Effects of losartan and enalapril at different doses on cardiac and renal interstitial matrix in spontaneously hypertensive rats

We have evaluated the effects of an ACE inhibitor, enalapril (ENA) and of an angiotensin II receptor blocker, losartan (LOS), administered either at hypotensive or non-hypotensive dosage, on the cardiac and renal structure of spontaneously hypertensive rats (SHR). Forty-eight rats were included in the study: eight SHR were treated with low-dose (ld, 1 mg/kg/day) ENA; eight with low-dose (ld, 0.5 mg/kg/day) LOS; eight with high-dose (hd, 25 mg/kg/day) ENA; eight with high-dose (hd, 15 mg/kg/day) LOS; while eight Wistar-Kyoto (WKY) and eight SHR were kept untreated (unt). Treatment was given from the 4th to the 12th week of age. Systolic blood pressure (SBP) was measured non-invasively every week. The left ventricular weight to body weight (RLVM) and the left + right kidney weight (RKW) to body weight was measured, and the cardiac and glomerular interstitial collagen content was evaluated using sirius red staining and image analysis. In addition, cardiac metalloproteinases activity (43 kDa MMP, MMP-2, and MMP-9) was evaluated by zymography. A significant reduction in RLVM was observed in SHR given ENA hd or LOS hd. Cardiac collagen was significantly reduced in SHR ENA hd and SHR LOS hd as well as in SHR LOS ld, but not in SHR ENA ld. The 43 kDa MMP collagenase activity was greater in WKY unt compared with SHR unt, being normalized only in SHR ENA hd. The gelatinase activity of MMP-9 showed a trend similar to 43 kDa MMP, but differences between SHR and WKY unt were only of borderline statistical significance. No difference among groups was observed in MMP-2 activity. No significant differences in RKW was observed between groups. However, the collagen content in the glomerular perivascular space was significantly reduced in all treated groups, including those given ld, compared with SHR unt. In conclusion, LOS and ENA showed a similar preventive effect on the increase of RLVM in SHR, but, at least in part, different effects on the extracellular matrix in different organs, being cardiac collagen less sensitive to low dose (ld) ACE inhibition.     

Effects of Hypotensive and Non-hypotensive Doses of Manidipine on Structure, Responses to Endothelin-1 and ICAM-1 Production in Mesenteric Small Resistance Arteries of Spontaneously Hypertensive Rats

Objective: We have evaluated the effects of a new calcium channel blocker, manidipine, given at both high, hypotensive and low, non-hypotensive doses, on vascular morphology, response to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). Methods: Ten SHR were treated with manidipine 3 mg/kg per day (high dose) and 10 with manidipine 0.3 mg/kg/ per day (low dose). The drug was administered by gavage from the 4th to 12th weeks of age. Eighteen Wistar-Kyoto (WKY) rats and 18 SHR were kept untreated as controls. Rats were killed at 13 weeks. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of indexes of vascular structure (media thickness, wall thickness, media/lumen ratio). Results: Systolic blood pressure was significantly reduced by the high dose of the drug, while no effect was observed with low-dose manidipine. A reduction in the media/lumen ratio was observed only in SHR treated with high-dose manidipine. The response to endothelin-1 in untreated SHR was significantly lower in comparison with WKY; a significant reduction was observed in SHR treated with high-dose manidipine. ICAM-1 vascular concentrations were higher in untreated SHR than in WKY controls. Both high- and low-dose manidipine reduced ICAM-1 concentrations toward normalization. Conclusions: Manidipine at high, hypotensive, but not at low, non-hypotensive doses has been proven to reduce structural alterations in mesenteric small resistance arteries, and to normalize vascular responses to endothelin-1. In addition, manidipine, at both low and high doses, may reduce ICAM-1 vascular production, thus suggesting a possible anti-atherogenic effect.     

Effects of hypotensive and non-hypotensive doses of manidipine on structure, responses to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats.

