Efectividad y tolerabilidad de lercanidipino en los pacientes hipertensos de alto riesgo. Datos del estudio LAURA / Effectiveness and tolerability of lercanidipine in very high risk hypertensive patients. Data of the LAURA study

Objetivo. Analizar la efectividad y tolerabilidad de lercanidipino en los pacientes hipertensos de riesgo cardiovascular alto y muy alto en condiciones de práctica clínica habitual. Pacientes y métodos. El estudio LAURA fue un estudio multicéntrico, prospectivo, no comparativo y abierto que incluyó a pacientes con hipertensión arterial esencial leve-moderada. Los pacientes recibieron durante 6 meses lercanidipino 10 mg/ día o 20 mg/día en caso de ausencia de control de presión arterial (PA). Se consideró buen control de PA < 140/90 mmHg (< 130/80 mmHg en diabéticos). Resultados. Del total de 3.175 pacientes hipertensos incluidos en el estudio, 1.542 (66,3 ± 14 años; 48 % mujeres) pertenecían a los grupos de riesgo cardiovascular alto (n = 722) o muy alto (n = 820), según la estratificación de las guías europeas de hipertensión de 2003. En estos pacientes las PA basales fueron: PA sistólica (PAS), 162,1 ± 13,1 mmHg; PA diastólica (PAD), 96,0 ± 8,1 mmHg, y presión de pulso (PP) 66,0 ± 5,0 mmHg. Al final del estudio, se observó un descenso de 26 y 16,8 mmHg en PAS y PAD, y de 9,2 mmHg en PP. Estas reducciones de PAS, PAD y PP fueron significativamente mayores que las detectadas en el subgrupo de riesgo medio-bajo (23, 15,8 y 9,2 mmHg, respectivamente; en todas ellas p < 0,05 frente al subgrupo de riesgo alto-muy alto). Al terminar el seguimiento el 38,2 % de los pacientes de riesgo alto-muy alto estaba con lercanidipino 10 mg, el 23,4 % lercanidipino 20 mg, y el 38,4 % restante con más medicación antihipertensiva añadida. El 53 % de los pacientes alcanzó el objetivo de PA sólo con lercanidipino en monoterapia. La incidencia de efectos adversos en el grupo total de hipertensos fue 11,5 %, siendo más frecuente la presencia de edema maleolar (5,1 %). No hubo diferencias significativas en cuanto a la presencia de efectos secundarios según los diferentes subgrupos de riesgo. Sólo el 1,7 % de los pacientes suspendieron el tratamiento debido a los efectos adversos. Conclusiones. Lercanidipino es un fármaco antihipertensivo eficaz y bien tolerado en los pacientes hipertensos de alto riesgo en condiciones de práctica clínica

Objective. To determine the effectiveness and tolerability of lercanidipine in high and very high cardiovascular risk hypertensive patients in conditions of clinical practice. Patients and methods. The LAURA study was a multicenter, prospective, non-comparative, open-label study that included patients with treated or untreated mild-to-moderate essential hypertension. Patients received lercanidipine 10 mg/day or 20 mg/day, when blood pressure (BP) control was not achieved, during 6 months. BP control was defined as systolic BP (SBP) < 140 mmHg and diastolic BP (DBP) < 90 mmHg (< 130 and < 80 mmHg for diabetics). Results. Out of the 3,175 hypertensive patients included in the LAURA study, 1,542 (66.3 ± 14 years; 48 % women) belonged to the high (n = 722) or very high (n = 820) risk groups according to the European guidelines on hypertension 2003. In these patients, baseline BP values were: SBP, 162.1 ± 13.1 mmHg; DBP, 96.0 ± 8.1 mmHg, and pulse pressure (PP), 66.0 ± 5.0 mmHg. At the end of the study, decreases of 26 and 16.8 mmHg in SBP and DBP and of 9.2 mmHg in PP were observed. These reductions in SBP, DBP and PP were significantly bigger than those observed in medium-low risk subgroup (23, 15.8 and 9.2 mmHg, respectively; in all of them p < 0.05 vs high-very high risk subgroup). At the end of the follow-up, 38.2 % of high-very high risk patients were taking lercanidipine 10 mg, 23.4 % lercanidipine 20 mg, and the rest 38.4 % with add-on antihypertensive therapy. A total of 53 % of patients were controlled with only lercanidipine in monotherapy. The incidence of adverse events was 11.5 %, the most frequent being ankle edema (5.1 %). There were no significant differences in the incidence of adverse events according to the different risk subgroups. Only 1.7 % of the patients discontinued the medication due to adverse events. Conclusions. Lercanidipine is an effective and well-tolerated antihypertensive drug in high and very high cardiovascular risk hypertensive patients in conditions of clinical practice

Lercanidipine is an effective and well tolerated antihypertensive drug regardless the cardiovascular risk profile: The LAURA study.

