Swimming training prevents coronary endothelial dysfunction in ovariectomized spontaneously hypertensive rats.

Estrogen deficiency and hypertension are considered major risk factors for the development of coronary heart disease. On the other hand, exercise training is considered an effective form to prevent and treat cardiovascular diseases. However, the effects of swimming training (SW) on coronary vascular reactivity in female ovariectomized hypertensive rats are not known. We aimed to evaluate the effects of SW on endothelium-dependent coronary vasodilation in ovariectomized hypertensive rats. Three-month old spontaneously hypertensive rats (SHR, n=50) were divided into four groups: sham (SH), sham plus swimming training (SSW), ovariectomized (OVX), and ovariectomized plus swimming training (OSW). The SW protocol (5 times/week, 60 min/day) was conducted for 8 weeks. The vasodilatory response was measured in isolated hearts in the absence and presence of a nitric oxide synthase inhibitor (L-NAME, 100 µM). Cardiac oxidative stress was evaluated in situ by dihydroethidium fluorescence, while the expression of antioxidant enzymes (SOD-2 and catalase) and their activities were assessed by western blotting and spectrophotometry, respectively. Vasodilation in SHR was significantly reduced by OVX, even in the presence of L-NAME, in conjunction with an increased oxidative stress. These effects were prevented by SW, and were associated with a decrease in oxidative stress. Superoxide dismutase 2 (SOD-2) and catalase expression increased only in the OSW group. However, no significant difference was found in the activity of these enzymes. In conclusion, SW prevented the endothelial dysfunction in the coronary bed of ovariectomized SHR associated with an increase in the expression of antioxidant enzymes, and therefore may prevent coronary heart disease in hypertensive postmenopausal women.

Cardiovascular risk factors in a population of Brazilian schoolchildren.

Epidemiological and clinical evidence suggests that a judicious diet, regular physical activity and blood pressure (BP) monitoring must start in early childhood to minimize the impact of modifiable cardiovascular risk factors. This study was designed to evaluate BP and metabolic parameters of schoolchildren from Vitória, Espírito Santo State, Brazil, and correlate them with cardiovascular risk factors. The study was conducted on 380 students aged 10-14 years (177 boys, 203 girls) enrolled in public schools. Baseline measurements included body mass index, BP and heart rate. The students were submitted to exercise spirometry on a treadmill. VO2max was obtained from exercise testing to voluntary exhaustion. Fasting serum total cholesterol (TC), LDL-C, HDL-C, triglycerides (TG), and glucose were measured. Nine point nine percent of the boys and 11.7% of the girls were hypertensive or had pre-hypertensive levels. There was no significant correlation between VO2max and TC, LDL-C, or TG in prepubertal children, but a slight negative correlation was detected in post-pubertal boys for HDL-C and TG. In addition, children with hypertension (3.4%) or pre-hypertensive levels (6.6%) also had comorbidity for overweight and blood lipid abnormalities (14% for triglycerides, 44.7% for TC, 25.9% for LDL-C, 52% for low HDL-C). The present study shows for the first time high correlations between prehypertensive blood pressure levels and the cardiovascular risk factors high TC, high LDL-C, low HDL-C in schoolchildren. These are important for the formulation of public health policies and strategies.

Testosterone induces apoptosis in cardiomyocytes by increasing proapoptotic signaling involving tumor necrosis factor-α and renin angiotensin system.

