Hypertensive Male Rats Research Articles

Effect of estrogen on neprilysin expression in uterus and kidney of Sprague–Dawley normotensive and heterozygous (mRen2)27-transgenic hypertensive rats

The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague–Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17β-estradiol (E2). We evaluated estrogen's influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1–7) [Ang-(1–7)] and on aminopeptidase (AMP), which degrades Ang-(1–7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31 ± 0.03 nmol/min/mg versus 0.18 ± 0.04 nmol/min/mg of protein, p < 0.05) and Tg(+) (0.26 ± 0.04 nmol/min/mg versus 0.13 ± 0.02 nmol/min/mg of protein, p < 0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female ( p < 0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1–7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent.

2-Methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension

When exposed to chronic hypoxia or toxin monocrotaline (MCT), female animals develop less severe pulmonary arterial hypertension (PH) compared to males; ovariectomy (OVX) exacerbates PH, and OVX animals treated with estradiol (E2) develop less severe disease. There is a line of evidence suggesting that cardiovascular protective effects of E2 are mediated by its major metabolite, 2-methoxyestradiol (2ME). Recently, we have shown that 2ME attenuates the development and retards the progression of MCT-induced pulmonary hypertension in male rats. We hypothesized that the protective effects of E2 in experimental PH are mediated by 2ME. Subsets of intact and OVX female rats were injected saline (Cont and OXV groups) or MCT (60 mg/kg; MCT and OVX-MCT groups) and some of OVX-MCT animals were treated with 2ME (10 μg/kg/h via osmotic minipumps; OVX-MCT + 2ME). After 28 days, MCT caused PH, i.e., increased right ventricular peak systolic pressure (RVPSP) and right ventricle/left ventricle + septum (RV/LV + S) ratio, induced inflammatory response in the lungs and caused media hypertrophy (media thickness and % media index) and adventitia widening of small size pulmonary arteries. Ovariectomy exacerbated the disease, i.e., further increased RVPSP, and RV/LV + S ratio, and augmented vascular remodeling and inflammatory response. In diseased OVX rats, treatment with 2ME prevented the worsening of PH and attenuated the inflammatory response and vascular remodeling. No mortality was recorded in the OVX-MCT + 2ME group vs. 10% and 36% mortality in the MCT and OVX-MCT group, respectively. This study suggests that 2-methoxyestradiol (a major non-estrogenic metabolite of E2) may mediate the protective effects of estradiol in MCT-induced PH, and warrants further evaluation of 2ME for treatment of PH.

Activities of antioxidant enzymes in two stages of pathology development in sucrose-fed rats

The activities of catalase in liver, heart and kidney as well as glutathione peroxidase and superoxide dismutase in liver, heart, kidney, and serum from hypertriglyceridemic and hypertensive female and male rats were measured at 3 and 8 months of daily administration of sucrose in their drinking water. This treatment induces high levels of serum triglycerides, central obesity, moderate hypertension, hyperinsulinemia, and an increase in lipoperoxidation, among other alterations. The experimental periods were chosen on the basis of previous observations: at 3 months the level of serum triglycerides increases significantly above the normal value and remains without major changes thereafter, but the blood pressure only rises significantly at about 4 months in males and 5 months in females. So, at 8 months the rats have been subjected to abnormal conditions for 3-4 months. The effect of these and the influence of sex on levels of antioxidant enzymes were investigated. Both factors, sucrose treatment and sex, were conducive to significant changes in those variables.

Gene Expression Pattern in Spontaneously Hypertensive Rats Exposed to Urban Particulate Matter (EHC-93)

