Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats

OBJECTIVES: It is generally accepted that short-term (4 weeks) inhibition of the renin-angiotensin system (RAS) of young spontaneously hypertensive rats (SHR) in their prehypertensive phase confers long-lasting protection from fully hypertensive levels in adulthood. However, there is very little data pertaining to the effects of such treatment in adult SHR with established hypertension. Therefore, we determined the relative effects of angiotensin converting enzyme (ACE) inhibition (perindopril), AT1 receptor blockade (candesartan cilexetil) and RAS-independent vasodilatation (hydralazine) and their withdrawal in adult SHR, on blood pressure measured by radiotelemetry, as well as on cardiac and vascular structure. METHODS: Adult male SHR were instrumented with radiotelemetry probes to measure blood pressure and heart rate continuously. SHR were given either vehicle, perindopril (1 mg/kg per day), candesartan cilexetil (2 mg/ kg per day) or hydralazine (30 mg/kg per day) at equieffective depressor doses for 4 weeks (treatment study). Separate groups of animals were also given identical treatments but were then monitored for a further 8 weeks after drug withdrawal (withdrawal study). An indirect in-vivo assessment of whole body vascular hypertrophy (mean arterial pressure during maximum vasoconstriction) was made during and after drug withdrawal, as was the pressor activity evoked by angiotensin I and angiotensin II. The effect of antihypertensive treatment on microalbuminuria was also assessed during and after drug withdrawal. Finally, left ventricular: body weight (Iv: bw) and mesenteric media: lumen ratios were determined either immediately after 4-week treatment (treatment study) or 8 weeks later (withdrawal study). RESULTS: Perindopril persistently lowered blood pressure in adult SHR whereas blood pressure returned to vehicle levels within approximately 4 and 15 days after withdrawal of hydralazine and candesartan cilexetil, respectively. Cardiac hypertrophy was reduced by all three treatments, but to a lesser extent by hydralazine (treatment study), and this regression of cardiac hypertrophy persisted only with both types of RAS inhibition (withdrawal study). Vascular hypertrophy, measured indirectly and directly, was also reduced by all three treatments, with perindopril and candesartan cilexetil causing hypotrophic and eutrophic remodelling, respectively (treatment study), although these changes were generally not maintained after drug withdrawal (withdrawal study). Angiotensin I-induced pressor responses were equally inhibited during treatment with either candesaran cilexetil or perindopril (and were unaffected by hydralazine) but normalized rapidly in both groups (within approximately 2-4 days) after withdrawal of RAS inhibition. In addition, there was a small age-related increase in microalbuminuria over the study period, which was not significantly affected by any treatment. CONCLUSIONS: Following 4-week treatment, candesartan cilexetil, perindopril and hydralazine caused similar antihypertensive effects; however, only perindopril persistently reduced blood pressure following drug withdrawal. Both types of RAS inhibition and hydralazine caused marked cardiac and vascular remodelling during treatment, whereas only the RAS inhibitors persistently regressed cardiac hypertrophy 8 weeks later. Collectively, these results indicate the importance of the RAS for the maintenance of hypertension and cardiovascular hypertrophy in adult SHR, as well as identifying differential effects of ACE inhibition and AT1 receptor blockade on persistent blood pressure reduction.     

Effects of chronic ACE inhibition on cardiac hypertrophy and coronary vascular reserve in spontaneously hypertensive rats with developed hypertension

