Enalapril can prevent vascular amplifier development in spontaneously hypertensive rats

Three groups of spontaneously hypertensive rats (SHR) were given enalapril (25 mg/kg/day) from 4 to 9 weeks, 4 to 14 weeks, and 14 to 20 weeks of age. The drug was stopped and observations continued for another 16-21 weeks. At selected times, we measured blood pressure, in vitro hindquarter vascular resistance properties, left ventricular weight/body weight ratio, and skeletal muscle vessel norepinephrine kinetics in treated and untreated SHR and in Wistar-Kyoto (WKY) rats. At the end of each treatment period, all cardiovascular variables were close to values of WKY rats and well below those of untreated SHR, and the norepinephrine or fractional rate constant was about 25% below those levels. After enalapril was stopped, blood pressure and left ventricular weight/body weight ratio increased in parallel to levels ranging from 30% to 50% of the normal difference between untreated SHR and WKY rats. However, in SHR treated from 4 to 9 weeks and from 4 to 14 weeks of age, hindquarter resistance properties remained close to WKY rat levels for the entire observation period of 16-21 weeks after treatment, suggesting suppression of the enhanced resistance responses of SHR (amplifier properties). In SHR treated from 14 to 20 weeks of age, suppression of amplifier properties was more transient, and they redeveloped partially 5-6 weeks after cessation of therapy. When enalapril was given up to 14 weeks of age, the long-term suppression of amplifier properties was probably mainly through prevention of smooth muscle hypertrophy in resistance vessels and possibly through other mechanisms (e.g., "rarefaction").(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of the renin-angiotensin and cardiac sympathetic nervous systems in the development of hypertension and left ventricular hypertrophy in spontaneously hypertensive rats.

To elucidate the relationship between the development of left ventricular hypertrophy (LVH) in hypertension and the development of both the cardiac sympathetic nervous and renin-angiotensin systems, as measured by norepinephrine and angiotensin II levels, respectively. In this longitudinal study, we compared blood pressure (BP), left ventricular weight, and norepinephrine (NE) and angiotensin II (Ang II) concentrations, in Spontaneously Hypertensive Rats (SHR) and age-matched Wistar-Kyoto (WKY) rats at 5, 10, 15, 20, and 28 wk of age. Blood pressure, plasma and ventricular Ang II and tissue NE were measured by the tail-cuff method, radioimmunoassay, and high-performance liquid chromatography (HPLC), respectively. At 5 wk, systolic blood pressure was the same in both strains. But the left ventricular plus septum weight to body weight (LVSW/BW) ratio was higher in SHR than in WKY rats (p < 0.01), which finding may have been related to the increased cardiac tissue NE concentration, and this increase tended to parallel the rise in blood pressure. Both left ventricle and forelimb muscle NE concentrations were significantly higher in SHR than in WKY rats at 5, 10, and 15 wk of age (p < 0.01, respectively), and were similar at 20 and 28 wk of age. The heart and plasma Ang II levels decreased with age, which results were in keeping with the known developmental tendencies of the biological aging progress. There was no significant difference in plasma Ang II levels between the two strains from 5 to 20 wk, whereas these levels were remarkably higher in WKY than in SHR rats at 28 wk (p< 0.01). Otherwise, the left ventricular tissue Ang II concentrations were significantly higher in SHR than in WKY rats at the late stage (from 15 to 28 wk), which may have contributed to the late-stage cardiac hypertrophy. These results suggested that the sympathetic nervous system (SNS) and the renin-angiotensin-system (RAS) in SHR may contribute to the pathogenesis of hypertension and LVH at the early and late stages, respectively.     

Effects of duration and severity of arterial hypertension and cardiac hypertrophy on coronary vasodilator reserve