To determine whether the antihypertensive effectiveness of lercanidipine was independent of the different cardiovascular risk levels. Patients with treated or untreated mild-to-moderate essential hypertension were included in a multicentre, prospective, non-comparative, open-label study. Patients received lercanidipine (10 mg/day, uptitrated to 20 mg/day) during 6 months. A total of 3175 patients, age 63 +/- 10 years, 51% women, were included. The cardiovascular risk was low in 237 patients, medium in 1396, high in 722, and very high in 820. At baseline, blood pressure (BP) was 159.5 +/- 11.7/95.2 +/- 7.4 mmHg. BP was progressively higher according to increase in cardiovascular risk. After 6 months of treatment, BP was 136.0 +/- 9.7/79.7 +/- 6.8 mmHg. The decrease in systolic BP and diastolic BP at each follow-up visit compared with baseline was statistically significant both in the intergroup and intragroup comparisons (p < 0.001). Mean decreases of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were -18.5/-13.8 mmHg in the low risk group, -23/-15.2 mmHg in the medium risk group, -24.4/-16.1 mmHg in the high risk group, and -27.4/-17.4 mmHg in the very high risk group. Most frequent side effects were oedema (5.1%), headache (3.3%), flushes (2.5%), and asthenia (1%). Only 1.7% of patients discontinued antihypertensive medication because of adverse events. Tolerability of lercanidipine was independent of the cardiovascular risk group. Lercanidipine was effective and well-tolerated in patients with mild-to-moderate hypertension in the daily practice. The effectiveness and safety of the drug were independent of the degree of cardiovascular risk.

Efectividad antihipertensiva y tolerabilidad de lercanidipino en diabéticos, en pacientes con hipertensión sistólica aislada y en ancianos. Análisis de subgrupos del estudio ELYPSE / Antihipertensive effectiveness and tolerability of lercanipidine in diabetics, isolated systolic hypertension patients and old men. ELYPSE study subgroup analysis

El estudio ELYPSE, recientemente publicado, es un estudio de farmacovigilancia que analizó la eficacia y tolerabilidad de lercanidipino (10 mg una vez al día) en 9.059 pacientes (61 ñ 11 años; 58 por ciento mujeres) con hipertensión grado 1 ó 2, durante 3 meses de seguimiento. Este estudio demostró que lercanidipino es un fármaco antihipertensivo eficaz y bien tolerado en la práctica clínica diaria, confirmando los datos observados previamente en ensayos clínicos. Ante los resultados del ELYPSE nos planteamos realizar un análisis de subgrupos especiales de pacientes, con el fin de determinar si los buenos resultados observados con el fármaco se demostraban también en poblaciones de alto riesgo. Analizamos tres subgrupos considerados de mayor riesgo cardiovascular: los diabéticos (n = 1.269), los pacientes con hipertensión sistólica aislada (HSA) (n = 1.024) y los ancianos (> 65 años) (n = 3.533). Comparamos la efectividad y tolerabilidad de lercanidipino en estos grupos con el resto de los pacientes del estudio (diabéticos frente a no diabéticos, HSA frente a no HSA y >65 años frente a <65). En el grupo de diabéticos, la presión arterial (PA) se redujo de 160,8 ñ 10,8/94,4 ñ 7,5 (basal) a 142,7ñ12/83ñ7,2 mmHg (final); la incidencia de efectos adversos fue 7,4 por ciento. En los pacientes con HSA, la PA descendió de 160,4ñ9,4/ 82,9ñ5,3 a 143,1ñ11,8/79 ñ 6,6 mmHg; la proporción de reacciones adversas fue 6,8 por ciento. En los ancianos la reducción de PA fue de 161,9 ñ 9,8/94,3 ñ 7,3 a 142,6 ñ 11,7/82,6 ñ 6,9; aparecieron reacciones adversas en el 7,2 por ciento. En los tres subgrupos se observó que los resultados en cuanto a efectividad y tolerabilidad del fármaco en estos pacientes son similares a los del resto de los hipertensos del estudio. En conclusión, se demuestra que lercanidipino es un antihipertensivo eficaz y bien tolerado en diabéticos, en pacientes con HSA y en ancianos. Por tanto, se puede considerar que este fármaco es una buena alternativa en el tratamiento de estos pacientes de alto riesgo en los que el control de PA es habitualmente difícil (AU)