Left ventricular hypertrophy due to hypertension is associated with a decrease of coronary vascular reserve. We have previously shown that chronic angiotensin converting enzyme (ACE) inhibition prevents cardiac hypertrophy and improves coronary vascular reserve when the treatment is started before appearance of hypertension in spontaneously hypertensive rats (SHR). However, the effects of starting chronic ACE inhibition when hypertension was already developed is not known. The goal of the present study was to assess the effects of chronic ACE inhibition on coronary vascular reserve and on the morphology of the coronary microvasculature when treatment was started after hypertension had developed. For this purpose, one group of SHR was treated from 3-8 months of age with cilazapril, a new ACE inhibitor, and compared with a group treated by placebo. At the end of treatment, cardiac hypertrophy, coronary vascular reserve, density and cross-sectional surface area of the myocardial capillaries (normalized for the myocardial mass) and wall/lumen ratio of the coronary arterioles were determined. Chronic ACE inhibition with cilazapril reduced cardiac hypertrophy and improved by more than 50% coronary vascular reserve in the left and right ventricles. In the left ventricle, the improvement was more pronounced in the subendocardium than in the subepicardium. Cilazapril increased the density and the cross-sectional surface area of the myocardial capillaries and decreased the wall/lumen ratio of the arterioles of the left ventricle. We conclude that chronic ACE inhibition can improve coronary vascular reserve, increase capillary density and capillary cross-sectional surface area and decrease the thickness of the media of coronary arterioles in SHR even when treatment is started after development of hypertension.     

Effects of long-term verapamil treatment on blood pressure, cardiac hypertrophy and collagen metabolism in spontaneously hypertensive rats

The effects of long-term treatment with verapamil on blood pressure, cardiac hypertrophy and collagen content, collagen concentration and prolyl hydroxylase activity were studied in spontaneously hypertensive rats (SHR). Verapamil administration (0.75 mg . ml-1 in drinking water) was commenced: to pregnant SHR 3 to 5 days before delivery and continued to the mothers and offspring during the nursing period; or to SHR at 10 weeks of age. Both groups were maintained on verapamil treatment up to the age of 45 weeks. Verapamil treatment significantly decreased blood pressure, heart rate and the ratio of ventricular weight to body weight in treated SHR. Verapamil did not significantly change the cardiac collagen concentration and prolyl hydroxylase activity. Since, however, the cardiac muscle mass was diminished by verapamil administration, treatment actually slightly reduced the collagen content of the heart. In the aorta collagen concentration was increased by verapamil treatment. Contrary to these results, minoxidil treatment was observed to increase the cardiac collagen concentration, content and prolyl hydroxylase activity in SHR. These results suggest that the factors governing myocardial connective tissue proliferation and regression may be independent of those governing muscle fibre hypertrophy and that particular drug actions on myocardial collagen metabolism must be taken into account.     

In vivo and in vitro effects of nebivolol on penile structures in hypertensive rats

BACKGROUND: Erectile dysfunction is associated with high blood pressure and antihypertensive treatment, especially diuretics and traditional beta-blockers. Nevertheless, new beta-blockers such as nebivolol present some differences with respect to the classic beta-blockers. The aim of this study was to determine the functional and morphologic effects of nebivolol on penile structures in hypertensive rats. METHODS: During a 6-month period, male spontaneously hypertensive rat (SHR) and Wistar-Kyoto (WKY) rats were studied. The groups were as follows: 1) untreated SHR (Untreated-SHR); 2) SHR given nebivolol 10 mg/kg/day (SHR+N); 3) SHR given amlodipine 3 mg/kg/day (SHR+AML); and 4) untreated WKY (untreated-WKY). Cavernous smooth muscle (CSM) and vascular smooth muscle (VSM) from cavernous arteries, as well as collagen type III (COL III) in cavernous tissue, were evaluated. RESULTS: After 6 months, SHR groups given nebivolol and amlodipine showed similar reductions in blood pressure compared with untreated SHR. However, only SHR+N and control WKY showed significantly lower values of CSM (P < 01), VSM (P < 01), and COL III (P < 01) when compared with untreated SHR and SHR+AML. In addition SHR+N showed a higher endothelial nitric oxide synthase expression in sinusoidal endothelium compared with SHR, and SHR+AML (P < 01). In vitro studies revealed that SHR+N displayed a better relaxation response to acetylcholine than untreated-SHR and SHR+AML (P < 01). CONCLUSION: Nebivolol presented equivalent BP control compared with amlodipine. However, only nebivolol showed a significant better functional outcome with a protective role against structural changes in erectile tissue that are caused by arterial hypertension.     

