temocapril-hydrochloride and Body-Weight

Whether temporary angiotensin II (AngII) blockade at the prediabetic stage attenuates renal injury in type 2 diabetic OLETF rats later in life was investigated. OLETF rats were treated with an AT(1) receptor antagonist (olmesartan, 0.01% in food), angiotensin-converting enzyme inhibitor (temocapril, 0.01% in food), a combination of the two, or hydralazine (25 mg/kg per d) at the prediabetic stage (4 to 11 wk of age) and then monitored without further treatment until 50 wk of age. At 11 wk of age, blood glucose levels and urinary protein excretion (U(protein)V) were similar between OLETF and control LETO rats. However, OLETF rats showed higher kidney AngII contents and type IV collagen mRNA expression than LETO rats at this age. These decreased with olmesartan, temocapril, and a combination of these but not with hydralazine. At 50 wk of age, diabetic OLETF rats showed higher BP, U(protein)V, and intrarenal AngII levels than LETO rats. Temporary AngII blockade did not affect glucose metabolism or the development of hypertension in OLETF rats but significantly suppressed proteinuria and ameliorated glomerular injury. However, no parameters were affected by temporary hydralazine treatment. The present study demonstrated that intrarenal AngII and type IV collagen expression are already augmented long before diabetes becomes apparent in OLETF rats. Furthermore, temporary AngII blockade at the prediabetic stage attenuates the progression of renal injury in these animals. These data suggest that early AngII blockade could be an effective strategy for preventing the development of type 2 diabetic renal injury later in life.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Collagen; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Hydralazine; Imidazoles; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Male; NADPH Oxidases; Olmesartan Medoxomil; Prediabetic State; Rats; Rats, Inbred OLETF; Receptors, Angiotensin; Renin; Tetrazoles; Thiazepines; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta

Background- We have recently identified that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H2O2 accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved.. Control and eNOS-/- mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H2O2, abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K(Ca) channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS-/- mice (n=6).. These results indicate that endothelium-derived H2O2 accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H2O2 theory.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Factors; Blood Pressure; Body Weight; Catalase; Endothelium, Vascular; Estradiol; Female; Glutathione; Hydrogen Peroxide; In Vitro Techniques; Isometric Contraction; Membrane Potentials; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Superoxide Dismutase; Thiazepines; Vasodilation

A high-fructose diet (HFD) has been shown to elevate blood pressure (BP) and to decrease insulin sensitivity in rats. Although running exercise can attenuate these phenomena, its effect on target organ protection is not clear. We investigated whether exercise training has renal protective effects in this model. Nine-week-old spontaneously hypertensive rats were allocated to groups that received HFD or a control diet (control group) for 15 weeks. At the age of 10 weeks, fructose-fed rats were allocated to groups that were given vehicle (FRU group), temocapril, an angiotensin converting enzyme inhibitor (TEM group), exercise training (EX group; treadmill running), or temocapril plus exercise training (TEM+EX group). BP was higher in the FRU group than in the control group. Exercise training tended to decrease BP and temocapril treatment decreased BP significantly. Proteinuria was similar in the five groups. Plasma leptin concentration and epididymal fat weight were lower in the EX and TEM+EX groups than in the FRU group. In the soleus muscle of the FRU group, the composite ratio of type I fiber was decreased and that of type IIa fiber was increased compared with those in the control group. Both temocapril and exercise training restored these ratios. The glomerular sclerosis index (GSI) was higher in the FRU group than in the control group. GSI was decreased equally in the TEM, EX, and TEM+EX groups and was positively correlated with plasma leptin concentration. The results suggest that exercise training ameliorates glomerular sclerosis through mechanisms other than a reduction in BP.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Composition; Body Weight; Diet; Fructose; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney Glomerulus; Leptin; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Organ Size; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Inbred SHR; Thiazepines

The aim of this study was to investigate whether a combined treatment of ACE inhibitor and exercise training is more effective than either treatment alone in alleviating the insulin resistant states in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes. OLETF rats (25 weeks old) were randomly divided into 5 groups; sedentary control, exercise-trained, temocapril (ACE inhibitor; 2 mg/kg/day)-treated, with and without exercise, and losartan (AT1 receptor antagonist; 1 mg/kg/day)-treated. Long-Evans Tokushima Otsuka rats were used as a non-diabetic control. Body weight, the amount of abdominal fat and blood pressure were higher for OLETF rats than for control rats. However, glucose infusion rate (GIR), an index of insulin resistance, was decreased greatly in OLETF rats. The fasting levels of blood glucose, insulin and lipids were also increased in the diabetic strain. In OLETF rats, both temocapril and losartan reversed hypertensive states significantly, whereas GIR and hyperlipidemia were improved when rats were treated with ACE inhibitors, but not with the AT1 receptor antagonist. Exercise training decreased body weight and the amount of abdominal fat, and also increased GIR in parallel with improved dislipidemia. The combination of the ACE inhibitor with exercise training also improved obesity, hyperinsulinemia, dislipidemia and fasting level of blood glucose, and this combination resulted in the greatest improvement of insulin resistance. These results suggest that the combination of ACE inhibitor and exercise training may be a beneficial treatment for mixed diabetic and hypertensive conditions.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Combined Modality Therapy; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Exercise Therapy; Glucose Clamp Technique; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Obesity; Physical Conditioning, Animal; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Thiazepines; Treatment Outcome

Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis.. To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription-polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis.. Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Coronary Vessels; Diabetes Mellitus; Fibrinolysis; Fibrosis; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardium; Obesity; Organ Size; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; RNA, Messenger; Thiazepines; Thromboplastin

Chronic inhibition of NO synthesis induces cardiac hypertrophy independent of systemic blood pressure (SBP) by increasing protein synthesis in vivo. We examined whether ACE inhibitors (ACEIs) enalapril and temocapril and angiotensin II type-I receptor antagonists (angiotensin receptor blockers [ARBs]) losartan and CS-866 can block cardiac hypertrophy and whether changes in activation of 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated protein kinase (ERK) are involved. The following 13 groups were studied: untreated Wistar-Kyoto rats and rats treated with NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME), D-NAME (the inactive isomer of L-NAME), L-NAME plus hydralazine, L-NAME plus enalapril (3 mg. kg(-1). d(-1)) or temocapril (1 or 10 mg. kg(-1). d(-1)), L-NAME plus losartan (10 mg. kg(-1). d(-1)) or CS-866 (1 or 10 mg. kg(-1). d(-1)), L-NAME plus temocapril-CS866 in combination (1 or 10 mg. kg(-1). d(-1)), and L-NAME plus rapamycin (0.5 mg. kg(-1). d(-1)). After 8 weeks of each experiment, ratios of coronary wall to lumen (wall/lumen) and left ventricular weight to body weight (LVW/BW) were quantified. L-NAME increased SBP, wall/lumen, and LVW/BW compared with that of control. ACEIs, ARBs, and hydralazine equally canceled the increase in SBP induced by L-NAME. However, ACEIs and ARBs equally (but not hydralazine) attenuated increase in wall/lumen and LVW/BW induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in myocardium (2.2-fold and 1.8-fold versus control, respectively). ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase. Thus, ACEIs and ARBs modulate different intracellular signaling pathways, inhibiting p70S6K or ERK, respectively, to elicit equal reduction of cardiac hypertrophy induced by chronic inhibition of NO synthesis in vivo.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Cardiomegaly; Coronary Vessels; Enalapril; Enzyme Inhibitors; Heart Rate; Heart Ventricles; Imidazoles; Losartan; Male; Mitogen-Activated Protein Kinases; Myocardium; Neutrophil Infiltration; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Olmesartan Medoxomil; Organ Size; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Ribosomal Protein S6 Kinases; Tetrazoles; Thiazepines

The aim of this study was to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor (AT) antagonist on insulin resistance, especially on muscle fiber composition in fructose-induced insulin-resistant and hypertensive rats. Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or a fructose-rich diet (FFR). For the last two weeks of a six-week period of either diet, the rats were treated with gum arabic solution as a vehicle (control or FFR), angiotensin-converting enzyme inhibitor (FFR+ACE), temocapril (1 mg/kg/ day) or an angiotensin II receptor antagonist (FFR+AT), CS-866 (0.3 mg/kg/day), by gavage, and then the euglycemic hyperinsulinemic glucose clamp technique was performed to evaluate insulin sensitivity. At the end of the glucose clamp, the soleus muscle was dissected for determination of the muscle fiber composition by ATPase methods. Blood pressure at the glucose clamp in the FFR group was significantly higher than that of the control group, and both temocapril and CS-866 significantly lowered the blood pressure of the FFR group. The average rate of glucose infusion during the glucose clamp, as a measure of insulin sensitivity (M value), was significantly lower in the FFR rats compared to the controls (15.4 +/- 0.4, 10.9 +/- 0.6 mg/kg/min, for control and FFR, respectively, P < .01). Both temocapril and CS-866 partially improved the M values compared to FFR (13.2 +/- 0.7, 12.8 +/- 0.5 mg/kg/min, for FFR+ACE, FFR+AT, respectively, P < .01 compared with FFR, P < .05 compared with control). The composite ratio of type I fibers of the soleus muscle was decreased significantly in the FFR rats compared with the controls (82% +/- 2%, 75% +/- 2%, for control and FFR, respectively, P < .01), and both temocapril and CS-866 restored a composite ratio of type I fibers to the same level as that of the controls (81% +/- 1%, 80% +/- 1% for FFR+ACE and FFR+AT, respectively). The M value was significantly correlated with the composition of type I and type II fibers. These results suggest that the fiber composition of skeletal muscle is correlated to insulin resistance, and that both ACE inhibitors and AT antagonists may modulate the muscle fiber composition in a hypertensive and insulin-resistant animal model, fructose-fed rats, to the same extent.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Body Weight; Dietary Carbohydrates; Fasting; Fructose; Glucose; Glucose Clamp Technique; Heart Rate; Hypertension; Imidazoles; Insulin Resistance; Magnesium; Male; Muscle Fibers, Fast-Twitch; Muscle Fibers, Skeletal; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Olmesartan Medoxomil; Rats; Rats, Sprague-Dawley; Tetrazoles; Thiazepines

