Alpha-tocopherol supplementation favorable effects on blood pressure, blood viscosity and cardiac remodeling of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) were separated into two groups (n = 6 per group) and, since 5 months old, received alpha-tocopherol (alpha-tocopherol acetate120 IU) or vehicle by daily gavage for 2 weeks. Blood viscosity, blood pressure (BP) and myocardial remodeling were analyzed. The SHRs treated with alpha-tocopherol showed a significant reduction of BP and a major reduction of blood viscosity in comparison with the control SHRs. The cardiac hypertrophy indices showed some differences when the two SHR groups were compared, the LV mass index was not different between the groups; however, the cardiomyocyte size was more than 20% smaller in SHRs treated with alpha-tocopherol than in control SHRs (P < .05). The intramyocardial vessels distribution was more than 45% greater in alpha-tocopherol-treated SHRs than in control rats, significantly improving the vessels-to-myocytes ratio in treated SHRs than in control SHRs (P < .05). In conclusion, present findings strongly suggest a beneficial effect of alpha-tocopherol supplementation to genetically hypertensive rats. This was observed by a reduction of both blood viscosity and BP, and a consequent cardiomyocyte hypertrophy in treated SHRs; an improvement of vessels-to-myocytes ratio in these rats was also observed.     

Amlodipine preserves the glomerular number in spontaneously hypertensive rats

The calcium channel blockers have individual pharmacological and therapeutic properties that may vary, but as a group, they are effective antihypertensive agents in patients with renal disease. Their effects on the kidney may extend beyond BP reduction alone. Fifteen one-year-old male spontaneously hypertensive rats (SHR) were separated in three groups: Initial control group (IC), Final control group (FC, SHR received standard rat chow and fresh water ad libitum during 15 weeks), Amlodipine group (Aml, SHR) received 0.2 mg/kg/day of amlodipine in addition to food and water during 15 weeks. The glomerular number was estimated using the disector method. In the Control group, the BP level increased almost 20 per cent in the first six weeks (from 186 +/- 11 to 223 +/- 16 mmHg, p<0.01) and then BP level increased almost 15 percent until week 15 (from 223 +/- 16 to 258 +/- 20 mmHg, p<0.01). In the same period, the Aml group showed a progressively low BP, reaching a level almost 50 per cent lower in the week 15 than in the week 1 (from 190 +/- 15 to 101+/-8 mmHg, p<0.01). Amlodipine treatment significantly decreased the serum creatinine, more than 12 per cent lower than the FC group (from 70.4 +/- 6.2 to 61.4 +/- 5.2 micromol/L, p<0.05). However, proteinuria was not different when groups were compared. The FC group reached a glomerular number almost 20 percent smaller than the IC and Aml groups (from 35 x 10(3) +/- 7 x 10(3) in IC group, 34 x 10(3) +/- 4 x 10(3) in Aml group to 27 x 10(3) +/- 3 x 10(3) in FC group, p<0.05). A possible protective effect of amlodipine against the loss of glomeruli in SHR is a major additional action of amlodipine in the treatment of hypertension mainly when the renal lesion already exists.     

Long-term intake of edible oils benefits blood pressure and myocardial structure in spontaneously hypertensive rat (SHR) and streptozotocin diabetic SHR

The beneficial effects of edible oils long-term supplementation in blood pressure (BP) and cardiac structure were investigated in spontaneously hypertensive rat (SHR) and streptozotocin diabetic (Db) SHR (45 mg/rat i.p.). Twenty-five 12-week old male SHR were divided into four SHR-Db groups and one SHR group, SHR-Db groups each receiving, respectively, olive oil, palm oil and fish oil, and another SHR-Db group with placebo by gavage on a daily basis for 6 weeks. Myocardial structures were analyzed through light microscopy and stereology. In SHR-Db, the BP and the myocardium were significantly altered by oil supplementation. The BP, the interstitial fibrosis and cardiomyocyte size showed a significant decrease in treated SHR-Db than in SHR or untreated SHR-Db. The myocardial microvasculature and number of cardiomyocytes were higher in all treated groups, especially in fish oil group. Long-term edible oil supplementation showed beneficial effects decreasing BP levels and offsetting adverse myocardial remodeling in diabetic SHR.     

