Elena Rodrigo

Endothelial dysfunction in spontaneously hypertensive rats: consequences of chronic treatment with losartan or captopril.

Background Hypertension is associated with endothelial dysfunction characterized by decreased endothelium-dependent relaxations and increased endothelium-dependent contractions. Angiotensin converting enzyme inhibitors and thromboxane A2 receptor antagonists decreased the endothelium dysfunction in hypertensive animals. Objective To investigate the effects of prolonged treatment with losartan on endothelium-dependent and -independent relaxations and contractions in aortic rings from spontaneously hypertensive rats (SHR). Materials and methods Male SHR aged 16 weeks were treated for 12 consecutive weeks either with 10 mg/kg losartan per day or with 60 mg/kg captopril per day administered via their drinking water. The systolic blood pressure was evaluated basally and during week 12. At the end of the treatment period, the vascular reactivity in aortic rings was studied. A group of rats treated with captopril was studied as a reference group. Results Losartan and captopril reduced the blood pressure significantly and comparably. Both drugs enhanced acetylcholine-induced relaxations and reduced the maximal contractile response to acetylcholine in the presence of NG-nitro-L arginine methyl ester (L-NAME). Contractile responses to phenylephrine, endothelin-I and U46619 were not affected by these treatments. Increased relaxing responses to superoxide dismutase were observed only in captopril-treated rats. Losartan reduced the contractile response to angiotensin II. By contrast, this contractile response was elevated in rats treated with captopril. Conclusions Prolonged antihypertensive treatments with losartan and captopril decreased the endothelial dysfunction in aortic rings from SHR not only by enhancing NO-dependent relaxations but also by reducing the contractions in response to an endothelium-derived contracting factor. The results further confirm that an endothelium-derived contracting factor plays a role in vascular dysfunction in SHR and the relationships between this factor and angiotensin II.

Nitric Oxide and Prostaglandins in the Prolonged Effects of Losartan and Ramipril in Hypertension

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)

Renal and Vascular Consequences of the Chronic Nitric Oxide Synthase Inhibition Effects of Antihypertensive Drugs

The effects of the administration of either the angiotensin converting enzyme (ACE) inhibitor, quinapril (10 mg/kg/day, orally), or the calcium antagonist, diltiazem (100 mg/kg/day, orally), on blood pressure (BP), renal function, and vascular reactivity in isolated perfused mesenteric beds were studied in rats treated for 8 weeks with the nitric oxide (NO) synthesis inhibitor, NG-nitro-L-arginine methyl ester (LNAME, 40 mg/kg/day). The oral administration of LNAME significantly increased systolic BP values, which reached the levels of 186 +/- 7 mm Hg at week 8. Both quinapril and diltiazem reduced this, although the ACE inhibitor was more effective than the calcium antagonist. The chronic inhibition of NO resulted in an increase in water excretion whether or not the increase in systolic BP was prevented by the coadministration of either quinapril or diltiazem. At the end of the experiment, LNAME-treated rats presented higher proteinuria than control rats (140 +/- 4 mg/24 hours v 21 +/- 1 mg/24 hours, P < .05). This elevated protein excretion was normalized by both antihypertensive drugs. None of the treatments was able to modify either natriuresis or plasma creatinine levels. Endothelium-dependent relaxations to acetylcholine (10(-12) to 10(-8) mol/L) were comparable in all groups. However, the vasoconstriction induced by either the continuous infusion of phenylephrine (10(-5) mol/L) or by a bolus of angiotensin II (1 nmol) was higher in the animals that received LNAME than in control ones. The antihypertensive therapy normalized the response to phenylephrine but not to angiotensin II. These data suggest that both quinapril and diltiazem are not only able to reduce BP elevation induced by the chronic administration of LNAME in rats, but also to prevent the renal damage and the hyperresponsiveness to phenylephrine induced by this NO synthesis inhibitor.

Losartan reduces constrictor responses to endothelin-1 and the thromboxane A2 analogue in aortic rings from spontaneously hypertensive rats: role of nitric oxide.

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.

Acute renal excretory actions of losartan in spontaneously hypertensive rats : role of AT2 receptors, prostaglandins, kinins and nitric oxide

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 μg/kg), the cyclo-oxygenase inhibitor meclofenamate (5 mg/kg) and the nitric oxide synthesis inhibitor NG-monomethyl-L-arginine (1 μg/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.

Effects of antihypertensive therapy on factors mediating endothelium-dependent relaxation in rats treated chronically with L-NAME.

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.

Chronic treatment with losartan ameliorates vascular dysfunction induced by aging in spontaneously hypertensive rats.

Objective To evaluate the effects of prolonged treatment with losartan on endothelium-dependent and endothelium-independent relaxations of aortic rings from adult and senescent spontaneously hypertensive rats, and to clarify whether these effects were due to specific mechanisms of the drug or a consequence of its blood-pressure-lowering action. Materials and methods Adult (aged 5 months) and senescent (aged 20 months) male spontaneously hypertensive rats were treated for 12 consecutive weeks with 10 mg/kg per day losartan. Systolic blood pressure and plasma concentration of nitrates were evaluated. We studied endothelium-dependent and endothelium-independent relaxations and response to angiotensin II of aortic rings from rats of each group. The direct effects of angiotensin II type 1 receptor antagonism on vascular reactivity of aortic rings from untreated adult and senescent rats that had been incubated beforehand with losartan were also studied. Results Losartan treatment comparably reduced blood pressure and increased plasma concentration of nitrates in rats of both age groups. Responses to acetylcholine and sodium nitroprusside were lower for rings from senescent than they were for rings from adult rats. Constrictor responses to angiotensin II were higher for rings from senescent than they were for rings from adult rats. Treatment with losartan increased the magnitude of relaxations in response to acetylcholine for rings from rats in both groups, but increased the magnitude of relaxations in response to nitroprusside only for rings from senescent spontaneously hypertensive rats. Incubation beforehand of aortic rings from untreated rats with losartan enhanced magnitude of relaxations in response both to acetylcholine and to nitroprusside only for rings from senescent spontaneously hypertensive rats. Conclusions The consequences of aging for endothelium-dependent and endothelium-independent relaxations of rings from spontaneously hypertensive rats are ameliorated by losartan treatment, suggesting that angiotensin II plays a role via type 1 receptors. The effects of losartan on senescent spontaneously hypertensive rats were due not only to its blood-pressure-lowering action but also to the blockade of specific mechanisms derived from angiotensin II type 1 receptor antagonism, which might involve an increase in availability of NO. J Hypertens 16:665–672

Differential effects of losartan and doxazosin on vascular function in senescent spontaneously hypertensive rats.

We evaluated the effects of treatment for 12 weeks with 10 mg/kg/day of either losartan or doxazosin on vascular function in senescent spontaneous hypertensive rats (SHR). Both doxazosin and losartan reduced blood pressure, although the former was more effective. In contrast, both drugs reduced relative aortic weight and increased plasma nitrates to a similar extent. Losartan, but not doxazosin, increased the magnitude of the response to acetylcholine (10(-9) to 10(-5) mol/L). Both treatments increased relaxations to sodium nitroprusside (10(-10) to 10(-6) mol/L). These data show that losartan may possess advantages over doxazosin in improving vascular function in senescent SHR. This report emphasizes the importance of angiotensin II in vascular function alterations induced by aging in SHR.