Cardiac hypertrophy is associated with a decrease in coronary reserve. However, factors which may modulate the interaction between myocardial growth and vascular proliferation, such as duration and severity of hypertrophy, have not been evaluated. We measured myocardial perfusion with microspheres in conscious, chronically instrumented. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats at 3, 7, and 15 months of age; and in SHR stroke-prone (SHR-SP) rats at 13-14 months of age. Myocardial perfusion was measured with microspheres in awake rats at rest and during maximal coronary dilation produced by dipyridamole infusion (2.0 mg/kg per min, iv). Arterial pressure was significantly elevated (P less than or equal to 0.05) in all hypertensive groups (vs. age-matched WKY), both at rest and during dipyridamole infusion. Left ventricular mass in the SHR rats was increased significantly (P less than or equal to 0.05) by 14%, 28%, and 29% at 3, 7, and 15 months, respectively. Left ventricular mass in the SHR-SP group was increased by 50% (P less than or equal to 0.05) compared to the 15-month-old WKY. Left ventricular minimal coronary vascular resistance (per gram) was significantly greater (P less than or equal to 0.05) in SHR at 7 months, and in the SHR-SP group (66% and 60%, respectively). Right ventricular minimal coronary vascular resistance was significantly greater (P less than or equal to 0.05) in SHR at 7 and 15 months (50%), and in the SHR-SP group (122%), compared to 15-month-old WKY. The results indicate the following: (1) the increase in minimal coronary vascular resistance between SHR and WKY rats was greatest when left ventricular hypertrophy peaked (7 months) and was no longer present after left ventricular hypertrophy had stabilized. (2) In 14-month-old SHR-SP rats, with more severe left ventricular hypertrophy and hypertension, minimal coronary vascular resistance was considerably higher than in SHR of approximately the same age. (3) Long-term arterial hypertension was associated with a higher right ventricular minimal coronary vascular resistance. Resistance appeared to change in proportion to the severity of hypertension, and the changes were independent of the presence of right ventricular hypertrophy.     

Beneficial and deleterious effects of rosiglitazone on hypertension development in spontaneously hypertensive rats

The antihypertensive effect of the peroxisome proliferator-activated receptor (PPAR)gamma agonist rosiglitazone has been reported in patients with diabetes or obesity. The correlation of PPARgamma expression with blood pressure and the therapeutic application of rosiglitazone in spontaneously hypertensive rats (SHR) were investigated in the present study. Systolic blood pressure of 21-week SHR was significantly higher than that of age-matched Wistar-Kyoto rats (WKY) (225 +/- 5 v 144 +/- 2 mm Hg, P <.05). Basal expression levels of PPARgamma proteins in vascular tissues of 21-week SHR were significantly lower than that of age-matched 21-week WKY (P <.05). This reduced expression of PPARgamma was not detected between 5- and 13- week SHR and age-matched WKY. Cardiac PPARgamma expression was also not different among different age groups between SHR and WKY. Chronic treatment with rosiglitazone, but not PPARalpha agonist Wy14643, significantly retarded hypertension development and reversed abnormally faster heart rate in young SHR. An unfavorable effect of rosiglitazone treatment was the increased heart-to-body weight ratio accompanied by left ventricular hypertrophy. In conclusion, vascular PPARgamma protein expression in adult SHR (21 weeks) is significantly decreased in comparison with the age-matched WKY. Chronic rosiglitazone treatment retards hypertension development, but the associated prohypertrophy effect calls for a cautious use of this thiazolidinedindione in the treatment of insulin resistance syndrome associated with hypertension.     

Prevention of hypertension and vascular changes by captopril treatment

Treatment of female spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats with captopril was carried out by the addition of the drug in the drinking water throughout pregnancy and lactation and after weaning. At 28 weeks of age, average systolic blood pressure of treated SHR was 113 +/- 3 mm Hg, which was below that of control SHR (188 +/- 3 mm Hg) and WKY rats (124 +/- 3 mm Hg). Body weight and heart rate of the SHR were not affected by the treatment. Tissue level of catecholamines was increased by captopril treatment in the superior cervical ganglia but remained unchanged in the plasma, heart, mesenteric arteries, and the adrenal glands of both SHR and WKY rats. Left ventricular weight, wall thickness, and internal diameter of the left ventricle in the SHR were reduced by the treatment. Morphometric measurements of the mesenteric arteries showed that vascular alterations present in the control SHR were prevented by the treatment. In the superior mesenteric artery and large mesenteric artery, smaller lumen size at maximal relaxation found in the control SHR was normalized to the level of the WKY rats. Hypertrophy of the medial wall in the superior mesenteric, large and small mesenteric arteries, and an increase in the number of smooth muscle cell layers in the large mesenteric artery of the SHR were prevented by the treatment. Perfusion study of the mesenteric vascular bed showed that reactivity of these vessels to norepinephrine was reduced, and sensitivity to norepinephrine (as determined by the effective dose that causes 50% of maximal response) was increased in the SHR by captopril treatment. Sensitivity of the tail artery in response to norepinephrine was not altered by the treatment. We conclude that long-term treatment with captopril of SHR before and after birth prevented the development of hypertension, structural and functional alterations of the mesenteric arteries, and cardiac hypertrophy.     