The effects of spironolactone monotherapy on blood pressure and myocardial remodeling in spontaneously hypertensive rats: A stereological study

The aim of this study was to evaluate the cardiac structure of spontaneously hypertensive rats (SHRs) treated with different doses of spironolactone. Twenty SHRs were separated into four groups and treated for 13 weeks, as follows: one control group and three spironolactone treatment groups receiving doses of 5, 10 or 30 mg/kg/day. The spironolactone treatment either attenuated or prevented the tendency for increased blood pressure. However, the myocardial structure was not significantly affected by the spironolactone monotherapy treatment (all doses); it showed hypertrophied cardiac myocytes, focal areas of reactive fibrosis, inflammatory infiltrate and a decrease in the density of intramyocardial microvessels. None of the cardiac myocyte stereological parameters in the left ventricular myocardium showed significant differences among the SHR groups. The cardiac myocyte volume density was around 80%, the cardiac myocyte surface density varied from 3.6 to 4.1 x 10(4) mm2/mm3 and the cardiac myocyte mean cross-sectional area varied from 351 to 415 micro m2. The connective tissue volume density of the SHRs treated with the highest dose of spironolactone was 75% lower than in the control SHRs, and this was the only significant difference found for this parameter among SHR groups. The intramyocardial vessels showed some differences when the control SHRs and the other SHRs were compared. The lowest intramyocardial vessel volume density was found in the control group (more than 20% lower than that in the treated SHRs), but no significant difference was detected among the treated SHRs (all doses). The intramyocardial vessel length density (Lv[v]) and surface density (Sv[v]) showed a similar tendency, being significantly greater in the treated SHRs than in the control rats. The Lv[v] was 45% greater in the high-dose spironolactone group than in the control group, and it was 28% greater in the high-dose spironolactone SHRs than in the other treated SHRs. The Sv[v] was 50% greater in the high-dose spironolactone SHRs than in both control and low-dose spironolactone SHRs. Long-term spironolactone monotherapy showed a partial effect in the preservation of intramyocardial vessels and also in the attenuation of interstitial fibrosis.     

Renal cortex remodeling in nitric oxide deficient rats treated with enalapril

The kidney NO synthase is one of the most important renal controlling systems. This paper aims the quantification of renal cortical components involved in blood pressure regulation under NOs blockade. Spontaneous hypertensive rats (SHRs) are submitted to chronic blockade of NOs by L-nitro-arginine-methyl-ester (L-NAME) and an ACE inhibitor (enalapril) in comparison with the normotensive Wistar rats. Twenty SHRs and 5 Wistar rats were divided in 5 groups and observed for 21 days for blood pressure (BP) and serum creatinine: control Wistar (5) (C-W), control SHR (5) (C-SHR), L-SHR (5) - received L-NAME 30 mg/kg/day, L+E-SHR (5) - received L-NAME and Enalapril maleate 15 mg/kg/day, E-SHR (5) - received Enalapril maleate. A quantitative morphometric study (glomerular density, Q_A[g1], interstitium volume density, Vv[i], tubular surface and length densities, Sv[t] and Lv[t]) were performed at the end. The BP reached 226±15 mmHg in L-SHR group. The BP difference between the L-SHR and the C-SHR groups was significant from the first week while the E-SHR group became significant from the second week. At the end of the experiment the BP of the E-SHR group was similar to the BP in the C-W group. The Q_A[g1] was similar among C-SHR, L-SHR and L+E-SHR groups and no difference was found between E-SHR and C-W groups. In the L-SHRs serum creatinine was greatly increased, and microscopy showed thickening of arteriolar tunica media with an increase of the wall-to-lumen ratio, perivascular fibrosis, inflammatory infiltrated, tubular atrophy and interstitial fibrosis with focal segmental glomerulosclerosis. The use of enalapril was not completely efficient in reducing BP and morphological injury when the hypertension of SHRs was increased with the NOs blockade suggesting that NO deficiency-induced hypertension is not entirely mediated by the RAAS.     

