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The effects of the chronic inhibition of nitric oxide (NO) on renal hemodynamics and tubular function were studied in rats treated for 8 weeks with the NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day). In addition, the effect of L-NAME administration on vasoactive systems (renin-angiotensin system, aldosterone, catecholamines, endothelin, and thromboxane A(2)) was evaluated. Chronic inhibition of NO significantly elevated blood pressure, reduced glomerular filtration rate and renal blood flow, blunted the pressure-diuresis-natriuresis response, and increased protein urine excretion. All these changes were associated with blunted nitrite production in response to acetylcholine in glomeruli. No changes were observed in the plasma levels of either renin activity, aldosterone, or endothelin in L-NAME-treated rats. Similarly, no differences were observed in the urinary excretion of thromboxane B(2) between both group of animals. By contrast, plasma concentrations of both epinephrine and norepinephrine were elevated in rats treated with L-NAME. In summary, the results show that chronic blockade of NO produced not only alterations in renal function, but also renal damage, suggesting an important renoprotective role of NO. An activation of sympathoadrenal system could participate in these renal alterations.

Objectives: To evaluate the relative participation of endothelium-derived factors mediating relaxation in response to acetylcholine in isolated mesenteric vascular beds from rats treated chronically with N(G)-nitro-L-arginine methylester (L-NAME); and to compare the consequences of prolonged treatment with either an angiotensin converting enzyme inhibitor or a calcium channel blocker on the components of acetylcholine-induced relaxation in this vascular preparation., Materials and Methods: Male Sprague- Dawley rats were treated for 8 weeks with L-NAME (40 mg/kg per day), quinapril (10 mg/kg per day), diltiazem (100 mg/kg per day), L-NAME + quinapril and L-NAME + diltiazem. Systolic blood pressure was estimated by a tail-cuff plethysmograph. Relaxing responses to acetylcholine (10(-12) to 10(-8) mol) in mesenteric vascular beds precontracted with phenylephrine (10(-5) mol/l) were studied in the presence and absence of L-NAME (10(-5) mol/l), L-NAME + indomethacin (10(-5) mol/l) or L-NAME + indomethacin + potassium chloride (6 x 10(-5) mol/l). The area under the dose- response curve was used to calculate the approximate participation of nitric oxide, prostaglandins or endothelium-derived hyperpolarizing factor in the acetylcholine-induced relaxation., Results: Chronic administration of L-NAME increased blood pressure levels and vascular responsiveness to phenylephrine. Treatments with either quinapril or diltiazem reduced blood pressure levels and attenuated the increased response to phenylephrine. Relaxing responses to acetylcholine were similar in all groups, independently of the treatment received. The calculated participation of endothelium-derived hyperpolarizing factor in the acetylcholine-induced relaxation was higher than that of nitric oxide and prostaglandins in all groups, but was higher in L-NAME-treated than in untreated rats. In contrast, the participation of both nitric oxide and prostaglandins was higher in control than in L-NAME-treated rats. Quinapril increased the participation of prostaglandins in L-NAME-treated rats. Diltiazem increased the participation of nitric oxide in L-NAME-treated rats., Conclusions: The administration of L-NAME in Sprague-Dawley rats increased the production of endothelium-derived hyperpolarizing factor as a compensatory mechanism to maintain acetylcholine-induced relaxation. Antihypertensive therapy with either quinapril or diltiazem produced a selective redistribution of the endothelial factors mediating acetylcholine-induced relaxation.

Objective: Our study was designed to investigate whether angiotensin II subtype 1 (AT1) receptors are involved in the constrictor responses evoked by endothelin-1 and the thromboxane A2 analogue U46619 in aortic rings from spontaneously hypertensive rats (SHR), by studying the effect of the AT1 receptor antagonist losartan. In addition, since nitric oxide seems to participate in the mechanism of action of losartan, we studied the effect of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), on the action of losartan., Materials and Methods: Dose-response curves of either endothelin-1 (10(-10) to 10(-7) mol/l) or U46619 (10(-10) to 10(-6) mol/l) were studied in the presence or absence of losartan (10(-5) mol/l) in aortic rings from SHR. Likewise, similar experiments were done in aortic rings pretreated with the nitric oxide synthesis inhibitor, L-NAME (10(-4) mol/l)., Results: Pre-incubation with losartan significantly reduced the contractile response to endothelin-1 compared with control rings, without modifying the value represented by 50% of the maximal response (pD2). The concentration-response curve to U46619 was shifted to the right in the presence of losartan, reducing the pD2 compared with control rings. The presence of captopril (10(-5) mol/l) in the incubation media did not alter the response to either endothelin-1 or U46619. The diminished response to both endothelin-1 and U46619 in the presence of losartan was reversed in L-NAME-pretreated rings., Conclusions: Angiotensin II seems to participate in the vasoconstriction induced by both endothelin-1 and the thromboxane A2 analogue through the stimulation of AT1 receptors in SHR aortic rings, because losartan inhibited this effect. Moreover, nitric oxide appears to be involved in this action of losartan.