We studied an alteration of calcineurin expression in the heart and its modification by cyclosporin A and an ACE inhibitor, temocapril, using Dahl salt-sensitive (DS) rats with hypertensive left ventricular hypertrophy (LVH) and congestive heart failure (CHF). Calcineurin protein expression in the LV myocardium was increased in the LVH stage, but then decreased during CHF transition. Chronic cyclosporin A treatment (10 mg/kg/day), which inhibits calcineurin activity, could not block the increases of LV weight and dimensions and did not improve the LV systolic function during the CHF transition. In contrast, chronic temocapril treatment (20 mg/kg/day) restored the downregulation of calcineurin expression, but progression of the hypertrophic process was inhibited. Therefore, cardiac calcineurin is increased in the hypertensive LVH and may be involved in the development of the adaptive hypertrophic process. However, calcineurin expression is downregulated during CHF transition and may no longer play a major role in the pathogenesis of myocardial hypertrophy in the failing hearts.

Topics: Adaptation, Physiological; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Body Weight; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Disease Progression; Down-Regulation; Electrocardiography; Heart Failure; Hemodynamics; Hypertension; Hypertrophy; Myocardium; Rats; Rats, Inbred Dahl; Thiazepines

The purpose of our study has to determine the myocardial protective effects of the angiotensin-converting enzyme (ACE) inhibitor temocapril (TEM, 7 mg/kg/day) simultaneously administered with doxorubicin (Adriamycin). Twenty male Sprague-Dawley rats were intraperitoneally administered a cumulative dose of 15 mg/kg of doxorubicin (each dose of 1.0 mg/kg x 15) for 3 weeks, and divided into TEM-untreated and -treated rats. Seven control rats were injected with saline intraperitoneally. Body weight, hemodynamics, and echocardiographic measurements including quantitative analysis of ultrasonic integrated backscatter (IB) were obtained for 12 weeks after treatment. Finally, rats were killed for histopathologic study. At 6 weeks, end-diastolic left ventricular diameter (LVD) and percentage fractional shortening (%FS) were similar in TEM-treated and TEM-untreated rats, but cyclic variation of IB (dB) significantly decreased in TEM-untreated rats (7.3 +/- 1.2; control rats, 9.7 +/- 0.9; p < 0.01). At 12 weeks, %FS decreased in TEM-untreated rats (26.1 +/- 6.1%: TEM-treated rats, 34.2 +/- 6.2; p < 0.05), and calibrated IB (dB) in TEM-untreated rats (15.5 +/- 0.5) increased as compared with that in TEM-treated rats (12.1 +/- 0.7; p < 0.01). Interstitial collagen accumulation increased in TEM-untreated rats and was inhibited in treated rats. Simultaneous administration of TEM with doxorubicin was beneficial in preventing doxorubicin-induced myocardial damage, and myocardial tissue characterization was useful for the early detection of myocardial damage and the assessment of therapy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Pressure; Body Weight; Cardiomyopathies; Collagen; Densitometry; Doxorubicin; Echocardiography; Male; Rats; Rats, Sprague-Dawley; Thiazepines

The aim of this study was to determine the role of tumor necrosis factor-alpha (TNF-alpha) in skeletal muscle tissue in insulin resistance and hypertension and the effect of anti-hypertensive medicine on skeletal muscle TNF-alpha in fructose-induced insulin-resistant and hypertensive rats (fructose-fed rats: FFR).. Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow. For the last 2 weeks of a 6-week period of either diet, the rats were treated with a vehicle (control or FFR); temocapril, an angiotensin converting enzyme inhibitor (ACEI); or CS-866, an angiotensin II type 1 receptor blocker (ARB). The euglycemic hyperinsulinemic glucose clamp technique was performed to evaluate insulin sensitivity (M value). TNF-alpha levels in soleus and extensor digitorum longus (EDL) muscles and epididymal fat pads were measured. We also measured the TNF-alpha concentration in an incubated medium secreted from soleus muscle strips with or without angiotensin II.. TNF-alpha levels were significantly higher in the soleus and EDL muscles, but not in the epididymal fat, in the FFRs compared with the control rats. Temocapril and CS-866 lowered systolic blood pressure, improved insulin resistance, and reduced TNF-alpha in both skeletal muscles. There were significant negative correlations between M values and TNF-alpha levels in both soleus and EDL muscles. Also, the soleus muscle strip incubation with 10(-7) mol/l angiotensin II increased TNF-alpha secreted into the incubation medium compared to the incubation without angiotensin II. These results suggest that skeletal muscle TNF-alpha is linked to insulin resistance and hypertension and that angiotensin II may be one of the factors that regulate skeletal muscle TNF-alpha.