OBJECTIVE: We have evaluated the effects of a new calcium channel blocker, manidipine, given at both high, hypotensive and low, non-hypotensive doses, on vascular morphology, response to endothelin-1 and ICAM-1 production in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). METHODS: Ten SHR were treated with manidipine 3 mg/kg per day (high dose) and 10 with manidipine 0.3 mg/kg/per day (low dose). The drug was administered by gavage from the 4th to 12th weeks of age. Eighteen Wistar-Kyoto (WKY) rats and 18 SHR were kept untreated as controls. Rats were killed at 13 weeks. Mesenteric small arteries were dissected and mounted on a micromyograph for determination of indexes of vascular structure (media thickness, wall thickness, media/lumen ratio). RESULTS: Systolic blood pressure was significantly reduced by the high dose of the drug, while no effect was observed with low-dose manidipine. A reduction in the media/lumen ratio was observed only in SHR treated with high-dose manidipine. The response to endothelin-1 in untreated SHR was significantly lower in comparison with WKY; a significant reduction was observed in SHR treated with high-dose manidipine. ICAM-1 vascular concentrations were higher in untreated SHR than in WKY controls. Both high- and low-dose manidipine reduced ICAM-1 concentrations toward normalization. CONCLUSIONS: Manidipine at high, hypotensive, but not at low, non-hypotensive doses has been proven to reduce structural alterations in mesenteric small resistance arteries, and to normalize vascular responses to endothelin-1. In addition, manidipine, at both low and high doses, may reduce ICAM-1 vascular production, thus suggesting a possible anti-atherogenic effect.     

Effects of indapamide, a thiazide-like diuretic, on structure of cerebral arterioles in hypertensive rats

We examined the effects of indapamide, a thiazide-like diuretic, on cerebral arterioles in spontaneously hypertensive rats (SHR). The structure and mechanics of cerebral arterioles were examined in untreated Wistar Kyoto rats (WKY) and SHR that were untreated or treated for 3 months with a low (1 mg/kg per day) or a high (10 mg/kg per day) dose of indapamide. We measured pressure, diameter, and cross-sectional area of the vessel wall (CSA) in maximally-dilated (EDTA) cerebral arterioles. Treatment of SHR with the high dose of indapamide normalized cerebral arteriolar mean pressure (62+/-4 [mean+/-SEM] versus 59+/-3 mm Hg in WKY and 88+/-6 mm Hg in untreated SHR; P<0.05), pulse pressure (13+/-1 versus 10+/-1 mm Hg in WKY and 20+/-1 mm Hg in untreated SHR; P<0.05), and CSA (1080+/-91 versus 1100+/-48 microm2 in WKY and 1439+/-40 microm2 in untreated SHR; P<0.05). In contrast, treatment of SHR with the low dose of indapamide did not normalize arteriolar mean (72+/-3) and pulse pressure (20+/-1 mm Hg), but did normalize CSA (1091+/-52 microm2). Treatment with either dose of indapamide failed to increase external diameter in cerebral arterioles of SHR (89+/-4 and 92+/-4 microm, respectively, versus 103+/-6 microm in WKY and 87+/-4 microm in untreated SHR). Finally, treatment with indapamide attenuated the rightward shift of the stress-strain curve in SHR, suggesting that treatment with indapamide attenuated increases in distensibility of cerebral arterioles in SHR. These findings suggest that, whereas thiazide-like diuretics may not attenuate eutrophic inward remodeling of cerebral arterioles in SHR, they may attenuate hypertrophic inward remodeling via a mechanism unrelated to their pressor effects.     

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.     