The acute vasodepressor effect of AT1 angiotensin receptor blockers losartan and CL329167 was compared in spontaneously hypertensive rats (SHR) pretreated and not pretreated with NG-monomethyl-L-arginine (LNMMA; 15 mg/kg i.v. bolus plus infusion at 10 mg/kg/h), an inhibitor of nitric oxide (NO) synthesis. The antihypertensive effect of losartan (30 mg/kg, i.v.) in SHR pretreated with LNMMA (-13 +/- 4 mmHg) was greatly diminished (P < 0.01) relative to the antihypertensive effect of losartan in SHR not pretreated with LNMMA (-44 +/- 8 mmHg). Similarly, the antihypertensive effect of CL329167 (5 mg/kg, i.v.) in SHR pretreated with LNMMA (-12 +/- 3 mmHg) was surpassed (P < 0.01) by the antihypertensive effect in SHR not pretreated with LNMMA. (-41 +/- 4 mmHg). However, pretreatment of SHR with LNMMA did not minimize the vasodepressor effect of prazosin, isoproterenol or sodium nitroprusside. The impairment in vasodepressor responsiveness to losartan in rats pretreated with LNMMA was not demonstrable in rats concurrently receiving sodium nitroprusside to correct for the loss of endogenous NO, or atrial natriuretic peptide which also increases vascular cGMP. These data suggest that a mechanism mediated by NO and/or cGMP is necessary for the full expression of the acute antihypertensive effect of AT1 angiotensin receptor blockers in SHR.

The acute administration of nitric oxide (NO) synthesis inhibitors reduces the renal capacity to excrete sodium under normal or volume expanded conditions and increases renovascular resistances in the absence of changes in systemic blood pressure (BP). This indicates a sensitivity of renal vasculature higher than that of systemic vessels to NO synthesis inhibition. Medullary circulation is the renovascular territory most dependent on NO availability. Thus, alterations in medullary blood flow seems to account for the blunted pressure-natriuresis and sodium retention during acute NO synthesis inhibition. By contrast, during chronic administration of L-arginine analogs, systemic BP rises and overrides initial sodium retention by a resetting of the pressure-natriuresis relationship. This BP increase appears to be dependent on an overexpression of the actions of vasoconstrictor systems due to an imbalance created by the diminished NO production. Prolonged NO synthesis inhibition not only elevates BP, but also produces renal vascular and parenchymal damage. Antihypertensive therapy impedes BP elevation and ameliorates kidney deterioration. Finally, there is evidence of the possibility that a certain alteration in the L-arginine-NO pathway exists in genetic models and in human essential hypertension. In conclusion, according to the data contained in the literature, NO plays a significant role in the regulation of systemic and renal hemodynamics and excretory function, and could participate in the development of hypertension.

Nitric oxide seems to be involved in the mechanisms underlying the antihypertensive and renal responses of losartan in spontaneously hypertensive rats (SHR). We investigated the contribution of nitric oxide to the effect of this angiotensin II (Ang II) type 1 (AT1) receptor antagonist on the constrictor response of phenylephrine in aortic rings from SHR. Furthermore, since it has been suggested that Ang II could bind to unblocked AT2 receptors, during administration of an AT1 receptor antagonist, we also studied the effect of the AT2 receptor antagonist PD 123319 on the contractile response to phenylephrine in aortic rings from SHR. To this end, we studied dose-response curves of phenylephrine (10(-9) to 10(-5) mol/L) in the presence and absence of losartan (10(-9), 10(-7), and 10(-5) mol/L) in SHR aortic rings. Preincubation with losartan reduced the constrictor response to phenylephrine but not to KCl (10 to 120 mmol/L) in a dose-dependent manner. On the other hand, the presence of captopril (10(-5) mol/L) in the incubation medium did not alter the response to phenylephrine, even at the dose of 10(-3) mol/L. The reduced response to phenylephrine in the presence of losartan was abolished in both endothelium-denuded rings and rings treated with a nitric oxide synthesis inhibitor. A similar situation was observed in PD 123319-pretreated rings, in which the effect of losartan on the contractile response to phenylephrine was reversed. Losartan was not able to stimulate the production of aortic cGMP compared with the control group. Likewise, losartan did not modify the relaxing responses to either acetylcholine or sodium nitroprusside in phenylephrine-preconstricted aortic rings. Furthermore, losartan did not alter isometric tension in aortic rings in either basal or phenylephrine-preconstricted conditions. These data demonstrate that Ang II potentiates the vasoconstriction induced by phenylephrine through the stimulation of AT1 receptors. Moreover, AT2 receptors and nitric oxide appear to be involved in this effect.