Reduction of cardiac fibrosis decreases systolic performance without affecting diastolic function in hypertensive rats

Pressure-overload left ventricular hypertrophy (LVH) is characterized by an increase in myocyte size and fibrosis. However, it is not clear how each of these components affects hypertensive heart disease (HHD). We have shown in 2 different rat models of hypertension that cardiac fibrosis can be reduced with N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), an antifibrotic peptide normally present in mammals. To assess how inhibition of fibrosis affects HHD, spontaneously hypertensive rats (SHR) and normotensive controls (WKY) were treated with Ac-SDKP or vehicle. Cardiac systolic and diastolic function were assessed using in vivo pressure-volume (PV) analysis. Left ventricle passive compliance was also determined ex vivo. We found that in SHR, Ac-SDKP normalized left ventricle total collagen content and interstitial collagen fraction without changing myocyte diameter or left ventricle mass. In WKY, collagen did not change significantly after treatment. Ac-SDKP did not affect left ventricle diastolic function, determined in vivo and ex vivo in SHR and WKY, whereas systolic function was significantly decreased in SHR treated with Ac-SDKP and unchanged in treated WKY. We concluded that in adult SHR, reducing left ventricle collagen deposition with Ac-SDKP does not improve diastolic function, whereas it decreases systolic performance. These findings suggest that total left ventricle collagen reduction per se does not necessarily benefit cardiac function. In HHD, other factors besides collagen quantity, such as myocyte hypertrophy and/or collagen type or cross-link, might be targeted to improve cardiac function.     

Effect of celiprolol on cardiac hypertrophy in hypertension.

The present study was undertaken to clarify whether celiprolol and atenolol, beta1-selective beta blockers with and without intrinsic sympathomimetic activity (ISA), respectively, might improve ischemic damage in the isolated perfused hearts of spontaneously hypertensive rats (SHR), and whether long-term treatment with celiprolol may reduce left ventricular hypertrophy (LVH) in patients with essential hypertension. Atenolol (50 mg/kg/day) or celiprolol (300 mg/kg/day) for 7 weeks significantly reduced the blood pressure in SHR to the same degree, and both drugs decreased the heart rate, but the magnitude of the fall in heart rate was significantly higher with atenolol treatment than with celiprolol treatment. Both treatments significantly reduced the ratio of LV weight to body weight in SHR and significantly improved the coronary reserve in SHR to the same extent. Both treatments significantly improved the extent of recovery of the pressure-rate product and the extent of percent recovery of the coronary flow after reperfusion following 30 min of ischemia in SHR. Celiprolol treatment in patients with essential hypertension for 12 months significantly decreased interventricular septal thickness (IVST)+LV posterior wall thickness (PWT) and LV mass index (LVMI), but there was no significant correlation between IVST+PWT or LVMI and blood pressure before and after treatment. IVST+PWT and LVMI were significantly decreased after 3 months of treatment and these LVH indices were significantly smaller after 6 and 12 months of treatment than after 3 months of treatment. In conclusion, both celiprolol and atenolol treatment reduced LVH and improved the ischemic damage in SHR. In essential hypertensive patients with LVH, celiprolol treatment effectively reduced blood pressure and achieved LVH regression.     

Influence of early antihypertensive treatment on vascular and cardiac design in SHR with and without renal hypertension.