Inhibition of Rho-kinase attenuates nephrosclerosis and improves survival in salt-loaded spontaneously hypertensive stroke-prone rats

OBJECTIVES: We examined whether the Rho/Rho-kinase pathway is involved in the pathogenesis of nephrosclerosis in severely hypertensive rats and assessed the effects of long-term treatment with a Rho-kinase inhibitor, fasudil, on kidney function, histological findings, gene expressions, and survival. We also attempted to elucidate the mechanisms involved. METHODS: We studied the following four groups: control Wistar-Kyoto rats (WKY), untreated salt-loaded spontaneously hypertensive stroke-prone rats (SHR-SP), low-dose fasudil (15 mg/kg per day)-treated SHR-SP, and high-dose fasudil (30 mg/kg per day)-treated SHR-SP. After 8 weeks' treatment, the effects of fasudil were examined. RESULTS: Untreated SHR-SP were characterized by increased blood pressure without circadian variation, decreased kidney function, abnormal renal morphological findings, and increased messenger RNA expression levels of transforming growth factor beta, collagen I, collagen III, p40phox, p47phox, plasminogen activator inhibitor 1, and intracellular adhesion molecule 1 in the renal cortex, compared with WKY. Long-term high-dose fasudil treatment significantly improved renal function (serum creatinine -32%, creatine clearance +39%), proteinuria (-92%) and histological findings (glomerular injury score -57%, arteriolar injury score -55%, fibrous area -40%, ED-1-positive cells -43%) without changing blood pressure or circadian variation, compared with untreated SHR-SP. In addition, fasudil significantly improved increased mRNA expression levels in the renal cortex. Furthermore, high-dose fasudil significantly prolonged survival time compared with untreated SHR-SP (P < 0.01). Low-dose fasudil treatment improved these variables slightly, but did not affect most significantly. CONCLUSION: The Rho/Rho-kinase pathway participates in the pathogenesis of nephrosclerosis in SHR-SP independently of blood pressure-lowering activity, partly by upregulation of the gene expressions of extracellular matrix, oxidative stress, adhesion molecules, and antifibrinolysis.     

Effects of chronic oral treatment with imidapril and TCV-116 on the responsiveness to angiotensin II in ventrolateral medulla of SHR.

OBJECTIVE: To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. RESULTS: Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). CONCLUSIONS: Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.     

Comparative effects of the angiotensin II receptor blocker, telmisartan, and the angiotensin-converting enzyme inhibitor, ramipril, on cerebrovascular structure in spontaneously hypertensive rats

OBJECTIVE: Antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEIs) reverses cerebral arteriolar remodeling, thus restoring dilatation and hence the lower limit of cerebral blood flow (CBF) autoregulation (LLCBF). The objective of this study was to determine whether angiotensin II receptor AT1 blockers (ARBs) produce the same effect. DESIGN: We examined the effects of treatment with an ARB [telmisartan (TEL), 1.93 +/- 0.04 mg/kg per day] or an ACEI [ramipril (RAM), 1.00 +/- 0.02 mg/kg per day] on the cerebral circulation in spontaneously hypertensive rats (SHR). METHODS: Arteriolar pressure and diameter (cranial window) and CBF (laser Doppler) were measured during stepwise hypotensive hemorrhage, before and after deactivation (ethylenediamine tetraacetic acid), in untreated Wistar-Kyoto (WKY) rats and SHR untreated or treated for 3 months with TEL or RAM in the drinking water. RESULTS: Treatment normalized arteriolar internal diameter (SHR, 38 +/- 3 microm; TEL, 52 +/- 2 microm; RAM, 50 +/- 2 microm; WKY, 58 +/- 4 microm), essentially by reversing eutrophic inward remodeling, and the LLCBF (SHR, 80 +/- 11 mmHg; TEL, 60 +/- 4 mmHg; RAM, 71 +/- 6 mmHg; WKY, 57 +/- 5 mmHg). CONCLUSION: The fact that the ARB (TEL) is as effective as an ACEI (RAM) in reversing cerebral arteriolar remodeling suggests that the cerebrovascular AT1 receptor is an underlying mechanism that promotes hypertensive eutrophic inward remodeling.     

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.     

Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in double-transgenic rats

We tested the hypothesis that the renin inhibitor aliskiren ameliorates organ damage in rats transgenic for human renin and angiotensinogen genes (double transgenic rat [dTGR]). Six-week-old dTGR were matched by albuminuria (2 mg per day) and divided into 5 groups. Untreated dTGR were compared with aliskiren (3 and 0.3 mg/kg per day)-treated and valsartan (Val; 10 and 1 mg/kg per day)-treated rats. Treatment was from week 6 through week 9. At week 6, all groups had elevated systolic blood pressure (BP). Untreated dTGR showed increased BP (202+/-4 mm Hg), serum creatinine, and albuminuria (34+/-5.7 mg per day) at week 7. At week 9, both doses of aliskiren lowered BP (115+/-6 and 139+/-5 mm Hg) and albuminuria (0.4+/-0.1 and 1.6+/-0.6 mg per day) and normalized serum creatinine. Although high-dose Val lowered BP (148+/-4 mm Hg) and albuminuria (2.1+/-0.7 mg per day), low-dose Val reduced BP (182+/-3 mm Hg) and albuminuria (24+/-3.8 mg per day) to a lesser extent. Mortality was 100% in untreated dTGR and 26% in Val (1 mg/kg per day) treated rats, whereas in all other groups, survival was 100%. dTGR treated with low-dose Val had cardiac hypertrophy (4.4+/-0.1 mg/g), increased left ventricular (LV) wall thickness, and diastolic dysfunction. LV atrial natriuretic peptide and beta-myosin heavy chain mRNA, albuminuria, fibrosis, and cell infiltration were also increased. In contrast, both aliskiren doses and the high-dose Val lowered BP to a similar extent and more effectively than low-dose Val. We conclude that in dTGR, equieffective antihypertensive doses of Val or aliskiren attenuated end-organ damage. Thus, renin inhibition compares favorably to angiotensin receptor blockade in reversing organ damage in dTGR.     

Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system.

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.     

Differential effect of low-dose thiazides on the renin angiotensin system in genetically hypertensive and normotensive rats

Fifty years since thiazide diuretics were introduced, they are established as first-line antihypertensive therapy. Because the thiazide dosing profile lessened, the blood pressure lowering mechanism may lie outside their diuretic properties. We evaluated this mechanism in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) by examining the effects of low-dose hydrochlorothiazide (HCTZ) administration on renin-angiotensin system components. The 7-day, 1.5 mg/kg per day HCTZ did not change systolic pressure (SBP) in WKY, but decreased SBP by 41 ± 2 mm Hg (P < .0001) in SHR, independent of increased water intake, urine output, or alterations in electrolyte excretion. HCTZ significantly increased the plasma concentrations of angiotensin I (Ang I) and angiotensin II (Ang II) in both WKY and SHR while reducing angiotensin-converting enzyme (ACE) activity and the Ang II/Ang I ratio (17.1 ± 2.9 before vs. 10.3 ± 2.9 after, P < .05) only in SHR. HCTZ increased cardiac ACE2 mRNA and activity, and neprilysin mRNA in WKY. Conversely in SHR, ACE2 activity was decreased and aside from a 75% increase in AT₁ mRNA in the HCTZ-treated SHR, the other variables remained unaltered. Measures of cardiac mas receptor mRNA showed no changes in response to treatment in both strains, although it was significantly lower in untreated SHR. These data, which document for the first time the effect of low-dose thiazide on the activity of the ACE2/Ang-(1-7)/mas receptor axis, suggest that the opposing arm of the system does not substantially contribute to the antihypertensive effect of thiazides.     

Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats.