Angiotensin II (A II), the active component of the renin-angiotensin system, plays a major role in the regulation of blood pressure and renal function. A II actions are mediated by the interaction of this peptide with specific receptors that have been classified into two major types. AT1 and AT2. AT1 receptors have been associated with all of the known cardiovascular and renal effects of A II. Losartan, the first nonpeptide A II-receptor antagonist, exerts its antihypertensive action through the inhibition of A II binding to AT1 receptors. However, additional mechanisms seem to be involved in the actions of losartan in the rat. Administration of the nitric oxide (NO)-synthase inhibitor, NG-nitro-L-arginine methyl ester (LNAME), prevented the hypotensive effect induced by losartan in spontaneously hypertensive rats (SHR). Similarly, pretreatment with LNAME reduced the increases in renal plasma flow and glomerular filtration rate produced by this AT1-receptor antagonist in SHR. Furthermore, concurrent administration of the prostaglandin (PG)-synthesis inhibitor indomethacin attenuated vasodepressor, diuretic, and natriuretic effects of losartan in SHR. Finally, it should be mentioned that losartan was able to reduce the "ex vivo" vasoconstriction induced by phenylephrine in aortic rings from SHR. This effect was not observed in endothelium-denuded rings, suggesting a mediatory role of an endothelium-derived factor in this effect of losartan. Consequently, these data suggest a contributory role of NO and PGs in the vasodepressor and renal actions of AT1-receptor antagonists in SHR.

We investigated the contribution of nitric oxide to the short-term blood pressure reduction caused by interruption of the renin-angiotensin system in angiotensin-dependent hypertension. The blood pressure of rats made hypertensive by coarctation of the aorta between the renal arteries at their origin fell after administration of the angiotensin-converting enzyme inhibitor ramiprilat (2 mg/kg IV; -75 +/- 5 mm Hg) or the angiotensin II antagonist losartan (30 mg/kg IV; -79 +/- 6 mm Hg). But the antihypertensive effect of these agents was attenuated in rats pretreated with NG-nitro-L-arginine methyl ester (10 mg/kg IV) to inhibit nitric oxide synthesis (ramiprilat, -23 +/- 7 mm Hg; losartan, -37 +/- 5 mm Hg). In rats made hypertensive by long-term infusion of angiotensin II (60 ng/min IV, 6 to 7 days), the vasodepressor response to discontinuation of the angiotensin II infusion also was attenuated by pretreatment with the nitric oxide synthesis inhibitor (-52 +/- 7 versus -31 +/- 7 mm Hg); this attenuation was not demonstrable in rats receiving sodium nitroprusside (1 microgram.kg-1.min-1 IV) to replace the loss of endogenous nitric oxide (-72 +/- 9 mm Hg). Pretreatment with NG-nitro-L-arginine methyl ester did not interfere with the vasodepressor effect of sodium nitroprusside or prazosin in rats with aortic coarctation-induced hypertension or with the blood pressure reduction caused by discontinuation of an infusion of phenylephrine in rats made hypertensive by long-term administration of this drug. These data suggest a contribution of nitric oxide to the blood pressure reduction caused by interruption of the renin-angiotensin system in models of established angiotensin-dependent hypertension.