Effect of chronic colchicine administration on the myocardium of the aging spontaneously hypertensive rat

Colchicine has been demonstrated to suppress the release of fibroblast growth factors, retard collagen formation and augment collagenase activity. Trials with colchicine in patients with hepatic fibrosis have suggested clinical benefit. The development of impaired myocardial function in the spontaneously hypertensive rat (SHR) is associated with a marked increase in myocardial fibrosis. The present study was carried out to test the hypothesis that chronic colchicine administration to the SHR would prevent the development of fibrosis and impaired myocardial performance.Colchicine (1 mg/l drinking water) was administered to male SHR and WKY rats from at age 13 months until 24 months or until evidence of heart failure was observed. Age-matched untreated SHR and colchicine treated and untreated WKY served as controls. At study, active and passive properties of isolated left ventricular muscle preparations were determined. Myocardial fibrosis was assessed by measuring hydroxyproline and histologic determination of interstitial cross-sectional area. Increases in LV hydroxyproline and interstitial area were found in untreated SHR relative to WKY; passive myocardial stiffness was increased and active muscle properties were depressed. In comparing colchicine treated vs untreated SHR, no differences in hydroxyproline, interstitial area or intrinsic myocardial function were found. In the WKY, colchicine increased myocardial interstitium and passive stiffness without changing hydroxyproline. Active myocardial function was not depressed.Thus, chronic colchicine administration neither attenuated the development of interstitial fibrosis nor prevented impaired myocardial function in the SHR. Colchicine treatment was associated with increased interstitium in WKY with increased passive myocardial stiffness. (Mol Cell Biochem 166: 45-54, 1997)     

Apocynin attenuates oxidative stress and hypertension in young spontaneously hypertensive rats independent of ADMA/NO pathway

Both NADPH oxidase-derived reactive oxygen species (ROS) and asymmetric dimethylarginine (ADMA) are increased in hypertension. Apocynin, an NADPH oxidase inhibitor, could inhibit ROS, thus we tested whether apocynin can block NADPH oxidase and prevent increases of ADMA and blood pressure (BP) in spontaneously hypertensive rats (SHRs). SHRs and Wistar Kyoto (WKY) rats, aged 4 weeks, were assigned to four groups: untreated SHRs and WKY rats, SHRs and WKY rats that received 2.5 mM apocynin for 8 weeks. BP was significantly higher in SHRs compared to WKY rats, which was attenuated by apocynin. Apocynin prevented p47phox translocation in SHR kidneys, but not the increase of superoxide and H(2)O(2). Additionally, apocynin did not protect SHRs against increased ADMA. Apocynin blocks NADPH oxidase to attenuate hypertension, but has little effect on the ADMA/nitric oxide (NO) pathway in young SHRs. The reduction of ROS and the preservation of NO simultaneously might be a better approach to restoring ROS-NO balance to prevent hypertension.     

Myocardial changes after spironolactone in spontaneous hypertensive rats. A laser scanning confocal microscopy study

The present study aims to objectivate by laser scanning confocal microscopy, the cardiac structure of the spontaneously hypertensive rats (SHR) treated with different doses of spironolactone, either alone or in combination with an angiotensin converting enzyme inhibitor or with a calcium channel blocker. Thirty SHRs were divided into six groups and treated during 13 weeks as follows: control, spironolactone (5, 10 and 30 mg/kg/day), spironolactone + enalapril and spironolactone + verapamil. Spironolactone action on the SHR blood pressure (BP) was dose-dependent. The cardiac hypertrophy was affected by the treatment with spironolactone (high dose) or a combination of spironolactone and Enalapril. The myocardial structure was less affected by the spironolactone monotherapy (at all doses) showing hypertrophied cardiac myocytes, focal areas of the reactive fibrosis, inflammatory infiltrate. The treatment with spironolactone in combination with enalapril or verapamil prevented these alterations. In conclusion, the monotherapy with spironolactone had only a limited effect in the preservation of the myocardial structure and in the attenuation of the interstitial fibrosis in SHRs, even after high dose. This action on the myocardium is more efficient when the spironolactone (even in medium dose) was associated with enalapril or verapamil.     

