Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition.

Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether, in spontaneously hypertensive rats, endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery, less in the aorta, and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta, which decreased by 38%. We conclude that in spontaneously hypertensive rats, endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophage may lead to a better understanding of the mechanism of action of this class of drugs.     

Endothelium-derived contracting factor released by serotonin in the aorta of the spontaneously hypertensive rat.

Contractions to serotonin are augmented in aortas with endothelium from spontaneously hypertensive rats (SHR) compared to normotensive controls (WKY). Experiments were designed to determine whether this is due to the release of a vasoconstrictor prostanoid from the endothelium. Rings of aortas with and without endothelium were taken from SHR and WKY and suspended in organ chambers for isometric tension recording. Contractions to serotonin were similar in rings without endothelium from both strains. The presence of the endothelium reduced the contractions to all concentrations of serotonin in the WKY; in the SHR the endothelium inhibited only the response to lower concentrations of serotonin. Indomethacin (or meclofenamate) reduced the contractions to high concentrations of serotonin only in rings from SHR with endothelium; it did not affect the response in SHR rings without endothelium or in rings from WKY (with and without endothelium). The endothelium inhibited contractions to norepinephrine only in the presence of indomethacin in both strains. These experiments suggest that serotonin stimulates the release of vasoconstrictor prostanoids from the endothelium of the SHR but not from the WKY aorta. Norepinephrine may release endothelium-derived contracting factor(s) in both strains.     

一氧化氮对自发性高血压大鼠血管内皮功能的作用

目的　探讨自发性高血压大鼠 (SHR)内皮舒张功能不全的发生机制。方法　采用体外灌注的方法测定大鼠胸主动脉环对不同浓度乙酰胆碱的舒张反应变化 ,并测定血清中NO-3浓度和动脉组织中环鸟苷酸水平。结果　与魏 凯二氏大鼠 (WKY)比较 ,SHR胸主动脉环对乙酰胆碱的舒张反应明显减弱。左旋硝基精氨酸 (L NNA)可明显抑制大鼠胸主动脉环对乙酰胆碱的舒张反应 ,但并不能消除SHR和WKY对乙酰胆碱舒张反应之间的差异。与WKY比较 ,SHR血中NO-3水平明显降低 (P<0 .0 1) ,动脉组织中环鸟苷酸含量降低 (P<0 .0 1)。结论　SHR内皮依赖的血管舒张功能减低 ;一氧化氮 (NO)的生成或释放不足可能直接参与了SHR血管内皮依赖的舒张功能不全。     

Increased oxidative stress impairs endothelial modulation of contractions in arteries from spontaneously hypertensive rats

OBJECTIVES: The endothelium modulates vascular contractions. We investigated the effects of oxidative stress on endothelial modulation of contractions in hypertension. METHODS: Changes in isometric tension of femoral arterial rings from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were recorded. RESULTS: The contractile response to norepinephrine of arteries with endothelium was greater in SHR than in WKY rats (P < 0.0001). Endothelium removal augmented the norepinephrine-induced contraction (P < 0.05). The augmentation was more pronounced in WKY than in SHR, which resulted in comparable contraction of arteries without endothelium in both strains. Nomega-nitro-L-arginine methyl ester (100 micromol/l) mimicked the effect of endothelium removal. Production of nitric oxide (NO, assessed by measuring nitrite/nitrate concentrations) during the contraction was not different between SHR and WKY. Vitamin C suppressed the contraction of arteries with endothelium from SHR but not from WKY (P < 0.05). Diphenyleneiodonium and apocynin, inhibitors of nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADPH) oxidase, attenuated the contraction of arteries with endothelium from SHR (P < 0.001) but not WKY, but did not affect contractions induced by serotonin. Superoxide generated by xanthine oxidase/hypoxanthine enhanced the norepinephrine-induced contraction of arteries with endothelium from WKY (P < 0.0001), and this effect was reversed by vitamin C. CONCLUSIONS: In rat femoral arteries, NO released from the endothelium modulates vascular contraction. In SHR, production of superoxide by NADH/NADPH oxidase, which may be activated by norepinephrine, is enhanced, resulting in the inactivation of NO and impairment of endothelial modulation of vascular contractions. Vascular oxidative stress may contribute to the altered circulation in hypertension by impairing endothelial modulation of vascular contractions.     

Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti-Thy-1 irreversible nephritis.

Blockade of the renin-angiotensin system has been established as a treatment for heart failure with hypertension and left ventricular hypertrophy, and for progressive kidney diseases. The present study was conducted to examine whether spironolactone, a mineralocorticoid receptor antagonist, alone or in combination with cilazapril, an angiotensin converting enzyme (ACE) inhibitor, ameliorates proteinuria and renal lesions in an immune-initiated progressive nephritis model. Wistar rats were uninephrectomized 7 days before injection of anti-Thy-1 monoclonal antibody 1-22-3 to induce progressive glomerulonephritis. The nephritic rats were untreated or treated with spironolactone (400 mg/kg body weight/day), cilazapril (1 mg/kg body weight/day), or both for 10 weeks. Proteinuria was increased in the untreated rats 1 week after nephritis induction and was maintained throughout the experiment. Compared with the untreated animals (212.9+/-49.2 mg/day), proteinuria was significantly reduced in the spironolactone-treated group (62.0+/-4.0 mg/day, p=0.0046) and the cilazapril-treated group (71.8+/-26.0 mg/day, p=0.0048) on day 70 after antibody injection. Further reduction of proteinuria (42.4+/-4.5 mg/day, p=0.0019 vs. the untreated group) and less renal cortex interstitial fibrotic change (fibrosis score: 142.0+/-18.4 vs. 80.3+/-18.5 in the untreated group, p=0.0123) were detected in the spironolactone plus cilazapril-treated group. Blood pressure did not differ among the three treatment groups. In conclusion, spironolactone ameliorates proteinuria to the same degree as cilazapril, and concomitant use of spironolactone and an ACE inhibitor further suppresses renal disease progression. These data suggest that concomitant treatment with spironolactone and an ACE inhibitor has beneficial effects on immune-initiated progressive kidney disease.     

Magnesium removal impairs the regulatory role of rat endothelium.

Vascular endothelium has been shown to play an important role in the regulation of vascular tone and, hence, impairment of the endothelium may induce hypertension. Although magnesium (Mg) deficiency could induce hypertension, the role of Mg on the endothelium is unclear. We examined the effects of Mg removal on endothelium-dependent and -independent responses using ring preparations of femoral arteries obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Norepinephrine (10(-9)-10(-4) M) evoked concentration-dependent contractions in arteries with endothelium. The maximal response was greater in SHR than in WKY. Removal of external Mg augmented the contraction in WKY but not in SHR. As a result, the contraction obtained in arteries with endothelium was identical in the two groups. Removal of the endothelium enhanced the contraction in both strains, with a greater response occurring in WKY than in SHR in Krebs, but not in Mg-free, solution. As a result, in arteries without endothelium, the contractions were identical in WKY and SHR both in Krebs and Mg-free solutions. Acetylcholine (10(-9)-10(-4) M) evoked concentration-dependent relaxation in arteries with, but not in those without, endothelium obtained from WKY and SHR. The relaxation did not differ between the two strains, nor was it altered by Mg removal. Thus, Mg removal impairs inhibitory function of the endothelium against contraction induced by norepinephrine, without affecting endothelium-dependent relaxation in response to acetylcholine, in the rat femoral artery. The effect of Mg removal is not apparent in SHR. The fact that after removal of external Mg the contraction in response to norepinephrine in arteries with endothelium is identical in WKY and SHR suggests that a normotensive artery with Mg deficiency may mimic a hypertensive artery through endothelial impairment.     

