Effects of low-dose chronic diltiazem treatment on hemodynamic changes in spontaneously hypertensive rats

The effects of long-term diltiazem treatment on hemodynamic and cardiovascular characteristics were investigated in young spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and their respective untreated controls. The drug was administered to treated rats over a period of 24 weeks. Body weight, left ventricular weight, mean arterial pressure (MAP), heart rate, max dp/dt or maximum velocity of the contractile element (Vmax) were not significantly different in diltiazem-treated SHR and untreated SHR. In diltiazem-treated SHR, cardiac index (CI) and stroke volume index (SI) were significantly increased and total peripheral resistance and the index of left ventricular compliance (delta P/delta V) were significantly decreased compared with untreated SHR. Left ventricular pumping ability in treated SHR was higher than that in untreated SHR, despite the low dose of diltiazem given. However, there was no significant difference between treated and untreated WKY. Long-term diltiazem treatment did not affect left ventricular function or biochemical properties in SHR and WKY. These data suggest that long-term diltiazem treatment improves pump function in SHR without changing blood pressure.     

Volume overload influence on hypertrophied myocardium function

The aim of this study was to demonstrate that hypertrophied cardiac muscle is more sensitive to volume-overload than normal cardiac muscle. We assessed the mechanical function of isolated left ventricular papillary muscle from male spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) submitted to volume overload caused by aortocaval fistula (ACF) for 30 days. Muscles were perfused with Krebs-Henseleit solution at 28 degrees C and studied isometrically at a stimulation rate of 0.2 Hz. The ACF increased the right and left ventricular weight-to-body weight ratio in WKY rats; it also promoted right ventricular hypertrophy and further increased the basal hypertrophy in the left ventricle from SHR. The arterial systolic pressure was greater in SHR than in WKY rats, and decreased with ACF in both groups. Developed tension (DT) and maximum rate of DT (+dT/dt) were greater in the SHR-control than in the WKY-control (P < 0.05); the time from peak tension to 50% relaxation (RT 1/2) was similar in these animals. ACF did not change any parameters in the SHR group and increased the resting tension in the WKY group. However, the significant difference observed between myocardial contraction performance in WKY-controls and SHR-controls disappeared when the SHR-ACF and WKY-controls were compared. Furthermore, RT 1/2 increased significantly in the SHR-ACF in relation to the WKY-controls. In conclusion, the data lead us to infer that volume-overload for 30 days promotes more mechanical functional changes in hypertrophied muscle than in normal cardiac muscle.     

Myocardial function during chronic food restriction in isolated hypertrophied cardiac muscle

BACKGROUND: The effect of food restriction (FR) on myocardial performance has been studied in normal hearts. Few experiments analyzed the effects of undernutrition on hearts subjected to cardiac overload. The aim of this study was to determine whether chronic FR promotes more significant changes in hypertrophied hearts than in normal hearts. METHODS: Myocardial performance was studied in isolated left ventricular papillary muscle from young male spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) submitted to FR or to control diet. The animals subjected to FR were fed 50% of the amount of food consumed by control groups for 60 days. Isolated muscles were studied while contracting isometrically and isotonically. RESULTS: FR decreased the body weight and the left ventricular weight in both groups. FR increased the left ventricular weight-to-body weight ratio in the WKY rats and tended to decrease this ratio in SHR (P = 0.055). The arterial systolic pressure was greater in SHR than in WKY groups and did not change with FR. In the animals with normal diet, myocardial performance was better in SHR than in WKY. FR increased time to tension to fall from peak to 50% of peak tension and time to peak tension in the WKY rats and time to peak tension in the SHR. CONCLUSIONS: FR for 60 days has a trend to attenuate the development of cardiac hypertrophy and does not promote more mechanical functional changes in the hypertrophied myocardium than in the normal cardiac muscle.     

Sympathetic nerves modify mitochondrial and capillary growth in normotensive and hypertensive rats