Epidemiological studies show associations of short-term exposure to particulate matter with morbidity and mortality. Although many studies investigate the health effects of ambient particulate matter, the associated mechanisms, and the causality, they often focus on classical parameters. The objective of the present study was to gain insight into the roles of a wide range of genes in this process. Particular attention has been paid to immediate oxidative stress in the lung. We isolated total lung RNA from spontaneously hypertensive male rats 2–40 h after exposure to reference EHC-93 (10 mg/kg). Our results show that exposure to particulate matter generates a time-dependent pattern of gene expression. From the 8799 genes or expressed sequence tags tested, we see that 132 genes were up- or downregulated shortly after exposure (i.e., 2–6 h), whereas after 15–21 h and 24–40 h, 46 and 56 genes showed altered expression, respectively. Focusing on the earliest point, 99 of the 132 genes were identified as unique. They include genes involved in an oxidative stress response (hemeoxygenase-1, metallothioneins, and thioredoxin reductase), an inflammatory response macrophage inflammatory protein-2, and tumor necrosis factor α), transcription factors belonging to the activating protein-1 family, and genes involved in cardiovascular functions. The present study, although not representing an ambient situation, is used to identify the biological pathways implicated in the initial injury response to PM exposure. Using Affymetrix chips, this study shows time-dependent gene expression, it identifies many genes that can be affected by exposure to particulate matter, and it confirms the involvement of oxidative stress in particulate-matter-related effects.

Effects of Long-Term Intervention with Lactobacillus helveticus-Fermented Milk on Bone Mineral Density and Bone Mineral Content in Growing Rats

Background:Lactobacillus helveticus-fermented milk has been shown to increase calcium absorption compared to ordinary sour milk. In the present study the possible effect of L. helveticus-fermented milk on bone was studied in growing rats. Methods: Spontaneously hypertensive male rats, which develop an osteoporotic bone disorder with age, were randomized into 5 groups (n = 10) receiving milk fermented with L. helveticus 16H and, as reference drinks, milk fermented with L. helveticus and Saccharomyces cerevisiae, sour milk, skim milk or water, for 14 weeks. After the intervention bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry. The femur weight, length and volume were measured before ashing. From the ashes the weight and mineral content were assessed. Results: As the body weight gain differed significantly between the groups, the results were related to the body weight. The L. helveticus-fermented milk intervention significantly increased the bone mineral density and bone mineral content compared to the sour milk, skim milk and water interventions. The mean values of the bone mineral density and bone mineral content were higher in the L. helveticus-fermented milk group compared to the Saccharomyces-fermented milk group but the difference was not statistically significant. Conclusion:L. helveticus-fermented milk increases bone mineral density and bone mineral content in relation to body weight in the long-term feeding of growing rats. The mechanism of L. helveticus remains to be discovered.

Contrasting effects of chronic ethanol feeding on centrally and peripherally evoked hypotension in telemetered female rats

Our previous studies have shown that ethanol compromises hypotension produced by centrally acting antihypertensive agents in normotensive and hypertensive male rats. The present study investigated whether female rats are as susceptible as male rats to the deleterious effect of ethanol on centrally evoked hypotension. The study was extended to investigate ethanol effects on the time-domain indices of variability in blood pressure [standard deviation of mean arterial pressure (SDMAP)] and heart rate [standard deviation of beat-to-beat intervals (SDRR) and root mean square of successive differences in R–R intervals (rMSSD)]. The hemodynamic effects of a single intraperitoneal dose of clonidine (30 μg/kg) were evaluated in radiotelemetered ethanol-fed (5%, 12 weeks) and pair-fed control Sprague–Dawley rats. In control rats, clonidine caused a significant reduction in MAP that continued for at least 6 h and was associated with reductions in SDMAP and SDRR but not rMSSD, suggesting inhibition of central sympathetic tone. A maximum hypotensive response of −16.4±1.7 mm Hg was demonstrated 40 min after clonidine administration. Ethanol feeding significantly attenuated clonidine hypotension whereas it potentiated the associated reduction in SDMAP. To verify the selectivity of ethanol–clonidine interaction, the effects of ethanol on peripherally mediated hemodynamic responses to hydralazine (0.5 mg/kg ip) were investigated. In contrast to its antagonistic effect on clonidine hypotension, ethanol significantly potentiated the hypotensive effect of hydralazine. Together, these findings demonstrate that chronic ethanol feeding exerts opposite effects on centrally (attenuation) and peripherally (potentiation) evoked hypotension in female rats. The interaction of ethanol with antihypertensive agents may not be related to changes in hemodynamic variability.

Role of sex, gonadectomy and sex hormones in the development of nitric oxide inhibition-induced hypertension.

