Regression of hypertensive myocardial fibrosis by Na(+)/H(+) exchange inhibition

We have recently reported that the inhibition of the Na(+)/H(+) exchanger (NHE) during 1 month in spontaneously hypertensive rats (SHR) is followed by regression of cardiomyocyte hypertrophy but not of myocardial fibrosis. The aim of this study was to evaluate whether a treatment of longer duration could reduce myocardial fibrosis and stiffness. SHR received 3.0 mg/kg per day of the specific NHE-1 inhibitor cariporide; the effect on cardiomyocyte cross-sectional area, myocardial collagen volume fraction, collagen synthesis, and myocardial stiffness (length-tension relation in left papillary muscles) was evaluated at several time points (after 1, 2, or 3 months). A slight decrease of approximately 5 mm Hg in systolic blood pressure was observed after 1 month of treatment with no further changes. After 2 and 3 months of treatment, the size of cardiomyocytes remained within normal values and myocardial fibrosis progressively decreased to normal level. Accordingly, myocardial stiffness and the serum levels of the carboxyterminal propeptide of procollagen type I, a marker of collagen type I synthesis, were normalized after 3 months. Left ventricular weight decreased from 910+/-43 (in untreated SHR) to 781+/-21 mg (treated SHR) after 3 months of treatment. No difference in body weight between treated and untreated SHR was observed after this period of treatment. The present data allow us to conclude that in the SHR the administration of an NHE-1 inhibitor for 2 or 3 months leads to the normalization of collagen type I synthesis, myocardial collagen volume fraction, and stiffness.     

Age-related changes in cholesterol and bile-acid metabolism in spontaneously hypertensive rats

Age-related changes in serum and liver cholesterol, phospholipid and triglyceride levels, serum lipoproteins, biliary secretion of cholesterol, phospholipids and bile acids, fecal excretion of sterols and bile acids, and the pool size of bile acids were examined in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKR). SHR showed distinct age- and sex-related changes when young and marked aged-rat hypercholesterolemia after 1 yr of age. (1) Cholesterol shifted from blood to the liver between 10 and 20 wk only in male SHR and not at all in WKR. (2) Serum lipoprotein percentages changes; α-lipoprotein decreased, pre-β-lipoprotein increased, but β-lipoprotein did not change. These changes appeared only in male SHR and after 13 to 15 wk of age. (3) Liver enlargement in SHR, although not detected at 5 to 6 wk, progressed more rapidly than in WKR, giving values almost double those in WKR after 13 to 15 wk. Liver enlargement in female SHR was much less than in the male. (4) Bile flow, biliary secretion, and the pool size of bile acids increased. However, when expressed on the basis of liver weight, these values were similar to those in WKR, suggesting that the increases were caused by the hepatomegaly. (5) Differences appeared in the bile acid composition. A large amount of β-muricholic acid was present in SHR of both sexes and the cholic acid percentage was low in male SHR. (6) Changes were observed in fecal bile acid excretion. Since the daily amounts in male SHR were similar to those in WKR, the hepatic synthesis activity (mg per day per 10 g liver) in male SHR was almost half that in WKR at all ages.     

结缔组织生长因子与高血压大鼠心肌纤维化相关性及伊贝沙坦的干预研究

目的探讨结缔组织生长因子(CTGF)在高血压大鼠心肌纤维化发生发展中的作用,以及伊贝沙坦改善高血压所致心室重构和心肌纤维化可能的作用机制。方法20只12周龄雄性自发性高血压大鼠(SHR)随机分为SHR组和伊贝沙坦(IRB)组各10只,IRB组每只大鼠予以伊贝沙坦50 mg.kg-1.d-1灌胃,给药时间12周,同时取10只12周龄雄性Wistar大鼠作为对照组(WKY组),用免疫组织化学的方法对转化生长因子β1(TGF-β1)、CTGF在3组大鼠的左室心肌的分布及表达进行半定量分析;用逆转录-聚合酶链反应检测TGF-β1、CTGF mRNA在心肌表达水平;用MOSSON染色法观察左室心肌胶原形态,图像分析测量胶原容积分数(CVF)和血管周围胶原面积(PVCA)。结果(1)左室重量指数(LVI)、CVF、PVCA在SHR大鼠组明显高于WKY大鼠组(P<0.01);与SHR组比较,伊贝沙坦组则显著降低(P<0.05)。(2)CTGF主要在血管平滑肌和心肌间质中表达,相关分析表明:CTGF与TGF-β1(r=0.562,P<0.05)、CVF(r=0.715,P<0.01)、PVCA(r=0.786,P<0.01)呈正相关;(3)CTGF及其mRNA在SHR组左室心肌中的表达较WKY组明显增强(P<0.05),与SHR组比较,IRB组则明显减少。结论高血压大鼠心室肌CTGF表达增加,伊贝沙坦能抑制高血压大鼠心室肌CGTF表达,且明显改善了高血压心室重构和心肌纤维化。     