Anabolic androgenic steroids lead to cardiac complications and have been shown to exhibit proapoptotic effects in cardiac cells; however, the mechanism involved in those effects is unclear. The aim of this study was to assess whether apoptosis and the activation of caspase-3 (Casp-3) induced by testosterone in high concentrations involves increments in tumor necrosis factor-α (TNF-α) concentrations and angiotensin-converting enzyme (ACE) activity in cardiomyocytes (H9c2) cell cultures. Cardiomyocytes were treated with testosterone (5 × 10(-6) mol/L), doxorubicin (9.2 × 10(-6) mol/L), testosterone + etanercept (Eta; 6.67 × 10(-5) mol/L), testosterone + losartan (Los; 10(-7) mol/L), and testosterone + AC-DEVD-CHO (10(-5) mol/L; Casp-3 inhibitor). Apoptosis was determined by flow cytometry and by the proteolytic activity of Casp-3. We demonstrated that incubation of H9c2 cells for 48 h with testosterone causes the apoptotic death of 60-70% of the cells and co-treatments with Eta, Los, or AC-DEVD-CHO reduced this effect. Testosterone also induces apoptosis (concentration dependent) and increases the proteolytic activity of Casp-3, which were reduced by co-treatments. TNF-α and ACE activities were elevated by testosterone treatment, while co-treatment with Los and Eta reduced these effects. We concluded that an interaction between testosterone, angiotensin II, and TNF-α induced apoptosis and Casp-3 activity in cultured cardiomyocytes, which contributed to the reduced viability of these cells induced by testosterone in toxic concentrations.

Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats.

BACKGROUND: There is growing interest in sex differences and RAS components. However, whether gender influences cardiac angiotensin I-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity is still unknown. In the present work, we determined the relationship between ACE and ACE2 activity, left ventricular function and gender in spontaneously hypertensive rats (SHRs). METHODOLOGY/PRINCIPAL FINDINGS: Twelve-week-old female (F) and male (M) SHRs were divided into 2 experimental groups (n = 7 in each group): sham (S) and gonadectomized (G). Fifty days after gonadectomy, we measured positive and negative first derivatives (dP/dt maximum left ventricle (LV) and dP/dt minimum LV, respectively), hypertrophy (morphometric analysis) and ACE and ACE2 catalytic activity (fluorimetrically). Expression of calcium handling proteins was measured by western blot. Male rats exhibited higher cardiac ACE and ACE2 activity as well as hypertrophy compared to female rats. Orchiectomy decreased the activity of these enzymes and hypertrophy, while ovariectomy increased hypertrophy and ACE2, but did not change ACE activity. For cardiac function, the male sham group had a lower +dP/dt than the female sham group. After gonadectomy, the +dP/dt increased in males and reduced in females. The male sham group had a lower -dP/dt than the female group. After gonadectomy, the -dP/dt increased in the male and decreased in the female groups when compared to the sham group. No difference was observed among the groups in SERCA2a protein expression. Gonadectomy increased protein expression of PLB (phospholamban) and the PLB to SERCA2a ratio in female rats, but did not change in male rats. CONCLUSION: Ovariectomy leads to increased cardiac hypertrophy, ACE2 activity, PLB expression and PLB to SERCA2a ratio, and worsening of hemodynamic variables, whereas in males the removal of testosterone has the opposite effects on RAS components.

Endothelium-dependent and endothelium-independent effects of adenosine diphosphate in renovascular hypertension.

Norepinephrine-induced responses in isolated perfused mesenteric vascular bed from normotensive and renovascular hypertensive rats were examined in the presence of adenosine diphosphate (ADP, 2 x 10(-6) M). Responses to norepinephrine were significantly greater in vessels from hypertensive rats. Norepinephrine-induced contractions increased after the removal of endothelium. N omega-Nitro-L-arginine (L-NOARG), a potent inhibitor of nitric oxide formation, similarly increased contractions. The greatest responses were obtained, however, after treatment of the vascular segments with methylene blue. The presence of ADP caused significant endothelium-dependent decreases in contractions. Although decreases caused by ADP in vessels with endothelium after treatment with L-NOARG were not statistically significant, a tendency to decreased responses seems to suggest that L-NOARG diminishes but does not completely prevent the effect of ADP in mesenteric vessels. Methylene blue partially reduced the endothelium-dependent ADP-induced relaxant effects in sham-operated nephrectomized rats. A tendency to increased contractions to norepinephrine was observed in the presence of ADP after removal of endothelium. Thus, in the mesenteric resistance arteries of the rat under stimulation by ADP, it appears that nitric oxide released from L-arginine and the activity of soluble guanylate cyclase account only in part for the endothelium-dependent decreased responses to norepinephrine. When nitric oxide formation or soluble guanylate cyclase activity are depressed simultaneously with endothelium damage, ADP released from platelets or red blood cells may be an important factor that acts synergically with vasoconstrictor stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Captopril prevents ventricular hypertrophy in sinoaortic denervated rats.