SHR心肌组织内血管紧张素转换酶活性的变化及西拉普利的作用

目的 探讨心肌组织内血管紧张素转换酶活性在自发性高血压大鼠不同发病阶段的变化及其与左室肥厚及心肌纤维化的关系以及西拉普利的作用。方法 用荧光测定法检测自发性高血压大鼠不同发病阶段心肌组织内血管紧张素转换酶的活性;应用大体及组织病理学检查结合图象分析等方法检测自发性高血压大鼠心肌肥厚和心肌纤维化的动态改变。结果 SHR心肌组织内血管紧张素转换酶活性在第6周和第14周时无明显改变,24周则为明显增高,与代表间质纤维化的参数CVF同步变化;代表血管周围时纤维化的参数PVCA则从第6周开始增高,第14和24周持续增加,代表左室肥厚的参数LV、LVI及CA从14周开始增加,24周更为明显;这些变化均与ACE的变化不同步,而与收缩压变化基本同步;西拉普利可使心肌组织内血管紧张素转换酶活性、代表左室肥厚及心肌纤维化的参数恢复至对照组的水平。结论 SHR心肌组织内血管紧张素转换酶活性在高血压的中晚期增高,与代表间质纤维化的参数CVF呈同步变化,提示心肌间质纤维化的发生可能与ACE的增高有关;西拉普利可有效地降低SHR心肌组织内血管紧张素转换酶活性并预防和逆转左室肥厚及心肌纤维化。     

Effect of Red Blood Cells and Hemoglobin on Spontaneously Hypertensive and Normotensive Rat Aortas

Experiments were designed to compare the contractile effect of red blood cells (RBC) on aortic rings with and without endothelium from normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Red blood cells of 4 week old WKY and SHR rats induced a negligible increase in tension of aortic rings, either with or without endothelium, being slightly more effective in SHR rats. However, red blood cells of 16 week old rats increased tension of WKY and SHR aortic rings, with endothelium at this age being more pronounced then red blood cells in 4 week old animals. The contractions induced by WKY and SHR red blood cells both in WKY and SHR aortic rings without endothelium at this age are significantly greater compared to the effect on aortic rings with endothelium. Red blood cell ghosts of rats of both strains increased the tension of the rings without endothelium of SHR aorta to near 50% of those induced by red blood cells, whereas they were ineffective in aortic rings without endothelium of WKY rats. Oxyhemoglobin increased the tension of 16 week SHR aortic rings both with and without endothelium, whereas the effect on the rings of WKY rats was negligible. This increase in tension was inhibited by BM 13505, nordihydroguaiaretic acid, and indomethacin in SHR rings both with and without endothelium, demonstrating an eicosanoid involvement in oxyhemoglobin-induced contractions. Hemoglobin or its metabolites may be involved in development or in maintenance of spontaneous hypertensin.     

Effects of renin-angiotensin system blockade in guinea pigs.

The goal of the present study was to compare the hemodynamic and biochemical effects of the renin inhibitor Ro 42-5892, the angiotensin converting enzyme inhibitor cilazapril, and the angiotensin II receptor blocker EXP132, the aldehyde derivative of DuP 753. The three drugs were evaluated in guinea pigs, previously treated with furosemide, using their maximal effective doses. Cilazapril decreased arterial blood pressure more than Ro 42-5892 and EXP132. In contrast, Ro 42-5892 and EXP132 had similar effects. The larger decrease of arterial pressure induced by cilazapril was not due to a larger decrease of angiotensin II in plasma and was not influenced by cyclooxygenase inhibition with indomethacin or by bradykinin antagonism with Hoe 140. After binephrectomy, most of the blood pressure-lowering effect of Ro 42-5892 disappeared. In contrast, cilazapril was still markedly effective, pointing to extrarenal effects. We conclude that in furosemide-treated guinea pigs, as opposed to previously published animal models, the decrease of arterial pressure induced by angiotensin converting enzyme inhibitors may be partly due to extrarenal effects not related to the renin-angiotensin system.     