The present study was designed to explore to what extent pressure reduction by antihypertensive therapy and pressure elevation by renal hypertension are able to affect structural vascular and cardiac changes in young spontaneously hypertensive rats (SHR). Pressure elevation in SHR was induced by means of superimposing 2 kidney, 1 clip renal hypertension (2K1C). Pressure reduction was achieved by means of the vasoselective calcium antagonist felodipine from 6 to 13 weeks of age in both clipped and unclipped SHR. Vascular structure of the skeletal muscle was assessed hemodynamically by perfusing a hindlimb preparation and left ventricular dimensions were calculated from pressure-volume relationships of isolated hearts arrested in diastole. Induction of renal hypertension in SHR resulted, besides augmentation of arterial pressure in a marked concentric left ventricular hypertrophy, i.e. elevations of wall thickness to internal radius ratio. Likewise, in renal hypertensive SHR, a structural adaptation of the skeletal muscle vascular bed occurred, reflected as elevations of minimal vascular resistance and maximal generated perfusion pressure. Antihypertensive treatment for 8 weeks with felodipine reduced and also prevented mean arterial pressure from increasing further in SHR, and in SHR with superimposed renal hypertension by approximately 15% (p < 0.001 for both). In renal hypertensive SHR, felodipine partly prevented the development of exaggerated structural changes, both in the heart and in the skeletal muscle vascular bed, as reflected by reduced wall thickness to internal radius ratio and reduced minimal vascular resistance by 22% and maximal pressure response by 10% respectively (p < 0.01 for both parameters).(ABSTRACT TRUNCATED AT 250 WORDS)     

自发性高血压大鼠心肌丝裂素活化蛋白激酶活性增加

新近研究表明丝裂素活化蛋白激酶（MAPK）是细胞增殖肥大的重要酶类，为各种细胞外的生长刺激信号引起细胞内信息传递的共同通路或汇聚点。本文通过观察自发性高血压大鼠（SHR）心肌MAPK活性和心肌肥大的关系，探讨SHR心肌肥大发生的可能细胞内信息传递机制。方法：4个月的SHR和WKY大鼠各8只，以心重／体重的比值表示心肌肥厚的程度，采用胶内磷酸化法测定心肌MAPK活性。结果：与WKY大鼠比较，SHR心肌MAPK活性增加107.0％（P＜0．01），心肌肥大程度增加38．3％（P＜0．01）。心肌MAPK活性与心肌肥大程度呈显著正相关（r=0．708，P＜0．05）。结论：SHR心肌肥厚可能涉及MAPK。     

Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure

OBJECTIVE: Extracellular matrix, particularly type I fibrillar collagen, provides tensile strength that allows cardiac muscle to perform systolic and diastolic functions. Collagen is induced during the transition from compensatory hypertrophy to heart failure. We hypothesized that cardiac stiffness during decompensatory hypertrophy is partly due to a decreased elastin:collagen ratio. MATERIALS AND METHODS: We prepared left ventricular tissue homogenates from spontaneously hypertensive rats (SHR) aged 30-36 weeks, which had compensatory hypertrophy with no heart failure, and from SHR aged 70-92 weeks, which had decompensatory hypertrophy with heart failure. Age- and sex-matched Wistar-Kyoto (WKY) rats were used as normotensive controls. In both SHR groups, increased levels of collagen were detected by immuno-blot analysis using type I collagen antibody. Elastin and collagen were quantitated by measuring desmosine/isodesmosine and hydroxyproline spectrophometrically, respectively. To determine whether the decrease in elastin content was due to increased elastinolytic activity of matrix metalloproteinase-2, we performed gelatin and elastin zymography on left ventricular tissue homogenates from control rats, SHR with compensatory hypertrophy and SHR with heart failure. RESULTS: The elastin:collagen ratio was 0.242 +/- 0.008 in hearts from WKY rats. In SHR without heart failure, the ratio was decreased to 0.073 +/- 0.003 and in decompensatory hypertrophy with heart failure, the ratio decreased to 0.012 +/- 0.005. Matrix metalloproteinase-2 activity was increased significantly in SHR with heart failure compared with controls (P < 0.001). The level of tissue inhibitor of metalloproteinase-4 was increased in compensatory hypertrophy and markedly reduced in heart failure. Decorin was strongly reduced in decompensatory heart failure compared with control hearts. CONCLUSIONS: Since collagen was induced in SHR with heart failure, decorin and elastin were decreased and the ratios of gelatinase A and elastase to tissue inhibitor of metalloproteinase-4 were increased, we conclude that heart failure is associated with adverse extracellular matrix remodeling.     