We tested the hypothesis that sympathetic nerves influence cardiocyte organelle volumes and capillarity in spontaneously hypertensive rats (SHR) with long-standing hypertension and left ventricular hypertrophy. SHR and their normotensive, Wistar Kyoto (WKY), controls were treated with 6-hydroxydopamine from birth to prevent the establishment of the sympathetic nervous system. To determine whether beta adrenergic receptors were the major pathway of sympathetic influence, another group of SHR and WKY were chronically treated from weaning with the beta 1 adrenergic antagonist, metoprolol. In SHR sympathectomy failed to alter, while metoprolol attenuated, hypertension. Stereological analyses of perfuse-fixed hearts showed that in both SHR and WKY mitochondria/myofibrils volume ratio was increased by long-term sympathectomy, mainly by limiting mitochondrial volume density, even though this intervention failed to alter left ventricular mass. In contrast, long-term beta 1 blockade attenuated hypertrophy in SHR but had no effect on mitochondria/myofibrils volume ratio. Capillary numerical density was increased significantly in sympathectomized SHR and WKY. However, despite this increase, capillary volume density was similar in control and sympathectomized rats, since capillary diameter was less in the latter. Metoprolol-treated SHR showed a trend toward higher capillary numerical densities consistent with their attenuation of hypertrophy. These findings indicate that sympathetic nerves, either directly or indirectly, inhibit cardiocyte mitochondrial growth and capillary proliferation during both normal and pressure-overload induced cardiac enlargement.     

Immunoreactive atrial natriuretic peptide in ventricles, atria, hypothalamus, and plasma of genetically hypertensive rats

To evaluate the role of extra-atrial atrial natriuretic peptide (ANP) in volume and blood pressure regulation, the plasma, atrial, ventricular, and hypothalamic levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured simultaneously in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at the ages of 2, 6, and 12 months. Plasma IR-ANP in the 12-month-old, conscious SHR was significantly higher than that of the WKY (300 +/- 18 versus 200 +/- 20 pg/ml, p less than 0.05, n = 9), while no differences in plasma IR-ANP levels were found between the strains in younger rats. Acute volume expansion with saline (1.1 ml/100 g body wt) in hypertensive as well as in normotensive rats resulted in marked increases in right atrial pressure and plasma IR-ANP concentration. The older SHR had attenuated ANP release to volume loading as shown by the shift of the ANP versus right atrial pressure curve to the right. Right auricular IR-ANP concentration decreased, while that of left auricle increased with increasing age in both strains. No substantial differences were noted in auricular ANP concentration between SHR and WKY. However, the total atrial IR-ANP content (micrograms/atria) was consistently lower in SHR compared with WKY. In both ventricles, IR-ANP concentrations and contents increased with increasing age in WKY and SHR, but the ventricular levels of ANP were reduced in ventricles of the SHR heart compared with normotensive controls. The depletion of total ventricular IR-ANP was greatest in SHR with greatest ventricular hypertrophy and coincided with the attenuated ANP release to acute volume load. The increase of left but not right ventricular weight occurring secondary to 6 weeks minoxidil treatment was accompanied by higher ANP concentration in both strains. In contrast to the ventricles, the hypothalamic IR-ANP concentration was significantly increased in SHR compared with that of WKY and decreased in both strains after 6 weeks' treatment with antihypertensive drugs. Thus, ventricular and hypothalamic, as well as atrial, ANP respond to increased pressure overload in genetically hypertensive rats. Our results suggest that chronic stimulation of ANP release from ventricles is associated with depleted stores of ANP from both ventricles and reduced response to acute volume load. Our findings that ventricular ANP increased with increasing weight and in response to a hypertrophic stimulus in WKY and was decreased in SHR with severe ventricular hypertrophy suggest that ANP may locally have an inhibitory effect on the development of cardiac hypertrophy.     

Effects of captopril on left ventricular structure and function in SHR with established hypertension

Summary While antihypertensive therapy is considered to be an important clinical intervention in hypertensive patients, its effects on cardiac structure and function have not been intensely evaluated. In this study we tested the hypotheses that lowering blood pressure (BP) with the angiotensin I-converting enzyme inhibitor captopril, would: 1) normalize left ventricular mass and increase the cardiocyte mitochondria/myofibrils volume (V_mito/V_myo) ratio; and 2) not compromise peak ventricular performance. We treated 16-week-old SHR and WKY with captopril (40–80 mg/kg) and hydrochlorothiazide (500 mg/l) via their drinking water. After six weeks of treatment peak cardiac performance was measured during rapid volume overload. Tissue samples from the left ventricular wall were analyzed by electron microscopy and stereology. Captopril lowered BP in SHR and WKY but had no affect on the left ventricular/body weight ratio. The only intracellular change in treated SHR was an increase in sarcoplasmic volume density. Treated WKY exhibited decreased midmyocardial mitochondrial volume density. At peak cardiac output, acceleration of flow and cardiac index were not affected by treatment. Stroke work at peak cardiac output was decreased in the treated groups due to a decrease in mean arterial pressure. In addition, captopril treatment resulted in a shift of the cardiac output (CO)-left ventricular end diastolic pressure (LVEDP) curves, such that LVEDP at peak cardiac output was approximately 50% less in the treated groups compared to their respective control groups. Although captopril was efficacious in lowering BP, it is suggested that lowering BP with this agent does not, at least within six weeks, lead to a reversal of hypertrophy or to a significant alteration in the volume densities of myofibrils and mitochondria. However, an important effect of this antihypertensive drug which may be of clinical significance, is that it leads to a leftward shift of the CO-LVEDP curve in both hypertensive and normotensive rats.     