Inhibitory actions of captopril on norepinephrine release from adrenergic nerve endings in spontaneously hypertensive rats

The purpose of the present study was to investigate the mechanisms of the hypotensive actions of an angiotensin converting enzyme inhibitor of the hypotensive actions of an angiotensin converting enzyme inhibitor (captopril) in hypertension. In perfused mesenteric vasculatures from spontaneously hypertensive rats (SHR, Okamoto and Aoki strain, 10-13 weeks of age) and age-matched normotensive Wistar Kyoto rats (WKY), the effects of captopril on vascular responsiveness and norepinephrine release from the adrenergic nerve endings were examined. The vasoconstrictor responses and norepinephrine release during the electrical nerve stimulation were significantly enhanced in SHR compared to those in age-matched WKY. Captopril reduced both vasoconstrictor responses and norepinephrine release during the electrical nerve stimulation, dose-dependently. These inhibitory effects of captopril were significantly greater in SHR than in WKY. The results demonstrate that captopril affects presynaptic sites on the resistance vessels and causes a decrease in electrically-stimulated norepinephrine release from the adrenergic nerve endings. The marked reduction of both pressor responses and norepinephrine release by captopril in SHR suggests an enhanced renin-angiotensin system in the vascular walls of hypertension.     

Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect

BACKGROUND : Hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors have beneficial effects beyond their cholesterol-lowering properties. The antioxidant mechanism of HMGCoA reductase inhibitors is not completely understood. OBJECTIVES : To elucidate the antioxidant effect of simvastatin. METHODS : We studied the influence of simvastatin treatment on the development of hypertension, modification of antioxidant systems, and reactivity of aortic rings in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. RESULTS : Simvastatin had no effect on blood pressure (BP). Simvastatin treatment (either 1 or 2 mg/kg body weight for 12 or 20 weeks) increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in SHR rats compared with untreated control SHR rats. Carbachol-induced relaxation of aortic rings was impaired in control SHR rats and was restored by simvastatin treatment. Addition of SOD improved the response in control SHR rats and did not have any effect in treated SHR rats. Addition of diethyldithiocarbamic acid, a selective inhibitor of SOD, produced a mild non-significant impairment in carbachol-induced relaxation in control SHR rats, suggesting a deficient antioxidant system in these animals. However, in treated SHR and in WKY rats, impairment of the relaxation was marked, implying that SOD activity in these animals was important to maintain endothelial function. In aortic rings without endothelium from SHR rats, contraction induced by free radicals was substantially higher than in WKY rats. This effect was attenuated in 1-mg-treated rats and abolished in 2-mg-treated rats. CONCLUSIONS : Simvastatin promotes intracellular antioxidant systems, fundamentally SOD, restoring endothelial function but not having any effect on blood pressure.     

The Influence of Chronic Captopril Treatment and its Withdrawal on Endothelium-Dependent Relaxation

The current experiments were designed to explore the relationship between the renin angiotensin system (RAS) and prostanoid formation in aortic ring preparations from spontaneously hypertensive rats (SHR). A further aim was to examine the mechanisms responsible for the reversal of the impaired acetylcholine (ACh) mediated relaxation induced by chronic administration of the angiotensin converting enzyme inhibitor captopril and the relationship of the ACh response to blood pressure. Rats were administered captopril (100 mg/kg/day) and their blood pressures monitored from 5 to 17 weeks of age. ACh-mediated relaxation was determined in aortic ring preparations from untreated and treated rats, and drug withdrawn rats. The influence of indomethacin, saralasin, SQ29548 and captopril on ACh-mediated responses was determined. It was found that chronic captopril treatment produced a marked suppression of the development of hypertension in the SHR. After the withdrawal of the drug the blood pressure remained significantly lower than in untreated animals for 4 weeks. ACh relaxation was impaired in SHR ring segments; this was reversed with captopril treatment and returned to the impaired state upon withdrawal of the drug. In vitro inhibition of the RAS did not significantly influence ACh relaxation. In contrast, impairment of the prostanoid system in vitro reversed the impaired relaxation. The results suggest that the influence of captopril on enhancing ACh relaxation in the SHR does not involve an acute interaction of local angiotensin II synthesis with prostanoid mechanisms. Importantly, the results highlight a dissociation between the impaired ACh relaxation and elevated blood pressure in the SHR.     