Aim: The effects of losartan on blood pressure and on renal function have mainly been attributed to AT1 receptor blockade. Experimental evidence suggests that these effects could also be related to the actions of angiotensin II through AT2 receptors or to vasodilatory systems. The present study was therefore designed to investigate the manner in which the acute effects of losartan on renal excretory function are affected during simultaneous administration of an AT2 receptor antagonist, a kinin B2 receptor antagonist, a cyclo-oxygenase inhibitor or a nitric oxide synthesis inhibitor., Materials and Methods: The AT2 receptor antagonist PD 123319 (10 mg/kg), the bradykinin B2 receptor antagonist Hoe 140 (30 mu g/kg), the cyclo-oxygenase inhibitor meclofenamate (5 mg/kg) and the nitric oxide synthesis inhibitor NG-monomethyl-L-arginine (1 mu g/kg per min) were administered separately with acute intravenous losartan (1 mg/kg) to spontaneously hypertensive rats and the effects on mean arterial pressure and renal excretory function were assessed., Results: Losartan reduced mean arterial pressure by 11.1 +/- 5.7 mmHg and increased the glomerular filtration rate, urine flow and sodium excretion rate. The decrease in mean arterial pressure was blocked in the presence of NG-monomethyl-L-arginine but not during concurrent administration of PD 123319, Hoe 140 or meclofenamate. The increase in glomerular filtration rate induced by losartan was blunted by Hoe 140, meclofenamate and NG-monomethyl-L-arginine. Co-administration of PD 123319, Hoe 140 or meclofenamate, but not of NG-monomethyl-L-arginine, partially blunted the diuresis and natriuresis induced by losartan., Conclusions: Nitric oxide participates in the antihypertensive action of losartan. Kinins, prostaglandins and nitric oxide appear to be involved in the effects of losartan on the glomerular filtration rate. The increases in urine flow and sodium excretion rate induced by losartan depend partially on AT2 receptors, kinins and prostaglandins.

We investigated the role of endogenous nitric oxide, kinins, and prostaglandins in the vasodepressor and renal excretory effects of the angiotensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor ramipril administered for 1 week to spontaneously hypertensive rats. To this end, either losartan (10 mg/kg per day) or ramipril (2.5 mg/kg per day) was administered in drinking water with or without simultaneous administration of (1) the nitric oxide synthesis inhibitor Ng-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg per day), (2) the cyclooxygenase inhibitor indomethacin (5 mg/kg per day), (3) the bradykinin B2 receptor antagonist Hoe 140 (0.5 mg/kg per day SC), or (4) L-NAME plus indomethacin. Both losartan and ramipril significantly reduced blood pressure as measured by the tail-cuff method. L-NAME increased blood pressure when administered solely or in combination with losartan. However, L-NAME attenuated the hypotensive effect of ramipril. Indomethacin did not affect blood pressure but it reduced the antihypertensive action of losartan and ramipril. Indomethacin administration did not potentiate the increase in blood pressure induced by L-NAME. However, the concurrent administration of both inhibitors almost totally blunted the vasodepressor action of ramipril. By contrast, losartan administration in the presence of L-NAME and indomethacin increased blood pressure to a level similar to that after losartan plus L-NAME. Hoe 140 did not modify either blood pressure or the hypotensive effects of losartan or ramipril. Increases in diuresis and water intake were observed during ramipril administration. Both effects were blunted only with the concurrent administration of L-NAME and indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the role of kinins in the acute depressor effect of captopril and ramiprilat in spontaneously hypertensive rats. Since the vasodepressor action of kinins may be linked to the generation of prostaglandins and endothelium-derived relaxing factors, we also investigated the role of prostaglandins and nitric oxide in the blood pressure reduction caused by angiotensin converting enzyme inhibitors. To this end, we contrasted the hypotensive effects of captopril (10 mg/kg i.v.), ramiprilat (2 mg/kg i.v.), and the angiotensin II antagonist DuP 753 (30 mg/kg i.v.) in spontaneously hypertensive rats with and without pretreatment with a kinin antagonist (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg-trifluoroacetic acid) (200 micrograms/kg/min i.v.), an inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine) (15 mg/kg + 10 mg/kg/hr i.v.), or an inhibitor of prostaglandin synthesis (indomethacin) (10 mg/kg i.v.). The kinin antagonist did not affect blood pressure in spontaneously hypertensive rats but did attenuate the hypotensive effect of captopril and ramiprilat; the kinin antagonist did not minimize the depressor action of DuP 753. The nitric oxide synthesis inhibitor increased blood pressure in spontaneously hypertensive rats and attenuated the hypotensive effect of captopril, ramiprilat, and DuP 753, but it did not impede the hypotensive effect of sodium nitroprusside. Pretreatment of hypertensive rats with indomethacin did not modify the acute hypotensive effect of ramiprilat or captopril. These data suggest a contribution of endogenous kinins and nitric oxide to the acute antihypertensive effect of captopril and ramiprilat in spontaneously hypertensive rats and of nitric oxide to the hypotensive effect of DuP 753.

Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 µg/kg, subsequent dose 0.07 µg kg-1·day-1 im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 ± 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 µM). Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with L-NAME, the L-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2- production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease. [ABSTRACT FROM AUTHOR]