Diverse effects of renal denervation on ventricular hypertrophy and blood pressure in DOCA-salt hypertensive rats

Cardiac hypertrophy that accompanies hypertension seems to be a phenomenon of multifactorial origin whose development does not seem to depend on an increased pressure load alone, but also on local growth factors and cardioadrenergic activity. The aim of the present study was to determine if sympathetic renal denervation and its effects on arterial pressure level can prevent cardiac hypertrophy and if it can also delay the onset and attenuate the severity of deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt treatment was initiated in rats seven days after uninephrectomy and contralateral renal denervation or sham renal denervation. DOCA (15 mg/kg, sc) or vehicle (soybean oil, 0.25 ml per animal) was administered twice a week for two weeks. Rats treated with DOCA or vehicle (control) were provided drinking water containing 1% NaCl and 0.03% KCl. At the end of the treatment period, mean arterial pressure (MAP) and heart rate measurements were made in conscious animals. Under ether anesthesia, the heart was removed and the right and left ventricles (including the septum) were separated and weighed. DOCA-salt treatment produced a significant increase in left ventricular weight/body weight (LVW/BW) ratio (2.44 ± 0.09 mg/g) and right ventricular weight/body weight (RVW/BW) ratio (0.53 ± 0.01 mg/g) compared to control (1.92 ± 0.04 and 0.48 ± 0.01 mg/g, respectively) rats. MAP was significantly higher (39%) in DOCA-salt rats. Renal denervation prevented (P>0.05) the development of hypertension in DOCA-salt rats but did not prevent the increase in LVW/BW (2.27 ± 0.03 mg/g) and RVW/BW (0.52 ± 0.01 mg/g). We have shown that the increase in arterial pressure level is not responsible for cardiac hypertrophy, which may be more related to other events associated with DOCA-salt hypertension, such as an increase in cardiac sympathetic activity

Effects of small doses of ouabain on the arterial blood pressure of anesthetized hypertensive and normotensive rats

Ouabain increases vascular resistance and may induce hypertension by inhibiting the Na+ pump. The effects of 0.18 and 18 µg/kg, and 1.8 mg/kg ouabain pretreatment on the phenylephrine (PHE; 0.1, 0.25 and 0.5 µg, in bolus)-evoked pressor responses were investigated using anesthetized normotensive (control and uninephrectomized) and hypertensive (1K1C and DOCA-salt treated) rats. Treatment with 18 µg/kg ouabain increased systolic and diastolic blood pressure in all groups studied. However, the magnitude of this increase was larger for the hypertensive 1K1C and DOCA-salt rats than for normotensive animals, while the pressor effect of 0.18 µg/kg ouabain was greater only in DOCA-salt rats. A very large dose (1.8 mg/kg) produced toxic effects on the normotensive control but not on uninephrectomized or 1K1C rats. Rat tail vascular beds were perfused to analyze the effects of 10 nM ouabain on the pressor response to PHE. In all animals, 10 nM ouabain increased the PHE pressor response, but this increase was larger in hypertensive DOCA-salt rats than in normotensive and 1K1C rats. Results suggested that a) increases in diastolic blood pressure induced by 18 µg/kg ouabain were larger in hypertensive than normotensive rats; b) in DOCA-salt rats, smaller ouabain doses had a stronger effect than in other groups; c) hypertensive and uninephrectomized rats were less sensitive to toxic doses of ouabain, and d) after treatment with 10 nM ouabain isolated tail vascular beds from DOCA-salt rats were more sensitive to the pressor effect of PHE than those from normotensive and 1K1C hypertensive rats. These data suggest that very small doses of ouabain, which might produce nanomolar plasma concentrations, enhance pressor reactivity in DOCA-salt hypertensive rats, supporting the idea that endogenous ouabain may contribute to the increase and maintenance of vascular tone in hypertension.