We had previously reported that sinoaortic denervation induces cardiac ventricular hypertrophy in rats. The objective of the present study was to determine whether this cardiac hypertrophy can be prevented by inhibition of angiotensin converting enzyme (ACE) with captopril, 20 mg/kg, administered sc twice daily for 15 days. The left ventricular weight/body weight ratio significantly increased (12%) in sinoaortic denervated (SAD) rats 15 days after surgery when compared with the sham-operated group (SO). Administration of captopril to SAD rats prevented this ventricular hypertrophy and decreased but did not completely abolish their high arterial pressure. No changes in the normal pattern of baroreceptor reflex activity were observed in the captopril-pretreated SAD or SO groups. These data suggest the participation of the angiotensin system in the development of cardiac hypertrophy in SAD rats.

Calpain activity of hypertrophic hearts from hypertensive rats.

Heart tissue contains large amounts of the Ca(2+)-activated proteinase calpain which has been assigned a specific function in the turnover of muscle protein. The objective of the present study was to determine calpain (E.C. 3.4.22.17)-like activity in homogenates of left ventricle from hypertensive rats that developed ventricular hypertrophy. Calpain activity was assayed using heat-denatured azocasein as a substrate in the presence of 1 mM calcium and corrected by subtraction of the Ca(2+)-independent activities. The latter were measured in the presence of 1 mM EGTA and the products read at 440 nm. Male Wistar rats (225 g) were assigned to control (N = 8, normal drinking water), salt (N = 6, drinking water containing 1% NaCl) and DOCA-salt (N = 6, deoxycorticosterone acetate, 8 mg/kg, sc, twice a week for 20 days plus drinking water containing 1% NaCl) groups. SHR (N = 6, spontaneously hypertensive rats) were also used. The calpain activity of the control group was at 3.90 +/- 0.22 mU/g wet weight tissue. Hypertension induced significant left ventricular hypertrophy in DOCA-salt rats (26%) and in SHR (54%) and a 30% decrease in calpain activity in both groups (P < 0.01). In the high salt load (salt group) calpain activity was also decreased, but this was not accompanied by hypertrophy. In the present indirect measurement of protein degradation capacity of heart tissue homogenates the proteolytic activity was activated (221%) by 1 mM calcium and inhibited (84%) by 1 mM EGTA after a 48-h incubation period, indicating the destruction of the calpain inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelial mediators of 17 beta-estradiol-induced coronary vasodilation in the isolated rat heart.

The present study was designed to determine relaxation in response to 17 beta-estradiol by isolated perfused hearts from intact normotensive male and female rats as well as the contribution of endothelium and its relaxing factors to this action. Baseline coronary perfusion pressure was determined and the vasoactive effects of 17 beta-estradiol (10 microM) were assessed by in bolus administration before and after endothelium denudation by infusion of 0.25 microM sodium deoxycholate or perfusion with 100 microM L-NAME, 2.8 microM indomethacin, 0.75 microM clotrimazole, 100 microM L-NAME plus 2.8 microM indomethacin, and 100 microM L-NAME plus 0.75 microM clotrimazole. Baseline coronary perfusion pressure differed significantly between males (84 +/- 2 mmHg, N = 61) and females (102 +/- 2 mmHg, N = 61). Bolus injection of 10 microM 17 beta-estradiol elicited a transient relaxing response in all groups, which was greater in coronary beds from females. For both sexes, the relaxing response to 17 beta-estradiol was at least in part endothelium-dependent. In the presence of the nitric oxide synthase inhibitor L-NAME, the relaxing response to 17 beta-estradiol was reduced only in females. Nevertheless, in the presence of indomethacin, a cyclooxygenase inhibitor, or clotrimazole, a cytochrome P450 inhibitor, the 17 beta-estradiol response was significantly reduced in both groups. In addition, combined treatment with L-NAME plus indomethacin or L-NAME plus clotrimazole also reduced the 17 beta-estradiol response in both groups. These results indicate the importance of prostacyclin and endothelium-derived hyperpolarizing factor in the relaxing response to 17 beta-estradiol. 17 beta-estradiol-induced relaxation may play an important role in the regulation of coronary tone and this may be one of the reasons why estrogen replacement therapy reduces the risk of coronary heart disease in postmenopausal women.