Atorvastatin prevents glomerulosclerosis and renal endothelial dysfunction in hypercholesterolaemic rabbits.

BACKGROUND: Numerous studies have shown that elevated plasma cholesterol can exacerbate renal disease. However, the effect of lipids on renal structure and vascular function in normal kidneys is less well established. Therefore, the aim of this study was to evaluate the impact of hypercholesterolaemia on glomerular structure and vascular reactivity of segmental arteries in rabbits. In addition, we also studied whether or not atorvastatin can prevent these structural and vascular alterations in hypercholesterolaemic rabbits. METHODS: Male New Zealand rabbits were fed either a normal rabbit chow or a diet containing 1% cholesterol and treated or not with atorvastatin (1 mg/kg/day) for 12 weeks. Dose-response curves to acetylcholine (10(-9)-10(-4) mol/l) and sodium nitroprusside (10(-9)-10(-4) mol/l) were studied in segmental arteries in the presence or absence of the thromboxane A2/PGH2 receptor antagonist ifetroban (10(-5) mol/l). Glomerular size and structure were also evaluated. RESULTS: Compared with control animals, hypercholesterolaemic rabbits presented glomerular hypertrophy and several types of injuries (capillary collapse, hyalinosis and alterations of Bowman's capsule), suggesting diffuse glomerulosclerosis. Segmental arteries also showed relaxing responses to acetylcholine and sodium nitroprusside which were lower than and similar to, respectively, those of control animals. The presence of ifetroban improved the acetylcholine response only in hypercholesterolaemic rabbits. Atorvastatin treatment prevented vascular and most glomerular changes associated with hypercholesterolaemia even in the presence of very high cholesterol levels. CONCLUSIONS: Atorvastatin exerts a protective effect on renal damage associated with hypercholesterolaemia even in the presence of deleterious levels of plasma cholesterol.

Relevance of endothelium-derived hyperpolarizing factor in the effects of hypertension on rat coronary relaxations.

OBJECTIVES: To evaluate the relative participation of nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and prostanoids in the relaxing responses induced by acetylcholine and isoproterenol in isolated coronary arteries from adult Wistar- Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male adult WKY rats and SHR were used in the study. Segments from left coronary arteries (approximately 350-380 microm internal diameter and 2 mm long) were mounted in an isometric myograph and pre-contracted with serotonin. Dose-response curves to acetylcholine and isoproterenol were carried out in absence and presence of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (LNAME), the inhibitor of the cyclo-oxygenase, indomethacin and KCI. Areas under the respective dose-response curves were used to calculate the approximate relative participation of NO, EDHF and prostanoids. RESULTS: Relaxations to either acetylcholine or isoproterenol were lower in SHR than in WKY rats. In WKY rats, presence of LNAME diminished (P< 0.05) relaxation to acetylcholine from 10(-9) to 10(-6) mol/l, and induced a contracting response at 10(-5) and 10(-4) mol/l of acetylcholine. Addition of indomethacin did not significantly affect dose-related relaxation to acetylcholine 10(-9) to 10(-6) mol/l in WKY rats, and reduced (P < 0.05) the contracting response observed at 10(-5) mol/l of acetylcholine. In SHR, addition of LNAME markedly reduced (P< 0.05) acetylcholine relaxations, but did not produce any contracting effect. Addition of indomethacin on top of LNAME slightly (P< 0.05) enhanced relaxing response to acetylcholine in SHR. Presence of LNAME in the media diminished (P < 0.05) relaxation to isoproterenol in both WKY rats and SHR. Addition of indomethacin on top of LNAME increased (P< 0.05) isoproterenol-relaxing response to levels similar to and higher than control conditions in WKY rats and SHR, respectively. Addition of KCI blunted both acetylcholine- and isoproterenol-relaxations in both groups. CONCLUSIONS: NO and EDHF are the main endothelium-derived relaxing factors underlying acetylcholine and isoproterenol relaxations in rat coronary arteries, respectively. EDHF reduction, and not only NO reduction play a key role in the diminished coronary relaxations induced by acetylcholine and isoproterenol in SHR. An arachidonic acid derivative with contracting activity released by acetylcholine and isoproterenol in a differential manner, could oppose the relaxing actions of NO and EDHF.