Attenuation of cardiac failure, dilatation, damage, and detrimental interstitial remodeling without regression of hypertrophy in hypertensive rats

Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99+/-0.02 g; untreated SHR, 1.40+/-0.02 g; treated SHR, 1.36+/-0.02 g; P<0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling.     

Acute effect of calcium blocker on renal hemodynamics in diabetic spontaneously hypertensive rat

This study was done to examine the acute effect of a calcium channel blocker on renal hemodynamics in the diabetic spontaneously hypertensive rat (SHR). Streptozortocin was used to induce diabetes, and barnidipine (B) was used as a calcium blocker. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate (PAH) and inulin, respectively. Rats were divided into two groups: nondiabetic SHR, N-SHR; diabetic SHR, DM-SHR. B increased RBF in N-SHR (7.44 ± 1.99 versus 8.50 ± 1.97 mL/min/g·kw) while there was no change in DM-SHR. B reduced renovascular resistance (RVR) in DM-SHR and N-SHR. B increased GFR in N-SHR (1.15 ± 0.24 versus 1.34 ± 0.25 mL/min/g·kw), in spite of no changes in DM-SHR. B did not modify filtration fraction (FF) in both groups. These results indicate (1) in SHR, B exerts beneficial effects on hypertensive renal damage by reducing mean arterial pressure (MAP), RVR, RBF, and GFR; (2) in diabetic SHR, B is less effective in restoring renal hyperfiltration in spite of reducing RVR.     

Persistent improvement of cardiovascular risk factors in spontaneously hypertensive rats following early short-term captopril treatment

This study was designed to determine whether an improvement in cardiovascular risk factors persists in spontaneously hypertensive rats (SHR) following withdrawal of angiotensin converting enzyme inhibitor (ACE-I) treatment. SHR were given deionized drinking water or captopril solution from four to sixteen weeks of age. At twelve weeks of age, rats from each group were instrumented with radiotelemetry devices for continuous monitoring of blood pressure. Mean arterial blood pressure was significantly lower in captopril-treated SHR during treatment (92+/-2 vs 147+/-1 mm Hg), and at twelve weeks after treatment withdrawal (131+/-2 vs 158+/-2 mm Hg). In addition, proteinuria, renal vascular resistance, plasma triglyceride levels, fasting glucose levels, post-prandial insulin levels, and heart weights were significantly reduced in the treated SHR compared to control SHR, at time-points between three to seven months after captopril withdrawal. Our findings indicate that short-term administration of an ACE-I during the developmental phase of hypertension in the SHR results in a long-term overall improvement of cardiovascular risk factors.     

Regression of hypertensive myocardial fibrosis by Na(+)/H(+) exchange inhibition

We have recently reported that the inhibition of the Na(+)/H(+) exchanger (NHE) during 1 month in spontaneously hypertensive rats (SHR) is followed by regression of cardiomyocyte hypertrophy but not of myocardial fibrosis. The aim of this study was to evaluate whether a treatment of longer duration could reduce myocardial fibrosis and stiffness. SHR received 3.0 mg/kg per day of the specific NHE-1 inhibitor cariporide; the effect on cardiomyocyte cross-sectional area, myocardial collagen volume fraction, collagen synthesis, and myocardial stiffness (length-tension relation in left papillary muscles) was evaluated at several time points (after 1, 2, or 3 months). A slight decrease of approximately 5 mm Hg in systolic blood pressure was observed after 1 month of treatment with no further changes. After 2 and 3 months of treatment, the size of cardiomyocytes remained within normal values and myocardial fibrosis progressively decreased to normal level. Accordingly, myocardial stiffness and the serum levels of the carboxyterminal propeptide of procollagen type I, a marker of collagen type I synthesis, were normalized after 3 months. Left ventricular weight decreased from 910+/-43 (in untreated SHR) to 781+/-21 mg (treated SHR) after 3 months of treatment. No difference in body weight between treated and untreated SHR was observed after this period of treatment. The present data allow us to conclude that in the SHR the administration of an NHE-1 inhibitor for 2 or 3 months leads to the normalization of collagen type I synthesis, myocardial collagen volume fraction, and stiffness.     