OBJECTIVES: Natural angiogenesis has been shown to be impaired in spontaneously hypertensive rats (SHR). The purpose of this study was to determine whether pathological angiogenesis in the setting of tissue ischemia is also impaired in SHR, and to what extent it is modified by angiotensin-converting enzyme (ACE) inhibition. METHODS: Ischemia was induced in the hindlimb of SHR by excision of the femoral artery, after which the animals were randomly assigned to receive low-dose perindopril (sub-antihypertensive, 0.2 mg/kg/day), high-dose perindopril (antihypertensive, 2.0 mg/kg/day), or vehicle for 3 weeks. Wistar-Kyoto rats (WKY) with femoral artery excision served as a control group. RESULTS: Tissue ACE activity in SHR was significantly increased compared to WKY (49.4+/-6.2 vs. 34.0+/-14.2 IU/mg, P<0.01). Administration of perindopril significantly reduced ACE activity in SHR (low dose: 12.4+/-2.3; high dose: 11.0+/-2.1 IU/mg, P<0.005). Angiogenesis of the ischemic limb muscles was significantly impaired at 4 weeks in SHR versus WKY as indicated by the lower capillary density in the former (364.5+/-43.0 vs. 463.8+/-63.0/mm(2), P<0.05) as well as the reduced hindlimb perfusion assessed by laser Doppler imaging (0.86+/-0.08 vs. 1.03+/-0.09, P<0.05). Administration of perindopril significantly augmented both the capillary density (low dose: 494.3+/-69.8; high dose: 543.9+/-76.9/mm(2), P<0.005) and the limb perfusion (low dose: 1.06+/-0.15; high dose: 1.05+/-0.12, P<0.05) of the ischemic limb in SHR. CONCLUSIONS: These findings indicate that pathological angiogenesis in the setting of tissue ischemia is impaired in SHR compared with WKY, and that this impairment can be reversed by ACE inhibition. The angiogenic properties of an ACE inhibitor may benefit patients with essential hypertension presenting with lower limb vascular insufficiency.     

Effects of antihypertensive therapy on cardiac sodium/hydrogen ion exchanger activity and hypertrophy in spontaneously hypertensive rats

BACKGROUND: Sodium/hydrogen ion exchange is hyperactive in hypertension. Myocardial sodium/hydrogen ion exchange hyperactivity accompanies the regression of cardiac hypertrophy in spontaneously hypertensive rats (SHR) after long term control of blood pressure with enalapril. Objectives: To explore whether this effect is shared by other antihypertensive agents or is specific to angiotensin-converting enzyme inhibition. ANIMALS AND METHODS: SHR and normotensive Wistar Kyoto (WKY) rats were treated for five weeks with enalapril (20 mg/kg/day), nifedipine (10 mg/kg/day) or losartan (40 mg/kg/day). Sodium/hydrogen ion exchange activity was estimated in terms of both steady intracellular pH in HEPES buffer and the rate of intracellular pH recovery from intracellular acid loads in isolated superfused 2'-7'-bis(2-carboxyethyl)-5,-(and-6)-carboxyfluorescein, acetoxymethyl ester form-loaded papillary muscles. RESULTS: Enalapril, nifedipine and losartan decreased systolic blood pressure in SHR to about the same value (140 3, 140 2 and 146 3 mmHg, respectively, at the end the treatment). However, the index of cardiac hypertrophy (heart weight to body weight ratio) was decreased to a smaller value with losartan than with nifedipine or enalapril (2.66 0.09, 3.06 0.05 and 2.86 0.04 mg/g respectively; P<0.05 ANOVA). For the untreated SHR, the index of cardiac hypertrophy was 3.30 0.04 mg/g. Myocardial sodium/hydrogen ion exchange hyperactivity in SHR was normalized by all treatments. CONCLUSIONS: The three treatments regressed cardiac hypertrophy and normalized sodium/hydrogen ion exchange exchange activity in SHR, and losartan was the most effective treatment for reversing cardiac hypertrophy, despite producing effects on blood pressure and sodium/hydrogen exchange activity similar to that of other antihypertensive drugs.     