QRS Voltage-Duration Product in the Identification of Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats

OBJECTIVE - Evaluation of the performance of the QRS voltage-duration product (VDP) for detection of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR). METHODS - Orthogonal electrocardiograms (ECG) were recorded in male SHR at the age of 12 and 20 weeks, when systolic blood pressure (sBP) reached the average values of 165±3 mmHg and 195±12 mmHg, respectively. Age- and sex- matched normotensive Wistar Kyoto (WKY) rats were used as controls. VDP was calculated as a product of maximum QRS spatial vector magnitude and QRS duration. Left ventricular mass (LVM) was weighed after rats were sacrificed. RESULTS - LVM in SHR at 12 and 20 weeks of age (0.86±0.05 g and 1.05±0.07 g, respectively) was significantly higher as compared with that in WKY (0.65±0.07 g and 0.70±0.02 g). The increase in LVM closely correlated with the sBP increase. VDP did not reflect the increase in LVM in SHR. VDP was lower in SHR as compared with that in WKY, and the difference was significant at the age of 20 weeks (18.2mVms compared with 10.7mVms, p<0.01). On the contrary, a significant increase in the VDP was observed in the control WKY at the age of 20 weeks without changes in LVM. The changes in VDP were influenced mainly by the changes in QRSmax. CONCLUSION - LVM was not the major determinant of QRS voltage changes and consequently of the VDP. These data point to the importance of the nonspatial determinants of the recorded QRS voltage in terms of the solid angle theory.

Enalapril alters the formation of the collagen matrix in spontaneously hypertensive rats

OBJECTIVE: To assess the effect of the inhibition of the angiotensin-converting enzyme on the collagen matrix (CM) of the heart of newborn spontaneously hypertensive rats (SHR) during embryonic development. METHODS: The study comprised the 2 following groups of SHR (n=5 each): treated group - rats conceived from SHR females treated with enalapril maleate (15 mg. kg-1.day-1) during gestation; and nontreated group - offspring of nontreated females. The newborns were euthanized within the first 24 hours after birth and their hearts were removed and processed for histological study. Three fields per animal were considered for computer-assisted digital analysis and determination of the volume densities (Vv) of the nuclei and CM. The images were segmented with the aid of Image Pro Plus® 4.5.029 software (Media Cybernetics). RESULTS: No difference was observed between the treated and nontreated groups in regard to body mass, cardiac mass, and the relation between cardiac and body mass. A significant reduction in the Vv[matrix] and a concomitant increase in the Vv[nuclei] were observed in the treated group as compared with those in the nontreated group. CONCLUSION: The treatment with enalapril of hypertensive rats during pregnancy alters the collagen content and structure of the myocardium of newborns.

Hemodynamic Effect of Laser Therapy in Spontaneously Hypertensive Rats

Systemic arterial hypertension (SAH) is considered to be the greatest risk factor for the development of neuro-cardiovascular pathologies, thus constituting a severe Public Health issue in the world. The Low-Level Laser Therapy (LLLT), or laser therapy, activates components of the cellular structure, therefore converting luminous energy into photochemical energy and leading to biophysical and biochemical reactions in the mitochondrial respiratory chain. The LLLT promotes cellular and tissue photobiomodulation by means of changes in metabolism, leading to molecular, cellular and systemic changes. The objective of this study was to analyze the action of low-level laser in the hemodynamic modulation of spontaneously hypertensive rats, in the long term. Animals (n = 16) were randomly divided into the Laser Group (n = 8), which received three weekly LLLT irradiations for seven weeks, and into the Sham Group (n = 8), which received three weekly simulations of laser for seven weeks, accounting for 21 applications in each group. After seven weeks, animals were cannulated by the implantation of a catheter in the left carotid artery. On the following day, the systemic arterial pressure was recorded. The Laser Group showed reduced levels of mean blood pressure, with statistically significant reduction (169 ± 4 mmHg* vs. 182 ± 4 mmHg from the Sham Group) and reduced levels of diastolic pressure (143 ± 4 mmHg* vs. 157 ± 3 mmHg from the Sham Group), revealing a 13 and 14 mmHg decrease, respectively. Besides, there was a concomitant important decline in heart rate (312 ± 14 bpm vs. 361 ± 13 bpm from the Sham Group). Therefore, laser therapy was able to produce hemodynamic changes, thus reducing pressure levels in spontaneously hypertensive rats.