Topics: Adipose Tissue; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Epididymis; Fructose; Glucose Clamp Technique; Heart Rate; Hypertension; Imidazoles; Insulin Resistance; Male; Muscle, Skeletal; Olmesartan Medoxomil; Rats; Rats, Sprague-Dawley; Tetrazoles; Thiazepines; Tumor Necrosis Factor-alpha

The effects of the angiotensin converting enzyme (ACE) blocker temocapril on the capillary network of the left ventricle were studied in stroke-prone spontaneously hypertensive rats (SHRSP). The ACE blocker was dissolved in the drinking water and supplied to 24 and 32 week old SHRSP ad libitum for 5 weeks. The capillaries of the wall of the left ventricle were studied using a double staining method to differentiate the arteriolar, intermediate and venular capillary portions. Capillary density increased and capillary domain areas decreased in all capillary portions compared with untreated control SHRSP in both age groups. The proportion of venular capillary portions was increased by temocapril treatment. The results indicate that the late start of ACE blockade caused the regression of the hypertrophied cardiomyocytes, which is characteristic of SHRSP, and the rearrangement of capillary portions. The plasma concentration of angiotensin II was significantly lower in temocapril-treated SHRSP compared to the control group. The implication is that intrinsic angiotensin II exerts an appreciable effect on the function, structure and capillary network in the left ventricular wall in SHRSP.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Capillaries; Coronary Vessels; Heart Rate; Heart Ventricles; Hypertension; Male; Rats; Rats, Inbred SHR; Thiazepines

We have shown previously that angiotensin-converting enzyme (ACE) inhibitors prevent coronary vascular remodeling (medial thickening and perivascular fibrosis) and myocardial remodeling (fibrosis and hypertrophy) in rats induced by long-term inhibition of nitric oxide (NO) synthesis with oral administration of N omega-nitro-L-arginine methyl ester (L-NAME). ACE inhibitors inhibit both the formation of angiotensin II and the catabolism of bradykinin. In this study, we aimed to determine the relative contribution of the latter two mechanisms to the beneficial effects of an ACE inhibitor on structural remodeling. First, we examined the effects of the ACE inhibitor temocapril and the angiotensin II AT1 subtype receptor antagonist CS-866 on the structural remodeling induced by administering L-NAME for 8 weeks. Temocapril and CS-866 were equally effective in preventing remodeling. Second, we examined whether the effect of temocapril on the remodeling induced by L-NAME was reduced by the bradykinin receptor antagonist HOE140. The latter drug did not alter the beneficial effect of temocapril on remodeling. In conclusion, although species differences must be considered to apply our conclusion to clinical conditions, the present results suggest that the inhibition of angiotensin II activity, mediated via the AT1 receptors, is responsible for the beneficial effects of an ACE inhibitor in our animal model of coronary vascular and myocardial remodeling induced by the long-term inhibition of NO synthesis.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradykinin; Cardiomegaly; Coronary Vessels; Fibrosis; Heart; Heart Rate; Imidazoles; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Olmesartan Medoxomil; Peptidyl-Dipeptidase A; Rats; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles; Thiazepines

We studied the effects of chronic treatment with a novel angiotensin converting enzyme inhibitor, alpha-[(2S,6R)-6-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino-5-oxo-2- (2-thienyl)perhydro-1,4-thiazepin-4-yl]acetic acid.HCl (CS622), and a vasodilator, hydralazine, on plasma atrial natriuretic factor (ANF) levels and kidney ANF receptors in spontaneously hypertensive rats (SHR). Plasma ANF level was decreased and cardiac hypertrophy reduced in CS622 treated SHR, but not in hydralazine treated SHR, although blood pressure was lowered similarly in both SHR groups. The binding capacity of kidney ANF receptors increased and the affinity decreased in CS622 treated SHR compared to untreated SHR. These results suggest that decrease of plasma ANF results from decreased cardiac load but not from lowered blood pressure, and that changes in ANF receptors result from increased plasma ANF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Heart; Hydralazine; Kidney; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Atrial Natriuretic Factor; Receptors, Cell Surface; Thiazepines