Exercise training attenuates blood pressure elevation and adverse remodeling in the aorta of spontaneously hypertensive rats

OBJECTIVE: To observe the extracellular matrix modifications and quantify the structural alterations of the aortic wall in spontaneously hypertensive rats (SHR) submitted to an aerobic physical activity (PA) protocol. MATERIAL AND METHODS: Three groups of five rats each were studied: sedentary normotensive Wistar rats (SED-Wistar) and SHR (divided in SHR that underwent a 1 h/day 5 days/week PA for 20 weeks (EX-SHR) and those that were restricted to cage-bound activity (SED-SHR). RESULTS: BP was lower in EX-SHRs and SED-Wistar rats (-35%) than in SED-SHRs. This difference became significant from the 3rd week of PA. The wall thickness was smaller in the EX-SHR and SED-Wistar (-45%) than in the SED-SHR (p<0.0001). In EX-SHR group, oxytalan and elaunin fibers were more pronounced than in the other groups, while SED-SHR and SED-Wistar rats showed an equivalent appearance of aortic elaunin fibers. EX-SHR and SED-Wistar rats showed more than 65% greater smooth muscle nuclei numerical density per unit area than SED-SHRs while SED-SHRs showed more than 45% smaller surface density of lamellae than both EX-SHR and SED-Wistar rats. However, no quantitative differences were found in the aortic wall comparing EX-SHR and SED-Wistar rats. CONCLUSION: PA might alter the aortic wall remodeling to adapt the artery to a hyperkinetic blood flow resulting in alterations of the extracellular matrix modulation and vascular resistance.     

Valsartan chronotherapy reverts the non-dipper pattern and improves blood pressure control through mediation of circadian rhythms of the renin-angiotensin system in spontaneous hypertension rats

ABSTRACT

Background: Numerous clinical studies have evaluated valsartan and found more efficacious control of blood pressure (BP) variability when administered before sleep. The treatment leads to improved outcomes when compared to administration upon awakening. The mechanism underlying this etiology is not fully understood. The present study investigates the safety and efficacy of asleep administration of valsartan in spontaneously hypertensive rats (SHR) with a non-dipping blood pressure pattern compared to SHRs receiving administration during awake time. Materials and Methods: 84 Male SHRs and 28 male Wistar-Kyoto rats (WKY) were kept under a strict alternating 12-h light/dark cycle. WKYs were utilized as a non-disease control. Meanwhile, SHRs were randomly divided into three groups: untreated, Valsartan asleep administration (VSA) and Valsartan awake administration (VWA) respectively. The VSA group was treated with valsartan (30 mg/kg/d) after the light onset, while the VWA group was treated with valsartan (30 mg/kg/d) after light offset. Both groups were treated for 6 weeks. Tail artery blood pressure was measured every 4 h via a noninvasive tail cuff blood pressure measurement method. HE and Masson staining were used to evaluate any damage within the target organs. ELISA was used to determine the 24-h plasma renin-angiotensin system (RAS) concentration at 4-h intervals. Results: Based on our findings, VSA significantly reduced 24-h and evening mean BP and restored the abnormal circadian rhythm compared to VWA, which attenuated injuries in the majority of target organs except for the kidneys. Furthermore, VSA was found to activate RAS during the light cycle and inhibit it during the dark cycle. Conversely, VWA was found to deactivate RAS throughout the day which may be related to the circadian BP rhythm. Conclusion: VSA may be more efficacious than VWA in controlling BP, circadian BP rhythm and blood RAS rhythm. Recent cardiovascular outcome investigations substantiate that chronotherapy treatment might be a novel therapeutic strategy for hypertension therapy.