Effects of One Resistance Exercise Session on Vascular Smooth Muscle of Hypertensive Rats

AbstractBackground:Hypertension is a public health problem and increases the incidence of cardiovascular diseases.Objective:To evaluate the effects of a resistance exercise session on the contractile and relaxing mechanisms of vascular smooth muscle in mesenteric arteries of NG-nitro L-arginine methyl ester (L-NAME)-induced hypertensive rats.Methods:Wistar rats were divided into three groups: control (C), hypertensive (H), and exercised hypertensive (EH). Hypertension was induced by administration of 20 mg/kg of L-NAME for 7 days prior to experimental protocols. The resistance exercise protocol consisted of 10 sets of 10 repetitions and intensity of 40% of one repetition maximum. The reactivity of vascular smooth muscle was evaluated by concentration‑response curves to phenylephrine (PHEN), potassium chloride (KCl) and sodium nitroprusside (SNP).Results:Rats treated with L-NAME showed an increase (p < 0.001) in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) compared to the initial period of induction. No difference in PHEN sensitivity was observed between groups H and EH. Acute resistance exercise reduced (p < 0.001) the contractile response induced by KCl at concentrations of 40 and 60 mM in group EH. Greater (p < 0.01) smooth muscle sensitivity to NPS was observed in group EH as compared to group H.Conclusion:One resistance exercise session reduces the contractile response induced by KCl in addition to increasing the sensitivity of smooth muscle to NO in mesenteric arteries of hypertensive rats.

Resistance Training in Spontaneously Hypertensive Rats with Severe Hypertension

Abstract Background: Resistance training (RT) has been recommended as a non-pharmacological treatment for moderate hypertension. In spite of the important role of exercise intensity on training prescription, there is still no data regarding the effects of RT intensity on severe hypertension (SH). Objective: This study examined the effects of two RT protocols (vertical ladder climbing), performed at different overloads of maximal weight carried (MWC), on blood pressure (BP) and muscle strength of spontaneously hypertensive rats (SHR) with SH. Methods: Fifteen male SHR ENT#091;206 ± 10 mmHg of systolic BP (SBP)ENT#093; and five Wistar Kyoto rats (WKY; 119 ± 10 mmHg of SBP) were divided into 4 groups: sedentary (SED-WKY) and SHR (SED-SHR); RT1-SHR training relative to body weight (~40% of MWC); and RT2-SHR training relative to MWC test (~70% of MWC). Systolic BP and heart rate (HR) were measured weekly using the tail-cuff method. The progression of muscle strength was determined once every fifteen days. The RT consisted of 3 weekly sessions on non-consecutive days for 12-weeks. Results: Both RT protocols prevented the increase in SBP (delta - 5 and -7 mmHg, respectively; p > 0.05), whereas SBP of the SED-SHR group increased by 19 mmHg (p < 0.05). There was a decrease in HR only for the RT1 group (p < 0.05). There was a higher increase in strength in the RT2 (140%; p < 0.05) group as compared with RT1 (11%; p > 0.05). Conclusions: Our data indicated that both RT protocols were effective in preventing chronic elevation of SBP in SH. Additionally, a higher RT overload induced a greater increase in muscle strength.