Evaluation of protein and peptide hydrolases in DOCA-salt hypertensive rat treated with chlorthalidone.

We have reported that chlorthalidone (Chlor) prevents the development of heart hypertrophy in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The present study was carried out to determine whether Chlor (8 mg/day per animal, added to the food, for 20 days) affects kidney and heart hypertrophy in DOCA-salt (8 mg/kg, sc, twice a week) rats by causing alterations in protein and peptide hydrolysis. Heart (left ventricle) and kidney enzyme activities were measured in tissue homogenates from normal-control, salt-control, DOCA-salt and DOCA-salt-Chlor male Wistar rats (N = 6 for each group), using azocasein as the substrate for proteolytic enzymes and specific peptides for prolylendopeptidase (PEP) and multicatalytic proteinase (MCP). The tissue weight/body weight ratio increased in parallel to elevation of blood pressure. The left ventricular muscle hypertrophy (26%, P < 0.05) present in the DOCA-salt hypertensive group was completely prevented by simultaneous Chlor treatment. Chlor treatment did not change the kidney hypertrophy (+79%, P < 0.;05) observed in the salt-control (+57%, P < 0.05) and DOCA-salt (+74%, P < 0.05) groups. The hydrolysis of peptides by PEP and MCP was similar in the normal and salt-control groups. The heart PEP activity was 24% higher (P < 0.01) in DOCA-salt rats, whereas MCP activity was not different when compared to control groups. DOCA-salt treatment increased MCP activity in the kidney by 44% while PEP activity did not differ from that of control groups. The hydrolysis of proteins by heart enzymes was increased by salt by 47%. Chlor treatment restored the reduction in protein hydrolysis induced by DOCA-salt (a 21% decrease, P < 0.05) to a level similar to that of the normal-control group. Similarly, Chlor coadministration prevented the 30% reduction in renal proteolytic activity elicited by DOCA-salt treatment. Although Chlor treatment prevented the DOCA-salt-induced reduction in protein hydrolysis, this response did not interfere with kidney hypertrophy. The mechanism by which hypertension produces hypertrophy is unclear, but our results suggest that this structural modification is not related to the activities of some peptidases, e.g. protein and peptide hydrolases.

Contractile reactivity of the perfused mesenteric vascular bed from sinoaortic denervated rats to norepinephrine, methoxamine and verapamil.

The contractile reactivity to norepinephrine, methoxamine, and verapamil of the perfused mesenteric vascular bed from sinoaortic denervated (SAD) and sham-operated (SO) rats was studied 3 to 30 days after surgery. A gradual but incomplete reduction of arterial hypertension was observed in SAD rats throughout the study. The norepinephrine- and methoxamine-induced dose-response curves were similar in both SAD and SO groups on day 3, but shifted to the left on days 7 and 15 and demonstrated a tendency to shift to the right at 30 days. Verapamil-induced vasodilation was similar in both groups. Enhanced mesenteric vascular responsiveness to endogenous catecholamines could contribute to the increased vascular resistance.

The cardiopulmonary reflexes of spontaneously hypertensive rats are normalized after regression of left ventricular hypertrophy and hypertension.