Beta-2 Adrenoceptor Mediated Vasodilation: Role in Cardiovascular Responses to Acute Stressors in Spontaneously Hypertensive Rats

The present paper summarizes our studies on the role of beta-2 adrenoceptor mediated vasodilatory mechanisms in the cardiovascular defense response of spontaneously hypertensive rats (SHR) and presents new data on the contribution of altered vascular responsiveness to vasodilators. SHR had similar blood pressure but exaggerated plasma norepinephrine (NE) and epinephrine (EPI) responses compared to their normotensive control strain, the Wistar-Kyoto (WKY), while the plasma catecholamine response of the first generation (F1) cross was intermediate. An examination of regional blood flow changes to footshock stress indicated that SHR compared to WKY had greater increases in mesenteric vascular resistance that appeared to be offset by more pronounced decreases in hindquarter vascular resistance. Blockade of beta-2 adrenoceptors, which are densely located in the skeletal muscle vasculature, led to greatly increased pressor responses to stress in SHR but was without effect in WKY. Results of our current work indicate that this response is due to increased stimulation of the beta-2 adrenoceptors during stress rather than to increased vascular reactivity. These results indicate that in SHR relative to WKY, the exaggerated sympatho-adrenal response to stress does not produce greater blood pressure responses because of the offsetting influences upon vasodilation and vasoconstriction.     

Effects of lisinopril upon cardiac hypertrophy, central and peripheral hemodynamics and neurohumoral factors in spontaneously hypertensive rats.

OBJECTIVE: Left ventricular function (LVF) after reversal of left ventricular hypertrophy (LVH) with antihypertensive therapy is still controversial. The present study was undertaken in spontaneously hypertensive rats (SHR) to determine whether LVF of the regressed heart with lisinopril is normally maintained. DESIGN: We compared cardiac function of SHR after reversal of LVH induced by lisinopril with that observed in control SHR and also with effects after a 4-week washout period. METHODS: Administration of lisinopril began at 15 weeks of age and continued for 20 weeks. Cardiac index, renal blood flow, leg muscle blood flow, plasma renin activity, atrial natriuretic peptide level, and norepinephrine concentration were determined. RESULTS: Lisinopril decreased body weight, blood pressure and left ventricular weight and increased leg muscle blood flow; cardiac index and renal blood flow were unaltered. Although norepinephrine concentration was unchanged, plasma renin activity increased and atrial natriuretic peptide decreased in treated SHR. Peak left ventricular pumping ability during volume loading was comparable in the two groups. After a 4-week washout period, left ventricular mass and blood pressure increased but remained lower than controls; cardiac index at rest and during volume loading was similar in the two groups. CONCLUSIONS: These data indicate that LVF of the regressed heart induced by lisinopril was well preserved at rest, during volume loading and also after spontaneous recurrence of hypertension in SHR.     

Structural and functional alterations of mesenteric vascular beds in spontaneously hypertensive rats

The morphology and reactivity of mesenteric arteries from spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar Kyoto rats (WKY) were investigated. Isolated, perfused mesenteric vascular beds were prepared from 6-, 11- and 18-week-old SHR and WKY. At these ages, the walls and media of large mesenteric arteries were significantly thicker in SHR than in WKY. The number of smooth muscle cell layers in the media was significantly larger in SHR than in WKY. This difference between SHR and WKY increased as rats grew older, in parallel with differences in the blood pressure. Flow rate-perfusion pressure curves indicated that the vascular basal resistance to flow increased more profoundly in SHR preparations than in WKY preparations as rats grew older. This may be related to the structural alterations of the resistance vessel wall in SHR. The pressor responses to KCl were greater in SHR preparations than in WKY preparations as rats grew older. This may be caused partly by the increase of the number of smooth muscle cell layers in the media of SHR resistance vessels. The pressor response to norepinephrine (NE) was significantly higher in SHR preparations than in WKY preparations at all ages investigated. In marked contrast to the vascular basal resistance and the pressor response to KCl, the pressor response to NE was extremely exaggerated in SHR at the age of 6 weeks. This extremely high NE response in younger SHR may not be caused by the structural alteration in resistance vessels. It may be caused by a functional change, which is regulated by the signal transduction process in smooth muscle cells of resistance vessels. These results suggest that the development of hypertension in SHR may be caused by genetic structural and functional abnormalities of resistance vessels. Both abnormalities may be caused by the hyperreactivity to NE through an altered signal transduction process in smooth muscle cells of resistance vessels in SHR.     