The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases Blood Pressure In Hypertensive Rats

Abstract Background: Labdane-type diterpenes induce lower blood pressure via relaxation of vascular smooth muscle; however, there are no studies describing the effects of labdanes in hypertensive rats. Objective: The present study was designed to investigate the cardiovascular actions of the labdane-type diterpene ent-3-acetoxy-labda-8(17), 13-dien-15-oic acid (labda-15-oic acid) in two-kidney 1 clip (2K-1C) renal hypertension. Methods: Vascular reactivity experiments were performed in aortic rings isolated from 2K-1C and normotensive (2K) male Wistar rats. Nitrate/nitrite (NOx) measurement was performed in aortas by colorimetric assay. Blood pressure measurements were performed in conscious rats. Results: Labda-15-oic acid (0.1-300 µmol/l) and forskolin (0.1 nmol/l - 1 µmol/l) relaxed endothelium-intact and endothelium-denuded aortas from both 2K-1C and 2K rats. Labda-15-oic acid was more effective at inducing relaxation in endothelium-intact aortas from 2K pre-contracted with phenylephrine when compared to the endothelium-denuded ones. Forskolin was more potent than labda-15-oic acid at inducing vascular relaxation in arteries from both 2K and 2K-1C rats. Labda-15-oic acid-induced increase in NOx levels was lower in arteries from 2K-1C rats when compared to 2K rats. Intravenous administration of labda-15-oic acid (0.3-3 mg/kg) or forskolin (0.1-1 mg/kg) induced hypotension in conscious 2K-1C and 2K rats. Conclusion: The present findings show that labda-15-oic acid induces vascular relaxation and hypotension in hypertensive rats.

The effects of supraphysiological supplementation of b-carotene in spontaneously hypertensive rats (SHR and SHR-sp)

Objective: to investigate the effect of administration of supraphysiological âcaroteno on biological parameters (ectoscopy and blood pressure), laboratory (malondialdehyde) and histological (liver and carotid arteries) of spontaneously hypertensive rats prone to stroke (SHR-sp).Methods: we used 36 male rats were divided into three groups, each containing 12 rats Wistar, SHR and SHR-sp, subdivided into six control animals and six animals treated with supraphysiological doses of âcaroteno for two periods of ten weeks interspersed with one week interruption. In the experiment were assessed daily physical examination and blood pressure (plethysmography). At sacrifice, blood was collected for measurement of serum malondialdehyde, liver and carotid arteries for histological examination.Results: temporary change in color of the fur, decreased significantly (p<0.0001) blood pressure (20mg supplementation âcaroteno) and serum levels of malondialdehyde (p<0.05) and increased amount of elastic fibers in the carotid wall of SHR and SHR-sp.Conclusion: supplementation of supraphysiological âcaroteno caused no toxic effects, showed positive response in the modulation of blood pressure and lower serum malondialdehyde. No significant morphological changes were found in both groups, except an increase in the number of elastic fibers in the muscle layer carotid suggesting elastosis in SHR and SHR-sp.

Myocyte necrosis is the basis for fibrosis in renovascular hypertensive rats

The pathogenesis of fibrosis and the functional features of pressure overload myocardial hypertrophy are still controversial. The objectives of the present study were to evaluate the function and morphology of the hypertrophied myocardium in renovascular hypertensive (RHT) rats. Male Wistar rats were sacrificed at week 4 (RHT4) and 8 (RHT8) after unilateral renal ischemia (Goldblatt II hypertension model). Normotensive rats were used as controls. Myocardial function was analyzed in isolated papillary muscle preparations, morphological features were defined by light microscopy, and myocardial hydroxyproline concentration (HOP) was determined by spectrophotometry. Renal artery clipping resulted in elevated systolic arterial pressure (RHT4: 178 ± 19 mmHg and RHT8: 194 ± 24 mmHg, P<0.05 vs control: 123 ± 7 mmHg). Myocardial hypertrophy was observed in both renovascular hypertensive groups. The myocardial HOP concentration was increased in the RHT8 group (control: 2.93 ± 0.38 µg/mg; RHT4: 3.02 ± 0.40 µg/mg; RHT8: 3.44 ± 0.45 µg/mg of dry tissue, P<0.05 vs control and RHT4 groups). The morphological study demonstrated myocyte necrosis, vascular damage and cellular inflammatory response throughout the experimental period. The increased cellularity was more intense in the adventitia of the arterioles. As a consequence of myocyte necrosis, there was an early, local, conjunctive stroma collapse with disarray and thickening of the argyrophilic interstitial fibers, followed by scarring. The functional data showed an increased passive myocardial stiffness in the RHT4 group. We conclude that renovascular hypertension induces myocyte and arteriole necrosis. Reparative fibrosis occurred as a consequence of the inflammatory response to necrosis. The mechanical behavior of the isolated papillary muscle was normal, except for an early increased myocardial passive stiffness