Evidence for a captopril-sensitive angiotensin converting enzyme in the hindquarter vasculature of SHR and WKY

Vascular angiotensin converting enzyme could contribute to the elevated vascular resistance found in hypertension. The purpose of this study was to determine if angiotensin converting enzyme activity was present in the hindquarter vasculature of one model of hypertension, the spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar-Kyoto rat (WKY). We evaluated the effect of a maximal blocking dose of captopril (0.5 mg) on the angiotensin I pressor response during the infusion of the hindquarter with an artificial perfusate. Angiotensin I (1000 ng/ml) produced a significant increase in peripheral vascular resistance (PVR) in both SHR and WKY, but the increase was greater in SHR. Captopril inhibited the elevation in PVR in both. A lower concentration of angiotensin I (250 ng/ml) produced a significant and similar pressor response in SHR (less than the pressor response to 1000 ng/ml) and WKY (same as the pressor response to 1000 ng/ml). Again, captopril prevented the elevation in PVR to A1 in both SHR and WKY. Because these studies were performed using an artificial perfusate, angiotensin converting enzyme must be present in the SHR and WKY hindquarter vasculature including resistance vessels.     

Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat.

To determine whether chronic antihypertensive therapy prevents the progression of cardiac hypertrophy and the deterioration in cardiac performance observed in spontaneously hypertensive rats (SHR) with long-term hypertension, 14-month-old female SHR and normotensive American Wistar rats (NWR) were treated for 10 months with an inhibitor of angiotensin I-converting enzyme, captopril (2 g/liter of drinking water). Captopril reduced the marked left ventricular hypertrophy of 24-month-old SHR (untreated, 4.37 +/- 0.2 mg/g of body weight; treated, 3.01 +/- 0.1 mg/g; P less than 0.02) to levels observed in 6-month-old SHR. Treatment prevented the reductions in baseline and maximal aortic blood flows that occurred in SHR between ages 12 and 24 months yet had no effect on the blood flows of NWR. The diminished maximal stroke volume of untreated SHR was ejected from a significantly increased left ventricular end-diastolic volume, so that the ejection-fraction index was markedly reduced (24-month-old untreated NWR, 84 +/- 3%; untreated SHR, 56 +/- 5%; P less than 0.001). Therapy restores this index in SHR to normal (77 +/- 4%). The relationship between ejection-fraction index, and afterload was also normal in treated SHR. Thus, chronic therapy with captopril produced a marked regression of cardiac hypertrophy and prevented the deterioration of cardiac performance in SHR with long-standing hypertension.     

Antihypertensive and vasodilator actions of antioxidants in spontaneously hypertensive rats

This study was designed to determine whether the antioxidants ascorbic acid, aminotriazole, and glutathione acutely reduce blood pressure (BP) by endothelium-independent or -dependent vasorelaxation in spontaneously hypertensive rats. Blood pressure of male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) was measured before and 4 h after administration of antioxidants. Thoracic aortic rings with and without endothelium were suspended in organ chambers for isometric tension recordings. Each of the antioxidants, administered in vivo, significantly decreased blood pressure in SHR but had no significant effect on BP in WKY rats. The endothelium-dependent impaired relaxation of SHR aortic rings to acetylcholine (ACh) was improved by prior in vivo administration of each antioxidant. ACh-induced relaxations of aortic rings from WKY was not affected by prior antioxidant treatment. Addition of each antioxidant directly to the organ chamber containing SHR or WKY aortas produced dose- and endothelium-dependent relaxations. Moreover, antioxidant pretreatment of SHR aortic rings significantly potentiated ACh-induced relaxations in these aortas, suggesting that this effect was endothelium dependent. Relaxations induced by the antioxidants alone or by ACh in the presence of antioxidants were inhibited by addition of either xanthine plus xanthine oxidase or nitro-l-arginine. These findings suggest that either excess production of oxidants or a deficiency of antioxidant systems may contribute to the high blood pressure and the endothelium-dependent impairment of vascular relaxation in SHR.     