Efectos de las estatinas sobre la presión arterial

Las estatinas han demostrado claramente su capacidad para disminuir la morbimortalidad cardiovascular debido principalmente a sus efectos sobre el colesterol sérico y las LDL, además de la estabilización de la placa y la reducción del riesgo trombótico. Sin embargo, en los últimos años diversos estudios indican que las estatinas tienen además efectos sobre la PA y la protección de órganos diana. Estos efectos pueden ser en parte dependientes de la reducción de la colesterolemia, pero otros mecanismos distintos a éste parecen intervenir en los efectos antihipertensivos de las estatinas. Entre ellos sus acciones sobre el manejo renal de sodio, la respuesta constrictora a diversos agentes, el remodelado vascular y diversas acciones sobre factores vasoactivos derivados del endotelio y el sistema renina angiotensina (AU)

Angiotensina ii e hipertensión arterial: consecuencias del antagonismo de sus receptores

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The protective role of atorvastatin on function, structure and ultrastructure in the aorta of dyslipidemic rabbits.

Responses to both an endothelium-dependent (acetylcholine 10(-9)-10(-5) mol/l) and an endothelium-independent vasodilator (sodium nitroprusside 10(-10)-10(-6) mol/l) were studied in aortic rings from rabbits fed or not with a diet containing 0.5% cholesterol plus 14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg/kg/day). Morphometric and ultrastructure analyses were also performed. Rabbits fed the dyslipidemic diet presented higher plasma cholesterol and triglyceride concentrations than controls (P < 0.05). This was associated with intima-media thickening and, consequently, aortic stenosis (29 +/- 3%) since vessel cross-sectional area did not change. Endothelial cells presented numerous alterations in dyslipidemic rabbits. Atorvastatin treatment only reduced plasma levels in dyslipidemic rabbits (P < 0.05), which were nevertheless higher than those of controls. In addition, it prevented the reduction in acetylcholine relaxation in hypercholesterolemic animals. Atorvastatin administration also enhanced the response to acetylcholine in rabbits fed a control diet. Likewise, atorvastatin treatment reduced lesion area and consequently increased aortic lumen in dyslipidemic rabbits but did not modify media thickening. It also prevented the majority of the ultrastructural changes observed in endothelial cells. In conclusion, chronic atorvastatin treatment exerts a protective role in vascular function, structure and ultrastructure even in the presence of high cholesterol and triglyceride plasma levels.

Effect of atorvastatin on endothelium-dependent constrictor factors in dyslipidemic rabbits.

Relaxations to acetylcholine and contractions to acetylcholine in the presence of the nitric oxide (NO) synthesis inhibitor (L-N(G)-nitroarginine methyl ester, L-NAME) were studied in aortic rings from rabbits fed either a control or a diet containing 0.5% cholesterol+14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg kg(-1) day(-1)). Rings were incubated with the endothelin (ET(A)) receptor antagonist BQ123, and/or the thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist ifetroban. In rabbits, high cholesterol and triglyceride plasma levels were associated with intimal thickening and blunted acetylcholine-relaxation as compared with controls. By contrast, acetylcholine+L-NAME response was higher. Incubation with either ifetroban or BQ123 increased acetylcholine-relaxation in both diet groups and it reduced the constrictor response only in dyslipidemic rabbits. Removal of endothelium reduced acetylcholine+L-NAME contraction in dyslipidemic rabbits, although increased it in control animals. Atorvastatin treatment reduced plasma lipid levels and lesion size in dyslipidemic animals. Likewise, it prevented acetylcholine-relaxation reduction. In addition, atorvastatin reduced constrictor response in dyslipidemic rabbits but only in rings with endothelium. Incubation with either ifetroban or BQ123 did not further modify these responses in atorvastatin-treated animals in any group. These data suggest that ET and TXA(2) availabilities seem to participate in the endothelial dysfunction associated with dyslipidemia. Atorvastatin treatment reduces intimal thickening and improves endothelial dysfunction in rabbits. This effect seems to be a consequence of its ability to act on ET and TXA(2) systems.