In this study we have evaluated the influence of sex, gonadectomy and sex hormones on the development of L-NAME-induced hypertension in the rat, focusing our investigation on blood pressure (BP), plasma renin activity (PRA), cardiac hypertrophy and proteinuria. Three experiments were performed to investigate: (i) the influence of sex on the development of L-NAME-induced hypertension; (ii) the effects of gonadectomy on the dimorphism of L-NAME-induced hypertension; and (iii) the effects of testosterone in ovariectomized female and of 17beta-oestradiol in orchidectomized male rats. Male L-NAME-treated rats had higher BP values than females. Orchidectomy of L-NAME-treated rats reduced BP to the levels of females and ovariectomy did not affect hypertension in females. Oestrogenized and orchidectomized males had a BP level similar to intact female L-NAME-treated rats. However, androgenization and ovariectomy did not change BP in female L-NAME-treated rats. PRA was greater in intact male L-NAME hypertensive rats than in female rats, and gonadectomy protected against the increase in PRA such that PRA was similar among all the groups. Intact female hypertensive rats showed significantly greater ventricular hypertrophy compared with male hypertensive rats. Male L-NAME hypertensive rats had increased proteinuria that was not present in female rats. Moreover, testosterone increased proteinuria in males and females regardless of the BP level. Male L-NAME-treated rats developed higher BP, PRA and proteinuria than female rats, but were more resistant to the development of cardiac hypertrophy. The higher PRA of male L-NAME-treated rats might be involved in the sex-dependent dimorphism of this model of hypertension.

Antihypertensive and Hypocholesterolemic Effects of Tofuyo in Spontaneously Hypertensive Rats

Tofuyo is a fermented soybean curd that has angiotensin I-converting enzyme (ACE) inhibitory activity in vitro. The aim of this study was to examine the antihypertensive and hypocholesterolemic effects of tofuyo in vivo. Spontaneously hypertensive male rats at 8 weeks of age were fed a diet containing lyophilized tofuyo for 6 weeks. At 13 weeks of age, the systolic blood pressure of rats in the tofuyo group was significantly lower than that in the control group. After feeding the experimental diets, the ACE activity of kidney was significantly lower in the tofuyo group than that in the control group. Total cholesterol in serum in the tofuyo group was significantly lower while the ratio of high density lipoprotein (HDL) to total cholesterol in the tofuyo group tended to be higher than that in the control group.

Conception and pharmacodynamic profile of drospirenone

Progesterone is more than a progestin. Beyond functions in cycle and pregnancy, progesterone binds with high affinity to the mineralocorticoid receptor (MR) acting as an antagonist, with obvious significance for electrolyte homeostasis, an array of MR-related functions in the circulation as well as in the CNS. Progesterone induces natriuresis at physiological concentrations. Lack of antimineralocorticoid activity with conventional progestins may account for sodium and water retention, minor elevation of blood pressure and “pill hypertension” in susceptible women on oral contraceptives. Ethinylestradiol (EE) contributes to this problem by distinct activation of the renin–angiotensin–aldosterone (RAAS) system. Drospirenone (DRSP: 6β,7β,15β,16β-dimethylene-3-oxo 17α-pregn-4-ene-21,17 carbolactone) is the first synthetic progestin with antialdosterone activity. DRSP and progesterone bind to PR in uterine (affinity of both is about 30% of R5020) and MR in kidney cytosol (affinity about 230 and 100% of aldosterone, respectively). Intrauterine administration of DRSP in silastic tubes induced maximum local progestational effects in rabbits. At systemic subcutaneous (s.c.) administration (McPhail-assay) full endometrial transformation was obtained at 1mg per animal per day. At 1–3 mg DRSP per animal per day subcutaneously, pregnancy maintenance after ovariectomy, antiovulatory activity, and antimineralocorticoid activity were seen in the respective assays in rats. The latter activity indicates about eight-fold higher potency than spironolactone. DRSP decreased blood pressure in male hypertensive rats, whereas an increase was noted under conventional progestins. DRSP also prevented hypertension and fetal growth retardation in pregnant rats after l-NAME, an inhibitor of nitric oxide synthase. DRSP has antiandrogenic activity. Feminizing effects were recorded during sexual differentiation in male fetuses at high doses. Powerful antiandrogenic effects were also seen in gonad intact and testosterone substituted castrated male rats. The antiandrogenic potency of DRSP is superior to that of spironolactone but below that of cyproterone acetate. Endometrial transformation, inhibition of ovulation, and antimineralocorticoid, i.e. natriuretic effects and mild antiandrogenic effects were recorded at the same range of oral doses (0.5–4 mg per day) in humans. Combined with EE (3 mg DRSP+30 μg EE), DRSP provides effective inhibition of ovulation and cycle control. Body weight compared to conventional oral contraceptives was reduced. DRSP (3 mg per day + 15, 20, or 30 μg ethinyl estradiol per day) prevented the mild increase of blood pressure seen under a conventional levonorgestrel-containing contraceptive and even tended to reduce pretreatment blood pressure. Studies on modulation (i.e. inhibition) of glucocorticoid effects at the MR in the CNS remain an unexplored and interesting area for research.