Abbreviations: Angiotensin-converting enzyme (ACE); Angiotensin converting enzyme inhibitors (ACEIs); Angiotensin II (ANG II); Analysis of variance (ANOVA); Angiotensin receptor blockers (ARBs); Blood Pressure (BP); Calcium Antagonists Calcium Channel Blockers (CCB); Chronic kidney diseases (CKD); Sodium carboxyl methyl cellulose (CMC-Na); Cardiac mass index (CMI); Cardiovascular diseases (CVD); Diastolic blood pressure (DBP); Enzyme-linked immunosorbent assay (ELISA); Hematoxylin-eosin (H&E); Kidney mass index (KMI); Liver mass index (LMI); Mean arterial blood pressure (MAP); Plasma renin concentration (PRC); Renin-angiotensin system (RAS); Rennin (REN); Systolic blood pressure (SBP); Student-Newman-Keuls q test (SNK-q test); Spontaneous hypertension rats (SHR); Valsartan asleep Administration (VSA); Valsartan awake Administration (VWA); Wistar-Kyoto (WKY); Mesor (M); Amplitude (A); Phase (φ).     

Effects of doxazosin on blood flow and mRNA expression of nitric oxide synthase in the spontaneously hypertensive rat genitourinary tract

Hypertension may impact pelvic arterial blood flow resulting in reduction of nitric oxide synthase (NOS) levels. Although doxazosin, an alpha(1)-adrenoceptor antagonist, has been shown to improve erectile dysfunction as well as benign prostatic hyperplasia (BPH) and hypertension, it is not clear whether these improvements using doxazosin are primarily due to direct actions on the prostate, urinary bladder and penis, possibly via inhibition of vascular alpha(1)-adrenoceptors, or other sites of actions. Therefore, we investigated effects of doxazosin to the spontaneously hypertensive rat (SHR) on blood flow and NOS levels in the genitourinary tract. Four groups of rats were assessed: group 1, SHRs treated with doxazosin (30 mg/kg/day) for 4 weeks; group 2, SHRs treated with nifedipine (30 mg/kg/day) for 4 weeks; group 3, untreated SHRs; and group 4, untreated Wistar-Kyoto (WKY) rats. Blood flow to the ventral prostate, dorsolateral prostate, urinary bladder and penis was determined using a fluorescent microsphere infusion technique. Expression levels of nNOS and eNOS mRNAs were quantified by real-time RT-PCR using SYBR Green I. Blood flow to the ventral prostate, dorsolateral prostate, urinary bladder and penis was significantly lower in untreated SHRs than WKY rats. Treatment with doxazosin increased blood flow to each tissue studied in SHRs. RT-PCR data indicated that untreated SHRs had lower mRNA expression levels of nNOS in the bladder and penis and eNOS in the penis than WKY rats and that administration of doxazosin to the SHR caused an increase in expression levels of these genes, i.e., up-regulation of nNOS in the bladder and penis and eNOS in the penis. However, nifedipine had no significant effects on blood flow and NOS levels in the SHR genitourinary tract. Our data demonstrate that doxazosin treatment causes differential alterations in blood flow and NOS levels in the SHR genitourinary tract. These findings may provide insight into the beneficial effects of alpha(1)-adrenoceptor antagonists, on prostate, bladder and penile function, when used to treat symptoms of BPH and elevated blood pressure.     

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.     

Stereology of cardiac hypertrophy induced by NO blockade in rats treated with enalapril and verapamil.

OBJECTIVE: To quantify the structural myocardial response when chronic NO blockade hypertension is treated with antihypertensive drugs. STUDY DESIGN: Four groups of 10 male Wistar rats each were separated as follows: control, L-arginine-methyl-ester (NAME), L-NAME + angiotenisin-converting inhibitor (enalapril), L-NAME + calcium channel blocker (verapamil). All animals' blood pressure (BP) was measured weekly. After 40 days of experimentation the heart mass/body mass ratio (HBR) was determined, and the volume densities of the cardiac components were shown by stereology (Vv[c] for cardiomyocytes, Vv[i] for cardiac interstitium and the mean cross-sectional area of cardiomyocytes, a[c]). RESULTS: Significant differences by comparison with the control group were: BP increased 71% and HBR increased 24% in the L-NAME group. Vv[c] was 15% smaller in L-NAME animals, while an increase of 11% occurred in the enalapril group and 7% in the verapamil group. Vv[i] increased 20% in the L-NAME group; however, it decreased 13% in the enalapril group and 10% in the verapamil group. a[c] Was 30% greater in the L-NAME group, 13.5% in the enalapril group and 8.5%, in the verapamil group. a[c] Was 12.5% smaller in the enalapril group and 16% smaller in the verapamil group when L-NAME rats were compared. CONCLUSION: Stereology revealed an equivalent effect of enalapril and verapamil in reducing BP, cardiomyocyte hypertrophy and interstitial fibrosis in rats with NO synthesis blockade after six weeks of treatment.     