Effects of chronic hypertension and left ventricular hypertrophy on the extent of infarct expansion in rats

Left ventricular hypertrophy is an adaptive response to long standing hypertension. However, the influence of left ventricular hypertrophy with hypertension on extent of infarct expansion has not been studied. We compared the effects of left ventricular hypertrophy with hypertension on infarct expansion in spontaneously hypertensive rats (SHR, n = 76), Wistar-Kyoto rats (WKY; n = 46) and spontaneously hypertensive rats treated with delapril, an angiotensin converting enzyme (ACE) inhibitor (SHRD; n = 39). The survival rates at 7 days after myocardial infarction were 41%, 24%, and 46% for WKY, SHR, and SHRD. The survival rate of SHR was significantly lower than those of both SHRD and WKY (P < .05). In the surviving rats (18 SHR, 19 WKY, 18 SHRD), both left ventricular cavity area (LCVA) and the infarct segment length per the noninfarct segment length (FW/IVS), measured as indices of left ventricular dilation, were significantly less in SHR and SHRD than in WKY, and the thickness of the left ventricular free wall (Wth), used as an index of left ventricular thinning, was significantly higher in both SHR and SHRD than in WKY (P < .01). However, there was no significant difference in FW/IVS, LCVA, and Wth between SHR and SHRD. Hemodynamic findings 1 week after coronary occlusion demonstrated that all rats were in heart failure, and there were no significant differences in hemodynamics among the three groups. In conclusion, our findings showed that hypertrophy with hypertension reduced infarct expansion, but that reduction of blood pressure by ACE inhibitor did not reduce infarct expansion more than hypertrophy did. However, this finding suggests that an ACE inhibitor may improve the rate of survival of patients with left ventricular hypertrophy with hypertension.     

Structural and functional consequence of neonatal sympathectomy on the blood vessels of spontaneously hypertensive rats

Neonatal sympathectomy of spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) was performed by a combined treatment with antiserum to nerve growth factor and guanethidine during the first 4 weeks after birth. The development of hypertension was completely prevented in the treated SHR: at 28 to 30 weeks of age, systolic blood pressure of treated SHR was 139 +/- 2 mm Hg as compared with 195 +/- 8 mm Hg in untreated SHR. The extent of sympathectomy was verified by histofluorescence. Fluorescence histochemistry for catecholamine-containing nerves showed a complete absence of adrenergic nerves in the mesenteric arteries of treated rats. A supersensitivity to norepinephrine was exhibited by mesenteric arteries, anococcygeus muscle, and tail arteries from the treated SHR and WKY. In the mesenteric vascular bed, maximal response to norepinephrine was significantly reduced by sympathectomy. Sympathectomy also abolished the responses (e.g., generation of excitatory junctional potentials) of tail arteries to electrical stimulation of perivascular nerves. Morphometric measurements of three categories of mesenteric arteries showed that sympathectomy had no effect on the hypertrophic change of smooth muscle cells in the conducting vessels, but it prevented the hyperplastic changes of the muscle cells from reactive, muscular arteries and small resistance vessels. These results suggest that one of the primary roles of the overactive sympathetic nervous system in the development of hypertension in SHR is manifested through its trophic effect on the arteries of SHR. This trophic effect appears to cause a hyperplastic change in the smooth muscle cells in the reactive and resistance vessels, thereby contributing to the development of hypertension in older SHR.     

Potassium depletion ameliorates hypertension in spontaneously hypertensive rats

The hemodynamic effect of moderate K+ depletion in hypertension is unknown. Since severe K+ depletion reduces systemic vascular resistance in normotensive rats, we determined the effect of K+ depletion on the natural history of hypertension in spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) and SHR were fed a K+-replete, a moderately K+-depleted, or a severely K+-depleted diet. After 6 weeks, systemic vascular resistance was reduced by 25% in WKY on the severely K+-depleted diet while mean arterial pressure and systemic vascular resistance were comparable in WKY on the other two diets. In SHR on the severely K+-depleted diet for 6 weeks, muscle K+ was reduced by 23% and growth rate by 65%. In SHR on the moderately K+-depleted diet, growth rate was reduced by 23% after 3 weeks. By 6 weeks, however, muscle K+ was reduced by 5 to 6% and growth rate was comparable to that in SHR receiving the K+-replete diet. The administration of either K+-depleted diet prevented the development of hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 122 +/- 3; K+-replete, 155 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups) and reversed established hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 128 +/- 3; K+-replete, 171 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups). The protective effect of K+ depletion was mediated by a 40% reduction in systemic vascular resistance. These results suggest that K+ depletion has a potent antihypertensive effect in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Reduced left ventricular hypertrophy following long-term water deprivation in the young spontaneously hypertensive rat