Cilnidipine improves spontaneously hypertensive rat coronary hemodynamics without altering cardiovascular mass and collagen

OBJECTIVE : The present study was designed to determine the effects of prolonged treatment with cilnidipine, a novel dihydropyridine calcium antagonist which blocks both L-type and N-type calcium channels, on systemic, regional and coronary hemodynamics, cardiovascular mass and collagen content in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. METHODS : Male 23-week-old WKY and SHR rats were divided into two groups for each strain. One group received cilnidipine (10 mg/kg per day), whereas their respective controls were given no therapy. Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic mass, and hydroxyproline concentration were determined after 12 weeks treatment. RESULTS : The data demonstrated that cilnidipine neither affected systemic hemodynamics nor cardiovascular mass and collagen content in WKY rats. The same treatment in the SHR reduced arterial pressure and total peripheral resistance without changes in heart rate and cardiac index. Ventricular and aortic mass indices as well as ventricular collagen content remained unchanged. There were no differences in organ blood flows between two SHR groups, whereas renal, liver and left ventricular coronary vascular resistances were reduced by cilnidipine. After dipyridamole infusion left ventricular minimal coronary vascular resistance decreased further in cilnidipine-treated SHR as compared with control SHR rats. CONCLUSION : These data suggest that cilnidipine, an L- and N- type calcium channel antagonist, exerted beneficial effects on coronary hemodynamics without altering cardiovascular mass or collagen content in SHR.     

Effects of chronic treatment with simvastatin on endothelial dysfunction in spontaneously hypertensive rats.

OBJECTIVE: To investigate the effects of chronic treatment with simvastatin (SV) on endothelium-dependent relaxation and ouabain-induced contractions in aortic rings from spontaneously hypertensive rats (SHR), comparing with normotensive Wistar-Kyoto rats (WKY). METHODS: After a 12-week period of administration of 1 or 2 mg/kg SV to SHR and WKY, systolic blood pressure (SBP) and vascular reactivity in endothelium-intact aortic rings were assessed. RESULTS: Relaxation in response to acetylcholine (ACh) in WKY remained unaltered, but in SHR treated with 1 mg/kg SV, enhanced ACh-induced relaxation (P<0.05 versus untreated SHR) reached values observed in untreated WKY. The 2 mg/kg treatment also improved ACh relaxation (P<0.01 and P<0.05 versus untreated SHR and WKY respectively). Inhibiting cyclo-oxygenase (COX) with indomethacin (INDO) improved ACh relaxation in SHR (P<0.05) but not in WKY, independent of treatment with SV. Inhibition of nitric oxide synthase (NOS) with N(G)-nitro-L-arginine (L-NOARG) abolished ACh relaxations in all cases (P<0.001). The result was unaltered when combining INDO plus L-NOARG. SV treatment also decreased ouabain-induced contractions in endothelium-intact aortic rings from SHR, diminishing the percentage effect of contraction from 64.56+/-2.95 (untreated SHR) to 26.98+/-7.06 and 38.10+/-8.21 (1 and 2 mg/kg treated SHR respectively). Response to ouabain in WKY was not significantly affected by SV treatment CONCLUSIONS: Chronic treatment of SHR with SV improves endothelium-dependent ACh relaxation of the aortic rings, probably by an NO-involving mechanism more than by inhibiting contractile COX-derived factors. An improvement in endothelial modulation of ouabain-induced contractions was also observed after treatment with SV in SHR, which might be due to an inhibition of a calcium-sodium exchanger.     

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.     

High dietary salt enhances acute depressor responses to metformin

The antidiabetic drug metformin lowers blood pressure (BP) more in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY), and the hypotensive effect is enhanced by high dietary salt. To determine whether enhanced hypotension is secondary to greater decreases in sympathetic nerve activity (SNA), we placed WKY and SHR on normal salt (0.3%), and SHR on high salt (8.0%) for 2 weeks and then measured anesthetized BP and lumbar SNA to metformin (0, 10, 50, and 100 mg/kg, given intravenously). Baseline BP were similar in SHR groups but lower in WKY. Although metformin decreased BP more in high salt SHR (50 mg/kg: ΔBP: −23 ± 1 mm Hg) than in normal salt SHR (−14 ± 1 mm Hg, P < .01) and less in WKY (−10 ± 1 mm Hg, P < .05), equivalent decreases in SNA were observed. We conclude that both strain and high salt potentiate acute depressor responses to metformin through mechanisms that are independent of SNA.