygenase activity) was higher (PϽ0.05) in kidneys from rats treated with the NO synthesis inhibitor relative to corresponding data in untreated rats (1015Ϯ95 versus 379Ϯ111 pmol CO/mg per hour). Similarly, relative to corresponding data in untreated rats, rats treated with the NO synthesis inhibitor displayed increased (PϽ0.05) urinary CO concentration (920Ϯ174 versus 2286Ϯ472 pmol/mL) and urinary CO excretion (4.7Ϯ0.4 versus 14.3Ϯ2.7 pmol/min). This study demonstrates that NO synthesis inhibition upregulates the urinary concentration and excretion rate of CO, and the HO-dependent generation of CO by renal homogenates, without affecting the expression of renal heme oxygenase isoforms. Our findings imply that endogenous NO is an inhibitory regulator of renal CO generation by HO. Key Words: kidney Ⅲ carbon monoxide Ⅲ nitric oxide Ⅲ heme oxygenase C arbon monoxide (CO), a product of heme metabolism by heme oxygenase isoforms (HO)-1 and -2, 1 has been linked to the regulation of arterial tone and/or reactivity. 2,3 Nitric oxide (NO), a product of L-arginine metabolism by NO synthase isoforms (NOS), is a major contributor to mechanisms of vasodilation in several vascular beds. 4 The heme-HO and the L-arginine-NOS pathways interact at multiple sites and influence each other's level of activity and function. 1,[5][6][7] On one hand, ex vivo studies indicate that CO inhibits NOS activity and attenuates the expression of vasodilatory mechanisms mediated by NO. 8 On the other hand, NO decreases the catalytic activity of HO, 9,10 promotes HO-1 protein expression 6,7,11 and cellular uptake of heme, 6 and interferes with the ability of CO to stimulate large conductance Ca ϩϩ -activated K ϩ channels in vascular smooth muscle cells 12 and produce vasodilation. 5,13 It is difficult to predict the impact of variations in NO synthesis on the activity of the heme-HO system, because NO downregulates the activity of constitutively-expressed HO-2 while upregulating HO-1 protein expression. 6,7,10,11 Information on this point is relevant to the notion that the status of NO synthesis conditions the vasomotor response to HO inhibition in gracilis muscle arterioles and renal interlobular arteries ex vivo, and in the rat kidney and hind limb in vivo. 5,14 For example, after NOS inhibition, an increase in HO product generation may help condition the associated intens...

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