Biochemical and physical parameters of cardiac hypertrophy accompanying hypertension were studied in water deprived versus non-deprived immature spontaneously hypertensive rats (SHR) and their normotensive progenitor strain, Wistar Kyoto (WKY). A 23.5 hour/day water deprivation schedule was maintained from 5 to 13 weeks of age in 23 SHR and 8 WKY rats to compare the non-deprived animals (16 SHR and 8 WKY controls). Water deprived SHR had lower left ventricular weight, lower total protein and hydroxyproline and the same total DNA as the non-deprived SHR. DNA concentration was higher in the deprived SHR than in the non-deprived SHR. No differences were found among the four groups in right ventricular weight or DNA concentration. Left to right ventricular weight ratio was significantly lower and left to right ventricular DNA concentration ratio significantly higher in the deprived SHR relative to non-deprived SHR. These data indicate that the water deprived SHR, which was less hypertensive than the non-deprived SHR, had less hypertrophy of their left ventricles. While water deprivation lowered mean arterial pressure in the WKY, also, there was no effect on left ventricular weight or biochemical indices of left ventricular cell size and cell number.     

Influence of early antihypertensive treatment on vascular and cardiac design in SHR with and without renal hypertension.

The present study was designed to explore to what extent pressure reduction by antihypertensive therapy and pressure elevation by renal hypertension are able to affect structural vascular and cardiac changes in young spontaneously hypertensive rats (SHR). Pressure elevation in SHR was induced by means of superimposing 2 kidney, 1 clip renal hypertension (2K1C). Pressure reduction was achieved by means of the vasoselective calcium antagonist felodipine from 6 to 13 weeks of age in both clipped and unclipped SHR. Vascular structure of the skeletal muscle was assessed hemodynamically by perfusing a hindlimb preparation and left ventricular dimensions were calculated from pressure-volume relationships of isolated hearts arrested in diastole. Induction of renal hypertension in SHR resulted, besides augmentation of arterial pressure in a marked concentric left ventricular hypertrophy, i.e. elevations of wall thickness to internal radius ratio. Likewise, in renal hypertensive SHR, a structural adaptation of the skeletal muscle vascular bed occurred, reflected as elevations of minimal vascular resistance and maximal generated perfusion pressure. Antihypertensive treatment for 8 weeks with felodipine reduced and also prevented mean arterial pressure from increasing further in SHR, and in SHR with superimposed renal hypertension by approximately 15% (p < 0.001 for both). In renal hypertensive SHR, felodipine partly prevented the development of exaggerated structural changes, both in the heart and in the skeletal muscle vascular bed, as reflected by reduced wall thickness to internal radius ratio and reduced minimal vascular resistance by 22% and maximal pressure response by 10% respectively (p < 0.01 for both parameters).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular Studies in Rats with Respect to Some Functional and Structural Relationships of Relevance in Hypertension and Ordinary Aging

Five current lines of cardiovascular studies in rats are outlined, mainly dealing with some functional and structural relationships of particular relevance for hypertension and ordinary aging: 1. Characteristics of the smooth muscles and their neurogenic control in ‘Windkessel’ arteries, conduit arteries, precapillary resistance vessels and venous capacitance vessels from normotensive rats (WKY) with comparisons to rats with primary hypertension (SHR). 2. Different types of structural renovascular adaptation, comparing aging with advancing SHR hypertension, with ‘high-pressure’ and ‘low-pressure’ kidneys in one-clip, two-kidney renal hypertension, and with hypertrophied kidneys in uninephrectomized normotensive rats. 3. Relationships between ‘structural autoregulation’, wall distensibility, vascular reactivity and smooth muscle sensitivity in SHR and WKY hindquarter resistance vessels along with aging. 4. Relationships between wall thickness, luminal dimension and cortractility in left ventricles from SHR and WKY during aging, and when one-clip, two-kidney hypertension is superimposed. 5. Interference with the capacity of the neurohormonal mechanisms counteracting blood loss in rats when on chronic low-salt diet.     