Cardiopulmonary reflexes are activated via changes in cardiac filling pressure (volume-sensitive reflex) and chemical stimulation (chemosensitive reflex). The sensitivity of the cardiopulmonary reflexes to these stimuli is impaired in the spontaneously hypertensive rat (SHR) and other models of hypertension and is thought to be associated with cardiac hypertrophy. The present study investigated whether the sensitivity of the cardiopulmonary reflexes in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. Untreated SHR and WKY rats were fed a normal diet. Another groups of rats were treated with enalapril (10 mg kg-1 day-1, mixed in the diet; SHRE or WKYE) for one month. After treatment, the volume-sensitive reflex was evaluated in each group by determining the decrease in magnitude of the efferent renal sympathetic nerve activity (RSNA) produced by acute isotonic saline volume expansion. Chemoreflex sensitivity was evaluated by examining the bradycardia response elicited by phenyldiguanide administration. Cardiac hypertrophy was determined from the left ventricular/body weight (LV/BW) ratio. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR as compared to WKY rats. As compared to the levels observed in normotensive WKY rats, however, enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE. SHR with established hypertension had a higher LV/BW ratio (45%) as compared to normotensive WKY rats. With enalapril treatment, the LV/BW ratio was reduced to 19% in SHRE. Finally, the reflex-induced bradycardia response produced by phenyldiguanide was significantly attenuated in SHR compared to WKY rats. Unlike the effects on the volume reflex, the sensitivity of the cardiac chemosensitive reflex to phenyldiguanide was not restored by enalapril treatment in SHRE. Taken together, these results indicate that the impairment of the volume-sensitive, but not the chemosensitive, reflex can be restored by treatment of SHR with enalapril. It is possible that by augmenting the gain of the volume-sensitive reflex control of RSNA, enalapril contributed to the reversal of cardiac hypertrophy and normalization of arterial blood pressure in SHR.

Chlorthalidone alters the vascular reactivity of DOC-salt hypertensive rats to norepinephrine.

Hypertension caused by deoxycorticosterone-salt (DOC-salt) may involve enhanced sympathetic tone and some diuretics may exert their antihypertensive action by modulating presynaptic adrenergic sensitivity. This study analyzes the noradrenergic sensitivity of the perfused mesentery isolated from DOC-salt hypertensive rats treated or not with chlorthalidone. Chlorthalidone treatment reduced arterial hypertension in DOC-salt treated rats (from 160 +/- 7 to 127 +/- 5 mmHg). The diuretic completely prevented the increase in sympathetic tone and blunted the decreased vagal tone observed in DOC-salt rats. Norepinephrine-induced vasoconstriction was enhanced in perfused mesenteries isolated from DOC-salt rats. This alteration was attenuated in preparations from chlorthalidone-treated DOC-salt animals. Blockade of neuronal catecholamine uptake using cocaine did not change these responses. These data suggest that chlorthalidone reduces the vascular hyperresponsiveness to catecholamines observed in DOC-salt treated hypertensive rats.

Oral administration of L-arginine decreases blood pressure and increases renal excretion of sodium and water in renovascular hypertensive rats.

The two-kidney, one-clip renovascular (2K1C) hypertension model is characterized by a reduction in renal flow on the clipped artery that activates the renin-angiotensin system. Endothelium dysfunction, including diminished nitric oxide production, is also believed to play a role in the pathophysiology of this model. Some studies have shown an effect of L-arginine (L-Arg, a nitric oxide precursor) on hypertension. In the present study we determined the ability of L-Arg (7 days of treatment) to reduce blood pressure and alter renal excretions of water, Na+ and K+ in a model of 2K1C-induced hypertension. Under ether anesthesia, male Wistar rats (150-170 g) had a silver clip (0.20 mm) placed around the left renal artery to produce the 2K1C renovascular hypertension model. In the experimental group, the drinking water was replaced with an L-Arg solution (10 mg/ml; average intake of 300 mg/day) from the 7th to the 14th day after surgery. Sham-operated rats were used as controls. At the end of the treatment period, mean blood pressure was measured in conscious animals. The animals were then killed and the kidneys were removed and weighed. There was a significant reduction of mean blood pressure in the L-Arg-treated group when compared to control (129 7 vs 168 6 mmHg, N = 8-10 per group; P<0.05). Concomitantly, a significant enhancement of water and Na+ excretion was observed in the 2K1C L-Arg-treated group when compared to control (water: 13.0 0.7 vs 9.2 0.5 ml/day, P<0.01; Na+: 1.1 0.05 vs 0.8 0.05 mEq/day, respectively, P<0.01). These results show that orally administered L-Arg acts on the kidney, possibly inducing changes in renal hemodynamics or tubular transport due to an increase in nitric oxide formation.