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.

Abnormal proliferative response of the carotid artery of spontaneously hypertensive rats after angioplasty may be related to the depolarized state of its smooth muscle cells

Hypertension is one of the major precursors of atherosclerotic vascular disease, and vascular smooth muscle abnormal cell replication is a key feature of plaque formation. The present study was conducted to examine the relationship between hypertension and smooth muscle cell proliferation after balloon injury and to correlate neointima formation with resting membrane potential of uninjured smooth muscle cells, since it has been suggested that altered vascular function in hypertension may be related to the resetting of the resting membrane potential in spontaneously hypertensive rats (SHR). Neointima formation was induced by balloon injury to the carotid arteries of SHR and renovascular hypertensive rats (1K-1C), as well as in their normotensive controls, i.e., Wistar Kyoto (WKY) and normal Wistar (NWR) rats. After 14 days the animals were killed and the carotid arteries were submitted to histomorphometric and immunohistochemical analyses. Resting membrane potential measurements showed that uninjured carotid arteries from SHR smooth muscle cells were significantly depolarized (-46.5 ± 1.9 mV) compared to NWR (-69 ± 1.4 mV), NWR 1K-1C (-60.8 ± 1.6 mV), WKY (-67.1 ± 3.2 mV) and WKY 1K-1C (-56.9 ± 1.2 mV). The SHR arteries responded to balloon injury with an enhanced neointima formation (neo/media = 3.97 ± 0.86) when compared to arteries of all the other groups (NWR 0.93 ± 0.65, NWR 1K-1C 1.24 ± 0.45, WKY 1.22 ± 0.32, WKY 1K-1C 1.15 ± 0.74). Our results indicate that the increased fibroproliferative response observed in SHR is not related to the hypertensive state but could be associated with the resetting of the carotid smooth muscle cell resting membrane potential to a more depolarized state.

Abnormalities of glucose metabolism in spontaneously hypertensive rats

Abnormalities in glucose metabolism and insulin action are frequently detected in patients with essential hypertension. Spontaneously hypertensive rats (SHR) have been used as an experimental model to understand this pathological condition. The objective of the present study was to assess glucose metabolism and insulin action in SHR and Wistar rats under fed and fasting conditions. Peripheral glucose utilization was estimated by kinetic studies with [6-³H]-glucose and gluconeogenetic activity was measured during continuous [14C]-bicarbonate infusion. Plasma glucose levels were higher in the SHR group. Plasma insulin levels in the fed state were higher in the SHR group (99.8 ± 6.5 µM) than in the control group (70.4 ± 3.6 µM). Muscle glycogen content was reduced in SHR compared to control under the various experimental conditions. Peripheral glucose utilization was slightly lower in the SHR group in the fed state (8.72 ± 0.55 vs 9.52 ± 0.80 mg kg-1 min-1 in controls). Serum free fatty acid levels, hepatic glycogen levels, hepatic phosphoenolpyruvate carboxykinase activity and gluconeogenetic activity were similar in the two groups. The presence of hyperglycemia and hyperinsulinemia and the slightly reduced peripheral glucose utilization suggest the presence of resistance to the action of insulin in peripheral tissues of SHR. Hepatic gluconeogenesis does not seem to contribute to the metabolic alterations detected in these animals.

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.