Exercise-induced myocardial capillary growth in the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) were studied to test the hypothesis that endurance exercise training can stimulate capillary growth and offset the decrement associated with the development of myocardial hypertrophy. The exercise group (SHR-T) was trained on a treadmill for 10 weeks at 70-90% maximum VO2 and compared to nontrained SHR and normotensive Wistar-Kyoto (WKY) at 16 weeks of age. Thus, the training program coincided with the development of hypertension and hypertrophy in SHR. Image analysis was used to study capillaries in one micron thick left ventricular tissue samples from perfuse-fixed hearts. Training did not affect left ventricular mass or blood pressure, but reversed the characteristic decrements in capillary surface area (CSA), volume (CV), and numerical density (CD). CSA and CV were most markedly affected by exercise, as mean values for these parameters increased by 31 and 40%, respectively, compared to SHR. The magnitude of these changes approximated the magnitude of hypertrophy as evidenced by left ventricular weight/body weight ratios (42% in SHR and 37% in SHR-T). Anatomical intercapillary distance was also normalized by training (means +/- SEM): SHR-T, 11.65 +/- 0.31; SHR, 13.97 +/- 0.37; WKY, 11.19 +/- 0.37. These data indicate that exercise stimulates capillary growth in the face of developing hypertension and its related left ventricular hypertrophy.     

Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats

OBJECTIVE: To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. RESULTS: Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. CONCLUSIONS: Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.     

Prolonged Effects of Short-Term Fosinopril on Blood Pressure and Vascular Morphology and Function in Rats

The aim of this study was to evaluate the delayed effects of an angiotensin converting enzyme (ACE) inhibitor on blood pressure and on structural and functional alterations in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). The ACE inhibitor fosinopril (25 mg/kg/day) was administered according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 15), and in a third group from 4 to 12 weeks of age (n = 12). Eighteen untreated SHR and 18 untreated Wistar-Kyoto rats served as controls. About half the animals in each group were killed at 13 weeks of age, and the remaining were killed at 38 weeks of age. After death, relative left ventricular mass (left ventricular weight/body weight) was calculated. Vascular morphology (media : lumen ratio) and function (responses to norepinephrine and acetylcholine) in mesenteric small resistance arteries were then assessed using a micromyographic technique.Short-term fosinopril, given either before or after the development of hypertension, persistently reduced (but did not normalize) systolic blood pressure, vascular structural alterations, and reactivity to norepinephrine in mesenteric resistance arteries in SHR. These favorable effects were maintained at least for 26 to 30 weeks after treatment withdrawal. The endothelium-dependent vasodilator response to acetylcholine was improved at 13 but not at 38 weeks of age, in treated SHR.Therefore, the vascular response to norepinephrine seems to be dependent mainly on the structure of the vessels, whereas endothelial function is probably more linked to the hemodynamic load.     

Prevention of coronary vasodilator reserve decrement in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) demonstrate an elevated minimal coronary vascular resistance by the seventh month of age. In an attempt to determine the role of long-standing hypertension in the etiological process of the elevated minimal coronary vascular resistance, we treated SHR and normotensive Wistar-Kyoto rats (WKY) with the vasodilator hydralazine from the time of weaning (1 month) until they were 7 to 8 months of age. The animals were instrumented 24 hours after their last drug dose and then studied on the following day. Using microspheres we measured myocardial perfusion in conscious rats at rest and during maximal coronary dilation induced with dipyridamole infusion. Hydralazine maintained arterial blood pressures in the normotensive range throughout the experimental period, but had little effect on left ventricular weight/body weight ratios (control SHR = 2.95 +/- 0.07, treated SHR = 2.73 +/- 0.08, control WKY = 2.39 +/- 0.09, mean +/- SEM). In treated SHR, left ventricular minimal coronary vascular resistance (per 100 g of tissue) was markedly lower (0.10 +/- 0.01) than in the controls (0.16 +/- 0.01) and not significantly different from that of WKY (0.11 +/- 0.01). Similar differences were noted in the nonhypertrophic right ventricle (treated SHR = 0.08 +/- 0.01, control SHR = 0.16 +/- 0.01, control WKY = 0.10 +/- 0.01). Total minimal coronary vascular resistance was also lower in both ventricles of the treated SHR compared with their nontreated controls. In WKY, hydralazine treatment significantly reduced blood pressure and total minimal coronary vascular resistance (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)