Effect of high ethanol intake on vascular reactivity to serotonin, vasopressin and acetylcholine in normotensive rats.

Chronic ethanol administration causes hypertension and alterations of vascular reactivity in rats. In several models of hypertension, alterations of vascular reactivity are believed to be secondary to the sustained increase in blood pressure. The present study investigated the effects of serotonin (5-hydroxytryptamine [5-HT]), vasopressin and acetylcholine (ACh) in the isolated perfused mesenteric arteries from Wistar rats submitted to an 8-week course of chronic ethanol intake (8 g/kg.day). No significant differences were observed in the dose-response curves with regard to: pressor effect of 0.04-10.0 nmole 5-HT; relaxant effect of 0.05-50.0 nmole ACh; or the pressor effects of two 1.5-nmole doses of vasopressin between control rats and ethanol-fed rats. These results suggest that modifications in arterial reactivity to endogenous vasoactive substances (observed in other studies involving more prolonged ethanol treatment in rats) may be, in part, secondary to the increase in blood pressure.

Relationship of inflammatory markers and pain in patients with head and neck cancer prior to anticancer therapy.

Pain is a common symptom in patients with cancer, including those with head and neck cancer (HNC). While studies suggest an association between chronic inflammation and pain, levels of inflammatory cytokines, such as C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α), have not been correlated with pain in HNC patients who are not currently undergoing anticancer treatment. The purpose of this study was to examine the relationship between these inflammatory markers and perceived pain in HNC patients prior to anticancer therapy. The study group consisted of 127 HNC patients and 9 healthy controls. Pain was assessed using the Brief Pain Inventory (BPI), and serum levels of CRP and TNF-α were determined using the particle-enhanced turbidimetric immunoassay (PETIA) and ELISA techniques, respectively. Patients experiencing pain had significantly higher levels of CRP (P<0.01) and TNF-α (P<0.05) compared with controls and with patients reporting no pain. There were significantly positive associations between pain, CRP level, and tumor stage. This is the first study to report a positive association between perceived pain and CRP in HNC patients at the time of diagnosis. The current findings suggest important associations between pain and inflammatory processes in HNC patients, with potential implications for future treatment strategies.

Roles of estrogen and progesterone in modulating renal nerve function in the rat kidney.

The maintenance of extracellular Na+ and Cl- concentrations in mammals depends, at least in part, on renal function. It has been shown that neural and endocrine mechanisms regulate extracellular fluid volume and transport of electrolytes along nephrons. Studies of sex hormones and renal nerves suggested that sex hormones modulate renal function, although this relationship is not well understood in the kidney. To better understand the role of these hormones on the effects that renal nerves have on Na+ and Cl- reabsorption, we studied the effects of renal denervation and oophorectomy in female rats. Oophorectomized (OVX) rats received 17ß-estradiol benzoate (OVE, 2.0 mg · kg(-1) · day(-1), sc) and progesterone (OVP, 1.7 mg · kg(-1) · day(-1), sc). We assessed Na+ and Cl- fractional excretion (FENa+ and FECl- , respectively) and renal and plasma catecholamine release concentrations. FENa+ , FECl- , water intake, urinary flow, and renal and plasma catecholamine release levels increased in OVX vs control rats. These effects were reversed by 17ß-estradiol benzoate but not by progesterone. Renal denervation did not alter FENa+ , FECl- , water intake, or urinary flow values vs controls. However, the renal catecholamine release level was decreased in the OVP (236.6 ± 36.1 ng/g) and denervated rat groups (D: 102.1 ± 15.7; ODE: 108.7 ± 23.2; ODP: 101.1 ± 22.1 ng/g). Furthermore, combining OVX + D (OD: 111.9 ± 25.4) decreased renal catecholamine release levels compared to either treatment alone. OVE normalized and OVP reduced renal catecholamine release levels, and the effects on plasma catecholamine release levels were reversed by ODE and ODP replacement in OD. These data suggest that progesterone may influence catecholamine release levels by renal innervation and that there are complex interactions among renal nerves, estrogen, and progesterone in the modulation of renal function.