Androgen receptor independent cardiovascular action of the antiandrogen flutamide.

We have previously shown that flutamide (specific antagonist of the androgen receptor) has antihypertensive effects. In the present study we examined the mechanisms of flutamide action in the vasculature. The vascular effects of flutamide were assayed in aortae isolated from male or female Sprague-Dawley rats and from rats or mice lacking a functional androgen receptor ( tfm, testicular feminization mutation). The effect of flutamide on coronary flow was tested in isolated hearts. In addition, male hypertensive rats with tfm mutation were treated with flutamide, and blood pressure was monitored. Flutamide induced a relaxation of rat aortae from all the strains used (maximum relaxation at 10 microM: 51.3+/-5.2% of phenylephrine contraction) and increased the coronary flow. The aortic relaxation to flutamide was abolished by endothelium removal, or by inhibition of nitric oxide synthase, guanylyl cyclase, and tyrosine kinase but not by calmodulin inhibition. Flutamide treatment attenuated the development of hypertension in mouse renin transgenic rats with the tfm mutation. Flutamide produces direct vasodilation by inducing release of NO from the endothelium and causes subsequent activation of soluble guanylyl cyclase in an active androgen receptor independent manner. This response may contribute to the observed antihypertensive actions of flutamide.

Female rats are protected against fructose-induced changes in metabolism and blood pressure.

The objective of this study was to determine whether the effects of a fructose diet, which causes hyperinsulinemia, insulin resistance, and hypertension in male rats, are dependent on sex. Blood pressure was measured via the tail-cuff method, and oral glucose tolerance tests were performed to assess insulin sensitivity. Blood pressure in female rats did not differ between fructose-fed and control rats at any time point (126 +/- 5 and 125 +/- 3 mmHg at week 9 for fructose-fed and control rats, respectively) nor was there a difference in any metabolic parameter measured. Furthermore, the vascular insulin resistance that is present in male fructose-fed rats was not observed. After ovariectomy, fructose caused a significant change in systolic blood pressure from baseline compared with fructose-fed ovary-intact rats (change of 21 +/- 5 vs. -2 +/- 4 mmHg). The results demonstrate that females do not develop hypertension or hyperinsulinemia upon fructose feeding except after ovariectomy, suggesting that female sex hormones may confer protection against the effects of a fructose diet.

Relationship among hyperinsulinemia, insulin resistance, and hypertension is dependent on sex.

Hyperinsulinemia and insulin resistance have been linked to hypertension; however, the influence of sex on this relationship has not been well studied. The purpose of this experiment was to compare the effects of chronic insulin treatment on insulin sensitivity and blood pressure in male and female rats. Male and female Wistar rats were treated with insulin (2 U/day) via subcutaneous sustained release implants for 5 wk. Systolic blood pressure was measured via the tail-cuff method before and after treatment, and insulin sensitivity was assessed with an oral glucose tolerance test. The insulin sensitivity of female rats was 4.5-fold greater than male rats. Chronic insulin treatment impaired insulin sensitivity in both sexes; however, this occurred to a greater degree in male rats. Blood pressure increased in male rats treated with insulin only. The results demonstrate that hyperinsulinemia and insulin resistance are associated with hypertension in male rats only. Therefore, the link between these conditions appears to depend on sex.

Haemodynamic effects of lead(II) acetate, ethanol, and their combination in rats.