Combined antihypertensive and cardioprotective effects of nebivolol and hydrochlorothiazide in spontaneous hypertensive rats

The antihypertensive and cardioprotective effects of the combination of nebivolol (NEB) and hydrochlorothiazide (HCTZ) in spontaneously hypertensive rats (SHR) were investigated. SHR and age-matched Wistar-Kyoto normotensive rats were randomly assigned to one of six groups: SHR treated with NEB (1 mg/kg/day, intragastric); SHR treated with HCTZ (5 mg/kg/day, intragastric); SHR treated with NEB plus HCTZ (1 + 2.5 mg/kg/day); SHR treated with NEB plus HCTZ (1 + 5 mg/kg/day), along with a SHR and a WKY control group. The effects of NEB and HCTZ on clinical chemistry parameters and on cardiac function and structure were evaluated. NEB and HCTZ in combination had synergistic antihypertensive effects and significantly reduced heart rate and blood pressure compared with monotherapy with either agent. These effects were independent of water intake, urine output and electrolyte excretion. NEB plus HCTZ was associated with reduced oxidative stress in terms of glutathione availability, lower angiotensin I levels as index of plasma renin activity and reduced clearance of urinary sodium compared with HCTZ alone. Cardiac morphometric data and antioxidant parameters indicate that NEB may influence cardiac structure by reducing hypertrophy and by enhancing the availability of endothelial nitric oxide - a unique characteristic of NEB. The authors suggest that a combination of NEB and HCTZ for the treatment of hypertension may be useful for the synergistic characteristics of both drugs.     

High salt intake accelerated cardiac remodeling in spontaneously hypertensive rats: time window of left ventricular functional transition and its relation to salt-loading doses

Salt-loading is an accelerator of hypertensive left ventricular (LV) remodeling. The relationship between salt-loading doses and the time window in which a transition from compensated to decompensated LV hypertrophy occurs in spontaneously hypertensive rats (SHR) is unclear. Eight-week-old male SHR and Wistar Kyoto rats (WKY) were randomized to receive normal (0.5% NaCl) and high salt diets (4% or 8% NaCl) for 12 weeks. Left ventricular remodeling was dynamically determined by echocardiography. LV invasive hemodynamics and morphologic staining [collagen deposition, cardiomyocte hypertrophy, DNA damage (8-hydroxy-2-deoxyguanosine, 8-OHdG) and apoptosis] were performed at time of sacrifice. Cardiac malonyldialdehyde (MDA) level was measured by ELISA. No differences between 4% and 8% salt diets, in terms of blood pressure (BP) levels, heart mass index, and myocardial fibrosis were observed either in SHR or in WKY. In high salt-loaded SHR, the LV ejection fraction and wall thickness peaked at 8 weeks after salt-loading, parallel with a progressive enlargement of the LV chamber size. Furthermore, when compared to 4% salt SHR, LV functions were significantly compromised in 8% salt SHR, accompanied by more prominent cardiomyoctye hypertrophy, oxidative stress (and related DNA damage), and apoptosis. Salt-loading for 12 weeks with 8% NaCl diet is more efficient to induce LV dysfunction than 4% NaCl diet does in SHR, possibly by initiating increased oxidative stress and resultant cardiac damage. Moreover, 8 to 12 weeks after 8% salt-loading is the key time window in which a transition from compensated to decompensated LV hypertrophy occurs.     