Kidney adaptation in nitric oxide-deficient Wistar and spontaneously hypertensive rats

We investigated the renal structural and functional consequences of nitric oxide (NO) deficiency co-treated with angiotensin-converting enzyme inhibitor (ACEi) in 20 adult male Wistar rats and 20 spontaneously hypertensive rats (SHR). The animals were separated into eight groups (n = 5) and treated for 30 days: Control, L-NAME (NO deficient group), Enalapril, L-NAME + Enalapril. The elevated blood pressure in NO deficient rats was partially reduced by enalapril. Serum creatinine was elevated in L-NAME-SHRs and effectively treated with enalapril. The proteinuria was significantly higher only in L-NAME-SHRs, and this was reduced by treatment with ACEi. The glomerular volume density (Vv(gl)) in L-NAME rats, both Wistar and SHR, was greater than in matched control rats, and enalapril treatment effectively prevented this Vv(gl) increase. No significant differences were observed in tubular volume density, Vv(tub), or tubular surface density, Sv(tub), in all Wistar groups. The Vv(tub) was smaller in L-NAME-SHRs than in control SHRs, and this tubular alteration was not prevented by enalapril. The Sv(tub) was not different among the SHR groups. In Wistar rats no changes were seen in vascular surface density, but a greatly increased cortical vascular volume density was seen in the enalapril treated rats. The vascular length density was greatly diminished in NO deficient rats that was effectively prevented with enalapril treatment. The vascular cortical renal stereological indices are normally reduced in SHRs. Administration of enalapril, but not L-NAME, changed this tendency. However, enalapril was not totally effective in preventing vascular damage in SHR NO deficient animals.     

Effect of an ACE inhibitor and an AT1 receptor antagonist on cardiac hypertrophy

The effect of long-term administration of delapril, an angiotensin converting enzyme inhibitor, and candesartan, an angiotensin II receptor blocker, on cardiac hypertrophy was investigated in spontaneously hypertensive rats (SHR). Delapril (2 mg/kg/day) and candesartan (2 mg/kg/day) were administered for 5 weeks to 15-week-old male SHR. Echocardiographic estimation of cardiac morphology and function revealed cardiac hypertrophy in SHR compared with Wistar-Kyoto rats (WKY) which were used as normal controls. Both treated groups revealed regression of cardiac hypertrophy estimated by echocardiography. Heart to body weight ratio of treated SHR was also smaller than that of untreated SHR. Plasma BNP and ANP concentrations were increased in untreated SHR and decreased in the treated groups. Histological examination was performed using light microscopy and the area of fibrosis was estimated by computer. Reduction of the fibrotic area was observed in SHR treated with delapril and candesartan, although the latter was not statistically significant. Immunohistochemical examination using anti-collagen monoclonal antibody showed a decrease of type I collagen in treated SHR as compared with untreated SHR. It is concluded that both angiotensin converting enzyme inhibitor and angiotensin II receptor blocker sufficiently reduce blood pressure in SHR associated with regression of cardiac remodeling.     