The aim of the study was to analyse the haemodynamic background of the hypertension-inducing effect of lead and the role of alcohol effect in hypertension caused by lead. Daily lead acetate doses of 0 or 500 mg/kg were administered to Sprague-Dawley male rats. One half of each group received water containing 5% w/v sugar (without ethanol), while the other half of each group received water containing 5% w/v sugar and 10% v/v ethanol, respectively, to drink. At the end of the 12th week ECG and haemodynamic tests were performed with the method of McDevitt and Nies (1976). The tests were repeated after the administration of 5 microg noradrenaline (NA) by i.v. infusion for 3 min. Lead acetate administration increased the arterial blood pressure and total peripheral resistance (TPR), the organ fractions of the cardiac output and blood flow of the parietal bone, and the vascular resistance of the liver and kidneys, and decreased the cardiac output, the blood flow of the liver and kidneys, and the vascular resistance of the parietal bone. Ethanol administration decreased the blood flow of the intestines and increased the vascular resistance of the intestines. Following the simultaneous administration of lead acetate and ethanol, lead acetate reversed (inhibited) the decreasing effect of ethanol on gastrointestinal organ fraction and blood flow. Lead acetate pre-treatment decreased the blood-pressure-increasing effect of NA; it augmented the increasing effect on vascular resistance of the stomach and the reducing effect on parietal bone organ fraction and blood flow. Lead acetate causes hypertension in male rats, in which the decreased blood flow to the kidneys may play a role; ethanol, ingested in a low dose, does not cause hypertension, and though it can decrease the enhanced vascular tone caused by lead, it is not able to prevent "lead-hypertension"; the considerably increased blood flow in the bones (parietal bone) caused by the lead salt may contribute to the increase and maintenance of the blood lead level. The anticipated mechanism may explain the increased cardiovascular risk proportional to the increased lead concentration in the bones.

Decreased endothelial size and connexin expression in rat caudal arteries during hypertension

Hypertension is accompanied by endothelial dysfunction. The present study has investigated endothelial cell morphology and connexin expression in the caudal artery of the rat during the development of hypertension. A significant increase in systolic blood pressure was detected from 9 weeks of age in spontaneously hypertensive male rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats, reaching a maximum by 11-12 weeks of age. Immunohistochemistry was used to quantify cell size and expression of connexins (Cxs) 37, 40 and 43 in the endothelium of prehypertensive (3-week-old) and hypertensive (12-week-old) rats. At 12 weeks, the size of endothelial cells and the expression of all three Cxs per endothelial cell were significantly less in SHR than WKY rats. At 3 weeks, there was no significant difference in cell size nor in the expression of Cxs 37 or 43; however, expression of Cx40 was significantly lower in SHR than in WKY rats. Between 3 and 12 weeks in WKY rats, there was no change in endothelial cell size, nor in the expression of Cxs 37, 40 and 43. In SHR, both cell size and Cx expression per endothelial cell were significantly decreased during the same developmental period, with a significant decrease in the density of Cx40 plaques. The development of hypertension in the SHR is accompanied by significant decreases in endothelial cell size and expression of Cx40, which may contribute to the endothelial dysfunction present in hypertension.

Dietary vitamin C supplementation decreases blood pressure in DOCA-salt hypertensive male Sprague-Dawley rats and this is associated with increased liver oxidative stress.

The effects of a vitamin C supplemented diet on blood pressure, body and liver weights, liver antioxidant status, iron and copper levels were investigated in DOCA-salt treated and untreated Sprague-Dawley (SD) male rats after 8 weeks of treatment. Vitamin C supplementation had no effect on blood pressure in SD rats but induced a significant decrease in blood pressure in DOCA-salt treated rats, the decrease being more efficient at 50 mg/kg of vitamin C than at 500 mg/kg. Hepatic lipid peroxidation and iron levels were significantly increased in DOCA-salt hypertensive rats whereas total hepatic antioxidant capacity (HAC), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were decreased. Vitamin C supplementation did not affect the overall antioxidant defences of control SD rat livers. In contrast, vitamin C supplementation accentuated the DOCA-salt induced accumulation of liver iron and lipid peroxidation. This occurred without any notable aggravation in the antioxidant deficiency of vitamin C supplemented DOCA-salt treated rat livers. Our data suggest that DOCA-salt treatment induces an accumulation of iron in rat livers which is responsible for the prooxidant effect of vitamin C. The normalization of blood pressure in DOCA-salt treated rats by vitamin C supplementation appears thus independent from liver antioxidant status.