Renal and vascular effects of chronic endothelin receptor antagonism in malignant hypertensive rats

The effect of the combined ET_A/ET_B endothelin receptor antagonist bosentan on blood pressure, vascular hypertrophy, and pathologic renal changes was investigated in a model of malignant hypertension, severe vascular hypertrophy, and enhanced vascular expression of endothelin-1, the deoxycorticosterone acetate (DOCA), and salt-treated spontaneously hypertensive rat (SHR). DOCA-salt treated SHR received 100 mg bosentan per kilogram weight per day mixed with their food. Systolic blood pressure of untreated DOCA-salt SHR rose to 241 ± 1.5 mm Hg, whereas that of bosentan-treated rats rose to 221 ± 5.1 mm Hg (P < .01). Cardiac and conduit artery mass were not affected by treatment. Small arteries from the coronary, renal, and mesenteric circulations showed a smaller media width and cross-sectional area of the media in rats treated with bosentan than in untreated rats. The kidneys showed the presence of fibrinoid necrosis in a high percentage of afferent arterioles and glomeruli of untreated DOCA-SHR. Some kidneys of treated rats exhibited less severe vascular hypertrophy and lesser extent of vascular or glomerular fibrinoid necrosis, but the renal injury score of bosentan-treated DOCA-SHR was only at the limit of significance from that of untreated rats (P = .06). These results suggest a role for endothelin-1 in blood pressure elevation and the severe vascular hypertrophy of small arteries of the coronary, renal, and mesenteric vasculature, but not of the heart or larger conduit vessels in the malignant hypertension that SHR develop after treatment with DOCA and salt. Although some bosentan-treated rats showed fewer renal lesions, a significant effect on renal pathology could not be unambigously demonstrated. Further studies will be necessary to determine whether endothelin antagonists may indeed offer some degree of renal protection and have therapeutic potential in severe or malignant hypertension.     

Pharmacodynamic Contribution to the Vasodilator Effect of Chronic AT(1) Receptor Blockade in SHR

-The present study investigated the pharmacodynamic contribution of AT(1) receptor blockade to the regional hemodynamic effects of long-term treatment with the AT(1) receptor antagonist candesartan cilexetil in adult spontaneously hypertensive rats (SHR). Blood pressure and Doppler flowmetry measurements were made during and after withdrawal of candesartan cilexetil, representing times of maximal and negligible blockade of AT(1) receptor-mediated vasoconstriction. There was marked renal, mesenteric, and hindquarter vasodilation in SHR treated for 4 weeks with candesartan cilexetil (2 mg/kg per day in drinking water, n=8) compared with vehicle (n=8). Blood pressure increased after withdrawal of candesartan cilexetil but was still reduced after 6 days, whereas regional flows and conductances did not reduce significantly compared with the last day of treatment. There was more prolonged inhibition of angiotensin (Ang) I-induced than Ang II-induced pressor responses after withdrawal of candesartan cilexetil, but these returned to control levels before blood pressure reached fully hypertensive levels. The renal and mesenteric vasoconstrictor effects of exogenously administered Ang I and Ang II returned to control levels just 2 days after withdrawal of candesartan cilexetil. Therefore, sustained inhibition of tonic Ang-mediated vasoconstriction caused by blockade of the AT(1) receptor is not the only factor contributing to the hemodynamic profile after long-term administration of candesartan cilexetil. In addition, compared with the vehicle group, blood pressures at maximum vasoconstriction and maximum vasodilation (an indirect measure of vascular hypertrophy) were significantly reduced in candesartan cilexetil-treated SHR on the last day of treatment, as was mesenteric media wall-to-lumen ratio in a separate group of similarly treated SHR. Collectively, these findings indicate that Ang-mediated vasoconstriction rapidly normalizes on withdrawal of AT(1) receptor blockade and that regression of vascular hypertrophy is important in determining blood pressure and hemodynamic status in candesartan cilexetil-treated SHR at this time.     

Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats

The antihypertensive effect of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone has been reported in patients with diabetes or obesity. The correlation of PPARgamma expression with blood pressure and the therapeutic application of rosiglitazone in spontaneously hypertensive rats (SHR) were investigated in the present study. Systolic blood pressure of 21-week SHR was significantly higher than that of age-matched Wistar-Kyoto rats (WKY) (225 +/- 5 v 144 +/- 2 mm Hg, P <.05). Basal expression levels of PPARgamma proteins in vascular tissues of 21-week SHR were significantly lower than that of age-matched 21-week WKY (P <.05). This reduced expression of PPARgamma was not detected between 5- and 13- week SHR and age-matched WKY. Cardiac PPARgamma expression was also not different among different age groups between SHR and WKY. Chronic treatment with rosiglitazone, but not PPARalpha agonist Wy14643, significantly retarded hypertension development and reversed abnormally faster heart rate in young SHR. An unfavorable effect of rosiglitazone treatment was the increased heart-to-body weight ratio accompanied by left ventricular hypertrophy. In conclusion, vascular PPARgamma protein expression in adult SHR (21 weeks) is significantly decreased in comparison with the age-matched WKY. Chronic rosiglitazone treatment retards hypertension development, but the associated prohypertrophy effect calls for a cautious use of this thiazolidinedindione in the treatment of insulin resistance syndrome associated with hypertension.     

Impaired vasodilator and chronotropic responses to 5-hydroxytryptamine in two models of hypertension-associated cardiac hypertrophy.

OBJECTIVE: In connection with hypertension, research concerning 5-hydroxytryptamine (5-HT) receptors and subtypes in the cardiovascular system has so far been predominantly focused on various vascular tissues. In this study, the effects of 5-HT were investigated in isolated hearts with experimental cardiac hypertrophy. DESIGN AND METHODS: Cardiac hypertrophy was induced by stenosing the abdominal aorta (ASR) of 5-week-old Wistar rats. The functional response to serotonin was measured in unpaced, ASR hearts (18-20 weeks) and compared with those of "sham" operated SHR and WKY rats. RESULTS: The ASR, less hypertensive than SHR, showed more pronounced cardiac hypertrophy. The positive chronotropic and coronary vasodilator response to 5-HT was reduced in hypertrophied hearts from SHR and ASR when compared to "sham" operated and normotensive controls. The positive chronotropic effect of 5-HT could be antagonised with ketanserin, without affecting the coronary vasodilation. 5-HT did not induce any change in contractile force. CONCLUSIONS: Cardiac hypertrophy is associated with impaired coronary vasodilator and chronotropic responsiveness to serotonin. The chronotropic response to 5-HT is mediated by the 5-HT2-receptor subtype.     

Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients

OBJECTIVES: To compare the effects of nebivolol and atenolol in 25 ambulatory hypertensive patients with impaired glucose tolerance. DESIGN: Clinic and ambulatory blood pressure, insulin sensitivity (euglycemic-hyperinsulinemic clamp), glucose tolerance (intravenous glucose tolerance test), systemic and regional haemodynamics were measured after 4 weeks of placebo and after each 16-week treatment period in a double-blind, crossover fashion. RESULTS: Nebivolol and atenolol similarly reduced (P< 0.001) clinic and ambulatory blood pressure by approximately 15/10 mmHg, systolic and diastolic. Clinic and ambulatory heart rate was reduced to a greater extent (P < 0.01) by atenolol than nebivolol. Atenolol was associated with an approximately 20% reduction in insulin sensitivity (insulin-induced glucose disposal rate/mean insulin concentration ratio, P < 0.01) and an approximately 10% reduction in glucose disappearance rate (K-value, P < 0.05), whereas these variables were not significantly modified with nebivolol. Cardiac output was reduced similarly (P < 0.05) by both drugs at rest but forearm blood flow, forearm vascular resistance or total peripheral resistance were unaffected. A significant inverse correlation coefficient between cardiac output and insulin sensitivity was found at baseline, suggesting that a compensatory increase in systemic blood flow occurs in hypertensive patients with progressively more marked insulin resistance. This relationship was unaffected by nebivolol but was lost with atenolol. CONCLUSIONS: These results indicate that insulin sensitivity was not modified significantly by nebivolol, whereas it was reduced by atenolol, although blood pressure was decreased to the same extent by both drugs. Neither drug induced systemic or forearm vasodilatation but the inverse relationship between cardiac output and insulin sensitivity was preserved with nebivolol but not with atenolol.