Differential development of vascular and cardiac hypertrophy in genetic hypertension. Relation to sympathetic function

We compared blood pressure, hindquarter vascular resistance properties, left ventricular weight, and norepinephrine kinetics, in spontaneously hypertensive rats (SHR) and weight-matched normotensive Wistar-Kyoto (WKY) rats at 4, 9, 14, 20, 30, and 50 weeks of age. At 4 weeks, systolic and mean blood pressure measurements were the same in both strains, but the vascular resistance of the fully dilated hindquarter bed was significantly higher in SHR than in WKY rats, with a much larger difference during maximum constriction. Plots of resistance at maximum dilatation and at maximum constriction against body weight suggest that a component of the increase in vascular muscle mass in SHR occurred in the neonatal period preceding hypertension followed by a later component related to the rise in blood pressure. By contrast, left ventricular hypertrophy was minimal at 4 weeks and most of its development paralleled the rise in blood pressure. Sympathetic activity, assessed by norepinephrine fractional rate constant, was higher in SHR than in WKY rats in the left ventricle and kidney through most of the period between 4 and 50 weeks, but was similar in both strains in the muscle bed. This pattern of sympathetic activity will accentuate hypertension once cardiac and vascular hypertrophy are fully established. In all regions, norepinephrine tissue concentration was higher in young SHR and could potentiate the trophic effects of growth factors in early vascular hypertrophy. We suggest that the initial (primary) component of vascular hypertrophy precedes the rise in blood pressure and may be critical in the pathogenesis of hypertension. Possible reasons for the short delay in the rise in blood pressure in young SHR, once the vascular "amplifier" has been established, include high vascularity, immaturity of smooth muscle, and delay in the development of left ventricular hypertrophy.     

伊贝沙坦逆转高血压左心室肥厚的细胞学机制

目的探讨伊贝沙坦(IBT)抗高血压左心室肥厚过程中,对心肌细胞凋亡和心肌肌浆网钙泵活性的影响。方法选用16周龄自发性高血压大鼠(SHR)24只,随机分为IBT组(8只)、蒸馏水(DW)组(8只)和SHR0组(8只),另选16只WKY大鼠作为正常对照,随机分为WKY0组(8只)和WKY1组(8只)。IBT组大鼠给予IBT(60 mg.kg-1.d-1)加适量蒸馏水灌胃14周。治疗前后,测量血压和左心室心肌肥厚指数(LVMI),原位末端脱氧核糖核苷酸转移酶介导的dUTP缺口末端标记法检测心肌细胞凋亡,并检测治疗后左心室心肌细胞肌浆网Ca2+-ATP酶活性。结果DW组LVMI、心肌细胞凋亡指数均显著高于WKY组,而IBT组明显低于DW组;DW组Ca2+-ATP酶活性明显低于IBT组及同龄WKY组,IBT组稍低于同龄WKY组;Ca2+-ATP酶活性与LVMI、心肌细胞凋亡指数呈显著负相关,LV-MI与心肌细胞凋亡指数呈显著正相关。结论IBT可能通过调节心肌细胞肌浆网钙泵活性以抑制高血压左心室肥厚过程中心肌细胞凋亡,从而逆转左心室肥厚。     

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.     

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.     