The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats.

Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 ± 1.1 pg/mL; MSV = 12.8 ± 1.2 pg/mL), TNF-α (FSV = 16.6 ± 1.2 pg/mL; MSV = 12.8 ± 1 pg/mL) and IL-6 (FSV = 10.3 ± 0.2 pg/mL; MSV = 7.2 ± 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-α) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. In conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.

Effect of tamoxifen on the coronary vascular reactivity of spontaneously hypertensive female rats.

Tamoxifen has been associated with a reduction in the incidence of myocardial infarction. However, the effects of tamoxifen on coronary reactivity have not been fully elucidated. The objective of this study was to determine the effects of chronic treatment with tamoxifen on coronary vascular reactivity in spontaneously hypertensive rats (SHR). Female SHR were divided into four groups (N = 7 each): sham-operated (SHAM), sham-operated and treated with tamoxifen (10 mg/kg) by gavage for 90 days (TAMOX), ovariectomized (OVX), and ovariectomized and treated with tamoxifen (OVX+TAMOX). Mean arterial pressure (MAP), heart rate (HR), coronary perfusion pressure (CPP), and coronary vascular reactivity were measured. MAP and HR were reduced (9.42 and 11.67%, respectively) in the OVX+TAMOX group compared to the OVX group (P < 0.01). The coronary vascular reactivity of the OVX+TAMOX group presented smaller vasoconstrictor responses to acetylcholine (2-64 µg) when compared to the OVX group (P < 0.01) and this response was similar to that of the SHAM group. The adenosine-induced vasodilator response was greater in the TAMOX group compared to the SHAM and OVX groups (P < 0.05). Baseline CPP was higher in OVX+TAMOX and TAMOX groups (136 ± 3.6 and 130 ± 1.5 mmHg) than in OVX and SHAM groups (96 ± 2 and 119 ± 2.3 mmHg; P < 0.01). Tamoxifen, when combined with OVX, attenuated the vasoconstriction induced by acetylcholine and increased the adenosine-induced vasodilatory response, as well as reducing the MAP, suggesting beneficial effects of tamoxifen therapy on coronary vascular reactivity after menopause.

Sex differences in the coronary vasodilation induced by 17 ß-oestradiol in the isolated perfused heart from spontaneously hypertensive rats.

AIM: The relaxation induced by oestrogen in the coronary vascular bed from normotensive rats has been well described. However, almost nothing is known about this action in spontaneously hypertensive rats (SHR). We investigated the effect of 17 ß-oestradiol (E(2) ) in coronary arteries from SHR as well as the contribution of the endothelium and the vascular smooth muscle to this action. METHODS: Coronary arteries from male and female rats were used. Mean arterial pressure (MAP) and baseline coronary perfusion pressure (CPP) were determined. The effects of 10 µm E(2) were assessed by in bolus administration before and after endothelium denudation (0.25 µm sodium deoxycholate) or perfusion with 100 µm N(ω)-nitro-L-arginine methyl ester (L-NAME), 2.8 µm indomethacin, 0.75 µm clotrimazole, 100 µm L-NAME after endothelium denudation (0.25 µm sodium deoxycholate), 100 µm L-NAME plus 2.8 µm indomethacin, 0.75 µm clotrimazole plus 2.8 µm indomethacin and 4 mm tetraethylammonium (TEA). RESULTS: MAP was higher in the male group, while CPP was higher in the female group (P<0.05). There were no differences in E(2)-induced relaxation between females and males (-17±1.6 vs. -17±2% respectively). Only in the female group the E(2) response was significantly attenuated after endothelium removal or perfusion with clotrimazole. The response to E(2) was reduced in both groups with L-NAME, L-NAME plus indomethacin, L-NAME after endothelium removal or TEA. CONCLUSIONS: Nitric oxide, endothelium-derived hyperpolarizing factor and potassium channels may have the most important role to E(2) response in the female group, whereas nitric oxide and potassium channels may have the most important role in the male group.