[Participation of endothelium-derived vasoconstrictor factors in arterial hypertension]. / Participación de los factores constrictores derivados del endotelio en la hipertensión arterial.

Vascular endothelial cells synthesize and release vasodilator (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor) and vasoconstrictor factors (thromboxane A2, prostaglandin H2, endothelin 1), which play a key role in the local regulation of vascular tone and participate in a crucial manner in the regulation of blood pressure. Hypertension has been shown to be associated with functional changes in the endothelium. In fact, decreased endothelium-dependent relaxations and increased endothelium-dependent contractions have been reported in both conduit arteries and resistance arteries obtained from various animal models of hypertension. During hypertension, the vessel wall experiences changes in the balance of the oxidative and the antioxidative enzyme system, resulting in increases in O2- release. This contributes to endothelial dysfunction by nitric oxide oxidation and the subsequent formation of peroxynitrite (ONOO-), a potent oxidant and potential mediator of vascular tissue injury. Finally, hypertension also allows the action or the production of vasoconstrictor factors such as endothelin 1 and thromboxane A2. As a consequence of these mechanisms, basal and/or stimulated nitric oxide availability is reduced, allowing vasoconstrictor systems, such as angiotensin II, sympathetic nervous system and others to over-express their actions. The mechanisms responsible for the alterations leading to endothelial dysfunction not only affect vasomotor tone, but also platelet aggregation and coagulation mechanisms.

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.

AT(1) receptor antagonism reduces endothelial dysfunction and intimal thickening in atherosclerotic rabbits.

The effects of angiotensin (AT)(1) receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5+/-6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P<0.05) intimal lesion to 2.4+/-0.7% and 2.7+/-0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT(1) receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT(1) receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.

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.

Factors involved in the effects of losartan on endothelial dysfunction induced by aging in SHR.

In the present study we investigated the effects of losartan (10 mg/kg/day; 12 weeks) on acetylcholine (Ach) induced relaxations in isolated mesenteric vascular beds (MVB) from adult and elderly spontaneous hypertensive rats (SHR). Experiments were done in absence or presence of either the NO synthesis inhibitor, L-NAME (10(-5) mol/liter), L-NAME + indomethacin (10(-5) mol/liter) or L-NAME + indomethacin + KCl (10(-5) mol/liter), to evaluate the participation of the factors (NO, PGs and EDHF, respectively) mediating Ach-relaxations. Systolic blood pressure levels were comparable in both groups. However, urinary nitrites excretion and Ach-response was lower in elderly than in adult SHR. The presence of L-NAME and L-NAME + indomethacin only reduced Ach-relaxations in untreated elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of endothelium-derived hyperpolarizing factor (EDHF) in Ach-relaxations was higher than that of nitric oxide (NO) and prostaglandins in both groups, although the EDHF component was lower in elderly when compared to adult SHR. Losartan treatment reduced blood pressure levels and enhanced dose-related Ach-relaxations and urinary nitrites in both groups. Presence of L-NAME and L-NAME + indomethacin blunted the enhancements induced by losartan on Ach-relaxations in both adult and elderly SHR. Further addition of KCl to the perfusion media totally blunted Ach-relaxation in both groups. The calculated participation of NO in Ach-relaxations was increased by losartan in both groups. Neither EDHF or prostanoids (PGs) components were clearly affected by losartan. In conclusion, (1) diminished EDHF availability accounts for the reduced Ach-relaxations produced by aging in MVB from SHR; (2) the enhancement of Ach-relaxations produced by losartan seems to be dependent on an increased NO availability; and (3) angiotensin II via angiotensin I type 1 receptor (AT1) plays an important role in the deleterious consequences of aging on endothelial function in SHR.

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.

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). MATERIAL 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 studies. A group of rats treated with captopril was studies 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-l 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, the kidney, and hypertension.

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.

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.

Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Role of nitric oxide and angiotensin II type 2 receptors.

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.

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.