苯那普利对自发性高血压大鼠血管内皮舒张功能的改善作用

目的 :探讨苯那普利能否改善自发性高血压大鼠 (SHR)血管内皮舒张功能。　　方法 :采用体外灌注法测定苯那普利治疗组 (治疗组 )及对照组胸主动脉环对乙酰胆碱的舒张反应 ,并比较两组血清中 NO3- 浓度、动脉组织中环鸟苷酸 (c GMP)水平。　　结果 :与对照组比较 ,治疗组胸主动脉环对乙酰胆碱的最大舒张反应明显增强 (P<0 .0 1)。左旋硝基精氨酸 (L-NNA)几乎完全消除了治疗组和对照组舒张反应之间的差异。治疗组血清 NO3-浓度和动脉组织 c GMP的含量均明显增加 (P均 <0 .0 1)。　　结论 :苯那普利长期治疗可明显改善 SHR血管内皮舒张功能 ,其机制可能是增加了内皮一氧化氮的合成或释放     

罗格列酮改善高血压大鼠血管对胰岛素的反应性

目的研究罗格列酮（RSG）对自发性高血压大鼠（SHR）的高血压状态、血糖和胰岛素水平的影响及其离体血管对胰岛素的反应性。方法将实验动物分为3组：正常大鼠（WKY）对照组（幼年16只,成年15只）、未治疗的SHR组（幼年9只,成年9只）、RSG治疗的SHR组〔幼年6只,成年6只,3mg/（kg.d）,口服,治疗2周〕。2周后,测量未治疗组和治疗组成年SHR的收缩压、血糖和胰岛素水平;分离胸主动脉,采用离体血管灌流方法,对比观察不同处理组离体主动脉对胰岛素的舒血管反应。结果在成年SHR中,未治疗组和治疗组收缩压、血糖和胰岛素水平均无显著差异〔（187±4）vs（181±5）mmHg,P〉0.05;（6.2±0.2）vs（5.3±0.3）mmol/L,P〉0.05;（23.8±3.7）vs（20.4±0.8）mU/L,P〉0.05〕。治疗组对胰岛素的舒血管反应与未治疗组无显著差异〔最大收缩率：（72±8）%vs（73±4）%,P〉0.05〕;在幼年SHR中,未治疗组和治疗组血糖和胰岛素水平亦无显著差异,但治疗组对胰岛素的舒血管反应较未治疗组显著增加〔（40±6）%vs（61±5）%,P〈0.01〕。结论短期RSG治疗可改善幼年SHR血管对胰岛素的反应性。     

Cysteinyl leukotrienes are involved in angiotensin II-induced contraction of aorta from spontaneously hypertensive rats

OBJECTIVE: Non specific lipoxygenase inhibitors have been reported to reduce the in vitro constrictor response and the in vivo pressor effect of angiotensin II in rats. The aim of this study was to assess the role of cysteinyl leukotrienes, in the vascular response to angiotensin II in spontaneously hypertensive rats (SHR). METHODS: Rings of thoracic aorta from SHR and normotensive Wistar-Kyoto rats (WKY) were compared in terms of contractile responses and release of cysteinyl leukotrienes in response to angiotensin II. RESULTS: Pretreatment with the specific 5-lipoxygenase inhibitor AA861 10 microM reduced the efficacy of angiotensin II in intact and endothelium-denuded aorta from SHR (% inhibition vs. control: 65+/-12.6% with endothelium (n=6), P<0.05; 43+/-7.2% without endothelium (n=6), P<0.05) but not in aorta from WKY. In addition, in aorta from SHR, the CysLT(1) receptor antagonist MK571 1 microM reduced by 55+/-6.1% (n=6, P<0.05) the contractile effects of angiotensin II in rings with endothelium but not in endothelium-denuded rings. Angiotensin II induced a 8.6+/-2.1-fold increase in cysteinyl leukotriene production in aorta rings from SHR with endothelium which was prevented by the AT(1) receptor antagonist losartan 1 microM but not by the AT(2) receptor antagonist PD123319 0.1 microM. In aorta rings from WKY, cysteinyl leukotriene production remained unchanged after exposition to angiotensin II. The cysteinyl leukotrienes (up to 0.1 microM) induced contractions in aorta rings from SHR but not from WKY. CONCLUSIONS: These data suggest that cysteinyl leukotrienes, acting at least in part on endothelial CysLT(1) receptors, are involved in the contractile response to angiotensin II in isolated aorta from SHR but not from WKY.     