Chronotherapy with active vitamin D3 in aged stroke-prone spontaneously hypertensive rats, a model of osteoporosis

The chronotherapeutic effects of 1-α-(OH) vitamin D3, a pro-drug of 1,25(OH)2 vitamin D3 (1,25(OH)2D3), were evaluated by repeated dosing of the drug in aged stroke-prone spontaneously hypertensive male rats, a model of osteoporosis. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Drug (0.5 μg/kg) or vehicle was given once daily at 2 or 14 h after lights on for 3 months. The severity of adverse effects such as body weight loss, hypercalcemia and hyperphosphatemia was significantly less when the drug was given at 14 h after lights on (14 HALO). Serum 1,25(OH)2 vitamin D3 concentrations of 2 h after lights on (2 HALO) group and 14 HALO group did not differ significantly after dosing. The decrease in parathyroid hormone (PTH) level 12 weeks after the start of the study was greater in the 14 HALO group than in the 2 HALO group. Urinary excretion of inorganic Ca and P in the 2 HALO group was greater than that in the 14 HALO group. Urinary excretion of deoxypyridiniline, an index of the bone resorption capacity of osteoclasts, was much suppressed in the 14 HALO group, suggesting that the efficacy of vitamin D3 for suppressing bone resorption might vary with the dosing time. The increase in bone density of both femurs, determined by dual-energy X-ray absorption at the end of the study, was greater in the 14 HALO group than in the 2 HALO group. This is the first study to show the dosing time-dependent efficacy and toxicity of active vitamin D3 in an animal model of osteoporosis. These results indicate that a chronopharmacological approach is beneficial for establishing a more effective and/or safer regimen of active vitamin D3 for the treatment of osteoporosis.

Gender and hypertension interact to regulate neuropeptide Y receptor responsiveness.

We have compared the interaction between gender and strain (normotensive Wistar Kyoto vs. spontaneously hypertensive rats) in the regulation of cardiovascular and renal Y1 and Y5-receptor-mediated responses to neuropeptide Y. Anaesthetized rats received intravenous infusions of 0.3-10 microg/kg per min neuropeptide Y (45 min each) or vehicle. Enhancements of mean arterial pressure, renovascular resistance, diuresis and natriuresis were measured. Parallel group comparisons were performed on male normotensive, female normotensive, male hypertensive and female hypertensive rats. Gender and strain significantly affected the cardiovascular and renal neuropeptide Y responses. While neuropeptide Y elevated mean arterial pressure and renovascular resistance in all four groups, the extent of the alterations differed up to two- to threefold between genders and/or strains. Neuropeptide Y-induced diuresis and natriuresis were similar in male and female normotensive rats, desensitized in male but augmented in female hypertensive rats. We conclude that previously reported cardiovascular and renal neuropeptide Y responses are regulated by gender and the presence of hypertension. However, at least for renal function alterations in female hypertensive vs. male normotensive rats cannot be predicted from those in male hypertensive and female normotensive rats.

17beta-estradiol restores endothelial nitric oxide release to shear stress in arterioles of male hypertensive rats.

Endothelial nitric oxide (NO)-mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase. Responses to increases in perfusate flow (from 0 to 25 microL/min) and to the calcium ionophore A23187 (5 x 10(-8) to 10(-6) mol/L), norepinephrine (NE; 10(-7) to 3 x 10(-7) mol/L), sodium nitroprusside (SNP; 10(-8) to 10(-6) mol/L), and adenosine (ADO; 10(-6) to 5 x 10(-5) mol/L) were studied in cannulated and pressurized gracilis muscle arterioles ( approximately 75 microm in diameter) isolated from 12-week-old male SHR before and after incubation with 10(-9) mol/L 17beta-estradiol (17beta-E(2)) for 16 to 18 hours. After incubation with 17beta-E(2), basal diameter of arterioles was significantly increased (by approximately 10%), and flow-induced dilation was significantly enhanced (79.8+/-2.9 versus 103.7+/-3.7 microm at 25 microL/min), resulting in a lowered shear stress (62.0+/-9.1 versus 32.5+/-4.2 dyne/cm(2)). Also, vasoconstrictions to A23187 were reversed to dilations (-18.7+/-2.2 versus 18.8+/-1.7 microm), and constrictions to NE were significantly attenuated (-30.7+/-3.0 versus -21.2+/-2.8 microm). These alterations were eliminated by ICI 182,780 (10(-7) mol/L), an estrogen receptor antagonist; 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (10(-5) mol/L), a transcription inhibitor; or N(omega)-nitro-L-arginine methyl ester (10(-4) mol/L), an inhibitor of NO synthase, whereas they were not affected by aminoguanidine (5 x 10(-5) mol/L), a specific inhibitor of inducible NO synthase. Arteriolar responses were not altered by incubation with 17alpha-estradiol. Estrogen, via a receptor-mediated pathway, upregulates endothelial NO synthase gene expression, leading to increased NO production, and restores the regulation of wall shear stress in arterioles of male SHR.