沉默信息调节因子相关酶3在自发性高血压大鼠心肌高表达与左心室肥厚相关

目的观察沉默信息调节因子相关酶3(sirtuin3)在自发性高血压大鼠(SHR)心肌中的表达,并探讨sirtuin3在高血压所致左心室肥厚(LVH)中的作用。方法 24只29周龄SHR随机分为SHR30周龄组(喂养1周,n=11)和SHR38周龄组(喂养9周,n=13),另选20只29周龄Wistar-Kyoto(WKY)大鼠随机分为WKY30周龄组(喂养1周,n=10)和WKY38周龄组(喂养9周,n=10)作为正常对照。各组测定尾动脉收缩压和左心室质量(LVM)/体质量。Masson染色法分析左心室肌间质纤维化程度,心脏超声测定心功能。采用免疫组化,Western-blot及实时荧光定量PCR来检测心肌组织中sirtuin3的蛋白及mRNA表达。结果与WKY30、38周龄组大鼠比较,SHR30、38周龄组的收缩压[30周龄(189.0±6.8)比(103.4±3.6)mmHg;38周龄(205.6±10.9)比(116.3±4.3)mmHg]、LVM/体质量[30周龄(2.94±0.11)比(2.56±0.21);38周龄(3.21±0.15)比(2.68±0.24)]、左心室收缩末期内径[30周龄(4.27±0.13)比(3.59±0.08)mm;38周龄(5.46±0.14)比(4.21±0.08)mm]、舒张末期室间隔厚度[30周龄(2.63±0.15)比(2.09±0.06)mm;38周龄(2.82±0.09)比(2.35±0.08)mm]、舒张末期左心室后壁厚度[30周龄(2.78±0.12)比(2.15±0.09)mm;38周龄(2.99±0.12)比(2.44±0.07)mm]、sirtuin3mRNA和蛋白表达升高(均P<0.05);左心室短轴缩短率、左心室舒张末期内径降低(均P<0.05),SHR大鼠表现出左心室明显肥厚,左心室收缩及舒张功能明显减低,并随着周龄的延长,心肌肥厚及心功能障碍加重(P<0.05)。结论心肌组织sirtuin3高表达与左心室肥厚密切相关。     

Effects of moderate diabetes on cardiac performance in spontaneously hypertensive and Wistar-Kyoto rats

To assess the effects of imposition of moderate diabetes on in vivo cardiac performance in gradually proceeding hypertension, spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY) were treated with streptozotocin (40 mg/kg) or vehicle at 8 weeks of age. Four and 20 weeks later, with the rats under ether anesthesia, peak cardiac output and stroke volume were measured during volume loading and peak left ventricular developed pressure and maximum rate of rise of pressure (dP/dtmax) were determined during aortic occlusion. Additionally, passive pressure-volume relations were obtained during saline infusion in potassium-arrested hearts, and the chamber stiffness constant was derived from one exponential function. There was a mortality of 16.1% in the diabetic SHR only. While basal and stressed cardiac performance was unchanged despite the already decreased mean arterial pressure and left ventricular weight at 4 weeks, the diabetic SHR revealed significant decreases in peak cardiac pumping indexes, peak left ventricular developed pressure, and dP/dtmax, with unchanged resting cardiac function, at 20 weeks. Changes seen in the diabetic WKY were reduced left ventricular weight at 4 weeks and reduced peak left ventricular dP/dtmax at 20 weeks. The chamber stiffness was unaltered with strain or diabetes. These data show that imposition of even moderate diabetes substantially influences the stress-loaded in vivo cardiac performance in the SHR, whereas it produces only minor changes in the WKY.     

Cosegregation analysis in genetic crosses suggests a protective role for atrial natriuretic factor against ventricular hypertrophy.

In most rat models studied to date, increased ventricular mass is associated with high ventricular expression of the atrial natriuretic factor (ANF) gene. However, it is unknown whether ANF plays a beneficial or detrimental role in the course of left ventricular hypertrophy or whether ANF gene expression could be genetically linked to cardiac mass. To address such questions, we performed a cosegregation analysis in genetic crosses of inbred strains of rats. To select strains with the appropriate phenotypic characteristics, we first compared the ventricular abundance of ANF mRNA to ventricular mass (corrected for body weight) in 2 recombinant inbred strains derived from Wistar-Kyoto (WKY)/spontaneously hypertensive rat (SHR) hybrid crosses, ie, WKY-derived hyperactive (WKHA) and WKY-derived hypertensive (WKHT) rats, as well as in their parental inbred strains. In the 2 such strains that were normotensive, we observed that ventricular mass was higher in WKHA than in WKY rats, yet ventricular ANF mRNA was less abundant in WKHA than in WKY rats. Within a segregating population of F2 animals generated from a cross between WKY and WKHA genitors, the abundance of ventricular ANF mRNA and peptide correlated inversely with left ventricular mass, in contrast to the positive correlation observed with beta-myosin heavy chain mRNA. Finally, in the equally hypertensive SHR and WKHT strains, we found that ventricular mass was higher in SHR than in WKHT, yet ventricular ANF mRNA was less abundant in SHR than in WKHT. These results demonstrate for the first time that low ventricular ANF gene expression can be linked genetically to high cardiac mass independently of blood pressure and are consistent with a protective role for ANF against 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.     