Cardiomyocyte volume-weighted nuclear volume and spironolactone therapy in spontaneously hypertensive rats

OBJECTIVE: To evaluate the blood pressure (BP) and cardiomyocyte nuclei hypertrophy of spontaneously hypertensive rats (SHR) treated with spironolactone and with spironolactone and an angiotensin-converting enzyme inhibitor and calcium channel blocker. STUDY DESIGN: Six groups with 5 SHR each were treated for 13 weeks: control group, spironolactone groups (5, 10 and 30 mg/kg/d, or low, moderate and high doses, respectively), and spironolactone and enlapril or/and verapamil. Blood pressure (BP) and cardiomyocyte volume-weighted nuclear volume (VWNV) were studied. RESULTS: The usual evolution of BP in young adult SHR was greatly altered by spironolactone treatment, with either attenuation or reversion of the BP tendency to increase. The treatments efficiently reduced the cardiomyocyte VWNV > 45%, confirming efficient action of both spironolactone monotherapy at moderate and high dose and spironolactone combined with enalapril or verapamil. However, the high dose of spironolactone, and spironolactone plus enalapril or verapamil showed no significant differences in cardiomyocyte VWNV. Correlation between VWNV and BP (13th week) suggested that BP degree influences cardiomyocyte VWNV. CONCLUSION: The effect of spironolactone monotherapy seems to be dose dependent, and the combination with enalapril or verapamil improves spironolactone efficiency in BP reduction but not in prevention/attenuation of cardiac myocyte nuclear hypertrophy.     

Myocardial hypertrophy of normotensive Wistar-Kyoto rats

In our studies with spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Wistar rats, we observed normotensive WKY rats with cardiac hypertrophy determined by a greater left ventricular (LV) mass (LVM)-to-body weight (BW) ratio (LVM/BW) than that of normotensive Wistar rats. Thus we compared the following parameters in SHR, WKY, and Wistar rats: LVM/BW, cell capacitance as index of total surface area of the myocytes, length, width, and cross-sectional area of cardiac myocytes, LV collagen volume fraction, and myocardial stiffness. The LVM/BW of WKY (2.41 +/- 0.03 mg/g, n = 41) was intermediate between SHR (2.82 +/- 0.04 mg/g, n = 47) and Wistar rats (1.98 +/- 0.04 mg/g, n = 28). A positive correlation between blood pressure and LVM was found in SHR, whereas no such relationship was observed in WKY or Wistar rats. Cell capacitance and cross-sectional area were not significantly different in SHR and WKY rats; these values were significantly higher than those of Wistar rats. The cell length was smaller but the width was similar in WKY compared with SHR. Papillary muscles isolated from the LV of WKY and SHR were stiffer than those from Wistar rats. Consistently, a greater level of myocardial fibrosis was detected in WKY and SHR compared with Wistar rats. These findings demonstrate blood pressure-independent cardiac hypertrophy in normotensive WKY rats.     

Beneficial effect of enalapril in spontaneously hypertensive rats cardiac remodeling with nitric oxide synthesis blockade

Aims . To study the efficiency of an angiotensin converting enzyme inhibitor on the blood pressure (BP) and the myocardium remodeling when spontaneously hypertensive rats (SHRs) are submitted to nitric oxide synthesis (NOs) blockade (with L-NAME) and simultaneously treated.
Methods . Young adult male SHRs were separated in four groups (n = 5) and treated for 20 days: Control, L-NAME, L-NAME+Enalapril, and Enalapril. The alterations of the BP, heart mass/body mass ratio and stereological parameters for myocytes, connective tissue and intramyocardial vessels were studied among the groups.
Results . The SHRs with NOs blockade showed a great modification of the myocardium with extensive areas of reparative and interstitial fibrosis and accentuated hypertrophy of the cardiac myocytes (cross sectional area 60% higher in animals taking L-NAME than in Control SHRs). Comparing the SHRs with NO deficiency (L-NAME group), the Control SHRs and the Enalapril treated SHRs significant differences were found in the BP and in all stereological parameters. The NO deficiency caused an important BP increment in SHRs that was partially attenuated by Enalapril. This Enalapril effect was more pronounced in Control SHRs. A significant increment of the intramyocardial vessels was observed in NO deficient SHRs and Control SHRs treated with Enalapril demonstrated by the stereology (greater microvascular densities in treated SHRs).
Conclusion . Enalapril administration showed a beneficial effect on vascular remodeling and myocardial hypertrophy in SHRs. In SHRs with NO blockade, however, the beneficial effect of Enalapril occurred only in vascular remodeling.