Exercise reverses peripheral insulin resistance in trained L-NAME-hypertensive rats.

Several studies have demonstrated an increase in peripheral resistance to insulin associated with hypertension. To assess the hemodynamic and metabolic effects of exercise training, normotensive and N(omega)-nitro-L-arginine methyl ester (L-NAME)-hypertensive male Wistar rats were submitted to low-intensity treadmill exercise training for 10 weeks and compared with their sedentary controls. Blood pressure signals were obtained and processed with a data acquisition system (CODAS, 1 kHz) to evaluate mean arterial pressure, heart rate, autonomic control of heart rate, and baroreflex sensitivity. Exercise training induced a nonsignificant 6.5-mm Hg decrease in mean arterial pressure in trained hypertensive rats (163+/-9 mm Hg) compared with sedentary hypertensive rats (169.5+/-5. 5 mm Hg). The hypertensive groups showed impairment of baroreflex function in response to changes in arterial pressure compared with sedentary controls. Furthermore, exercise training improved the tachycardic response to decreasing arterial pressure and reduced intrinsic heart rate in trained control rats compared with all other groups. Sedentary hypertensive rats presented a decrease in body weight compared with normotensive animals. Basal evaluation of the glucose/insulin ratio showed increased insulin resistance in sedentary (28.4+/-3) and trained (23.5+/-2.7) hypertensive rats compared with sedentary control rats (40.5+/-3). However, the glucose/insulin ratio evaluated during the exercise session in trained rats showed an improvement in insulin resistance (54.5+/-5 for control rats and 44+/-9 for hypertensive rats). In conclusion, L-NAME-induced hypertension is accompanied by an increase in insulin resistance in rats. The improvement in peripheral insulin sensitivity during exercise and the body weight gain observed in trained hypertensive rats may support the positive role of physical activity in the management of hypertension.

Isradipine and insulin sensitivity in hypertensive rats.

The present study was designed to investigate the effect of a reduction in blood pressure, by using the calcium channel antagonist isradipine, on insulin sensitivity and vascular responses to insulin in conscious spontaneously hypertensive male rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and blood flows. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp technique. Two groups of rats received isradipine at a dose of 0.05 or 0.15 mg. kg-1. h-1, whereas a third group received a continuous infusion of vehicle (15% DMSO). Both doses of isradipine were found to decrease mean blood pressure (-25 +/- 4 mmHg at the dose of 0.05 mg. kg-1. h-1 and -20 +/- 2 mmHg at the dose of 0.15 mg. kg-1. h-1) and to improve insulin sensitivity. Moreover, in the rats treated with the low dose of isradipine, we observed vasodilations in renal, superior mesenteric, and hindquarter vascular beds. In the untreated group, the euglycemic infusion of insulin (4 mU. kg-1. min-1) was found to cause vasoconstrictions in superior mesenteric and hindquarter vascular beds, but no changes in mean blood pressure, heart rate, or renal vascular conductance were found. In contrast, in the isradipine-treated groups, the same dose of insulin was found to produce vasodilations in the renal vascular bed and to abolish the vasoconstrictor responses previously observed. We concluded that short-term treatment with isradipine in SHR can lower blood pressure and improve insulin sensitivity, mainly through hemodynamic factors, as supported by experiments with hydralazine as a positive vasodilator control.