High-dose, not low-dose insulin increases the vasoconstrictor effect of norepinephrine in spontaneously hypertensive rats: effects of antihypertensive treatment

The effect of insulin on the vasoconstriction induced by norepinephrine is presently controversial. Therefore, the aims of our study were: (1) to evaluate the effect of low- and high-dose insulin on the concentration-response curve to norepinephrine in small resistance arteries of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) before and after the development of hypertension, and (2) to evaluate the effects of antihypertensive treatment on vascular response to insulin and norepinephrine. Fifty-six rats were included in the study. Six SHR were treated with enalapril and 6 with candesartan cilexetil from the 4th to the 12th week of age, while 10 WKY and 14 SHR were kept untreated. Two additional groups of 10 untreated SHR and 10 WKY were killed at 4 weeks of age, in a prehypertensive phase. Mesenteric small arteries were dissected and mounted on a micromyograph. A dose-response curve to norepinephrine was performed at cumulative concentrations in the presence or absence of low- and high-dose insulin. We found that only high-dose insulin increased the vascular response to norepinephrine in 12-week-old SHR, but not in 4-week-old SHR or in age-matched WKY. The increased responsiveness to norepinephrine disappeared after preincubation of the vessels with a selective inhibitor of endothelin-1 type A receptors. After antihypertensive treatment with enalapril or candesartan cilexetil, the potentiation of the vasoconstrictor response to norepinephrine was abolished. In conclusion, insulin at high, nonphysiological doses seems to induce an increase in the reactivity to norepinephrine in mesenteric small arteries of SHR, possibly mediated by a local production of endothelin-1. Antihypertensive treatment with an ACE inhibitor or an angiotensin II receptor blocker may normalize this altered response. This mechanism may be relevant in the development of hypertension in SHR.     

Improvement in metabolic risk factors for coronary heart disease associated with cilazapril treatment.

Patients with hypertension tend to be glucose intolerant, hyperinsulinemic, and dyslipedemic. Since all of these changes increase risk of coronary heart disease (CHD), it is important to know what effect antihypertensive treatment has on these variables. The current open-labelled, uncontrolled study was initiated in order to extend our understanding of these issues. This study was performed in 19 patients with hypertension who were started on an angiotensin converting enzyme (ACE)-inhibitor, cilazapril, with hydrochlorothiazide (HC) added if needed to control blood pressure. Plasma glucose and insulin responses to oral glucose and lipid concentrations were measured before, 26, and 52 weeks after starting treatment. Patients treated with either cilazapril (n = 9) or cilazapril+HC (n = 10) did not differ in terms of original (mean +/- SEM) blood pressure (159 +/- 5/101 +/- 1 v 156 +/- 4/103 +/- 2 mm Hg), age (53 +/- 2 v 54 +/- 2 years), sex distribution (5M:4F v 7M:3F), or body mass index (24.4 +/- 0.5 v 24.2 +/- 0.9 kg/m2). Blood pressure was also similar after 26 (137 +/- 4/88 +/- 1 v 133 +/- 3/90 +/- 1 mm Hg) and 52 (137 +/- 4/87 +/- 1 v 134 +/- 4/89 +/- 2 mm Hg) weeks of treatment. Plasma glucose and insulin responses decreased by 8 +/- 3% (P less than .05) and 25 +/- 9% (P less than .002), respectively, in cilazapril-treated patients, but did not change in those treated with cilazapril plus HC.(ABSTRACT TRUNCATED AT 250 WORDS)