Development of left ventricular hypertrophy in young spontaneously hypertensive rats after peripheral sympathectomy.

The effects of peripheral sympathectomy with nerve growth factor antiserum (NGFAS) on blood pressure, systemic hemodynamics, myocardial function, myocardial hypertrophy, and renin were studied in male spontaneously hypertensive (SH) rats of the Okamoto strain and normotensive control Kyoto-Wistar (WKY) rats. NGFAS prevented the developing of hypertension in the SH rats but did not alter blood pressure in the WKY rats. The NGFAS-treated SH rats developed the same hemodynamic abnormalities as the sham-treated rats, including increased peripheral vascular resistance and depressed cardiac output; Indices of left ventricular performance, including peak flow velocity, stroke power, stroke work, dP/dtmax, and flow acceleration (dF/dt), were diminished in the SH rats compared to the WKY rats. NGFAS treatment further depressed ventricular function in the SH rats, but had little effect on the WKY rats; Plasma renin activity in both the SH and WKY rats was unaffected by NGFAS treatment. Although NGFAS treatment effectively prevented the development of hypertension in the SH rats, it did not influence the development of left ventricular hypertrophy as reflected by increases in left ventricular mass, RNA, DNA, and hydroxyproline content. The data suggest that the development of myocardial hypertrophy and myocardial dysfunction in the SH rat is in part independent of hypertension and plasma renin activity.     

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 long-term cardiac hypertrophy on coronary vasodilator reserve in SHR rats

The effects of long-term left ventricular (LV) hypertrophy on coronary vascular reserve have not been extensively investigated. To test the hypothesis that the duration of LV hypertrophy may modulate coronary vascular reserve, a newly developed pulsed Doppler flowmeter was used to compare the characteristics of coronary reactive hyperemia in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The data suggest that coronary reactive hyperemic responses in the rat are markedly different from those in larger animals and humans, e.g., peak/rest blood flow velocity ratio and the repayment/debt area ratio were 30 to 50% of those observed in larger laboratory animals. Because minimal coronary vascular resistance is similar in the rat and larger animals, the relatively high myocardial oxygen consumption at rest and consequent high myocardial blood flow at rest probably account for the alteration of coronary reactive hyperemia in the rat. In SHR rats, the characteristics of coronary reactive hyperemia decreased during developing (3-month-old) and peak (7-month-old) LV hypertrophy compared with those in their age-matched WKY controls. However, in 12-month-old SHR rats with stable LV hypertrophy, the coronary reactive hyperemic response was similar to that of 12-month-old WKY rats. Mean arterial pressures were significantly elevated in each of the 3 SHR groups. These data suggest a significant decrement in coronary vascular reserve during actively developing and peak LV hypertrophy, but the decrement disappears during stabilized hypertrophy. These studies suggest that the duration of LV hypertrophy may modulate the interaction between pathologic increases in cardiac mass and growth of the coronary vasculature.     

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.     

Ventricular performance in spontaneously hypertensive rats (SHR) with reduced cardiac mass

Summary This study was designed to investigate the effect of 4 weeks of captopril treatment on cardiac mass and performance in spontaneously hypertensive rats (SHR). Left (LV) and right (RV) ventricular mass of SHR and normotensive WKY rats was reduced (p<0.01). Mean arterial pressure (MAP) and total peripheral resistance index (TPRI) in the treated SHR and WKY were reduced; cardiac (CI) and stroke (SI) indices remained unaltered in SHR but increased in WKY. Ventricular performance (i.e., cardiac pumping ability), assessed by rapid blood infusion, did not differ between untreated SHR and WKY, and between treated and untreated WKY rats. However, the ventricular performance curves for the treated SHR shifted down and to the right from the untreated SHR (p<0.01). Moreover, when MAP of treated SHR (with regressed LV mass) was elevated to their pretreatment levels, cardiac performance curves shifted further rightward and downward. In contrast, the performance curves of treated WKY whose MAP was also elevated to the level of untreated WKY were no different from those of untreated WKY. These data demonstrate that captopril treatment (at doses used in this study) reduced MAP in SHR through decreased TPRI while decreasing biventricular mass. Furthermore, the cardiac-pumping ability of previously hypertrophied SHR hearts was reduced, suggesting that certain antihypertensive agents that diminish cardiac mass could produce impaired cardiac function when called upon to increase performance (e.g., when MAP is suddenly raised).