Effects of long-term verapamil treatment on blood pressure, cardiac hypertrophy and collagen metabolism in spontaneously hypertensive rats

The effects of long-term treatment with verapamil on blood pressure, cardiac hypertrophy and collagen content, collagen concentration and prolyl hydroxylase activity were studied in spontaneously hypertensive rats (SHR). Verapamil administration (0.75 mg . ml-1 in drinking water) was commenced: to pregnant SHR 3 to 5 days before delivery and continued to the mothers and offspring during the nursing period; or to SHR at 10 weeks of age. Both groups were maintained on verapamil treatment up to the age of 45 weeks. Verapamil treatment significantly decreased blood pressure, heart rate and the ratio of ventricular weight to body weight in treated SHR. Verapamil did not significantly change the cardiac collagen concentration and prolyl hydroxylase activity. Since, however, the cardiac muscle mass was diminished by verapamil administration, treatment actually slightly reduced the collagen content of the heart. In the aorta collagen concentration was increased by verapamil treatment. Contrary to these results, minoxidil treatment was observed to increase the cardiac collagen concentration, content and prolyl hydroxylase activity in SHR. These results suggest that the factors governing myocardial connective tissue proliferation and regression may be independent of those governing muscle fibre hypertrophy and that particular drug actions on myocardial collagen metabolism must be taken into account.     

Attenuation of cardiac failure, dilatation, damage, and detrimental interstitial remodeling without regression of hypertrophy in hypertensive rats

Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99+/-0.02 g; untreated SHR, 1.40+/-0.02 g; treated SHR, 1.36+/-0.02 g; P<0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling.     

Characterization of myocardial hypertrophy in prehypertensive spontaneously hypertensive rats: interaction between adrenergic and nitrosative pathways

OBJECTIVE AND METHODS: Left ventricular hypertrophy in human and experimental hypertension is not always associated with pressure overload but seems to precede an increase in blood pressure. In this study, performed in male 5-week-old prehypertensive spontaneously hypertensive rats (SHR; n = 65) and age-matched Wistar-Kyoto rats (n = 56), the relationship between myocardial structure and activation of the adrenergic and nitric oxide systems was evaluated. RESULTS: Body weight, blood pressure and heart rate were similar in both groups. A higher left ventricle/body weight ratio was found in SHR, as a result of greater mononuclear (+47%) and binuclear (+43%) myocyte volumes, without changes in interstitial collagen. Both adrenergic and nitric oxide pathways were activated in SHR, as expressed by higher myocardial norepinephrine content, tyrosine hydroxylase activity, myocardial nitric oxide synthase 3 expression and protein nitration, indicating greater peroxynitrite (ONOO) generation from nitric oxide and superoxide. No difference was measured in nitric oxide synthase 1 expression, whereas nitric oxide synthase 2 was undetectable. A positive correlation between myocardial tyrosine hydroxylase activity and protein nitration was observed in SHR (r = 0.328; P < 0.01). Early treatment with a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl, from the third to the fifth week of age, reduced ONOO generation, protein nitration and sympathetic activation in SHR without changes in myocardial structure. CONCLUSION: In prehypertensive SHR, left ventricular hypertrophy is associated with adrenergic and nitrosative imbalance. Early superoxide dismutase mimetic treatment in SHR effectively reduces higher myocardial ONOO generation, sympathetic activation, and heart rate without affecting the development of myocardial hypertrophy.     

替米沙坦对自发性高血压大鼠左心室重塑的影响

目的探讨替米沙坦对自发性高血压大鼠(SHR)左心室重塑的影响。方法l6只16周龄雄性SHR,随机分为替米沙坦治疗组和SHR空白对照组;另设同源的WKY大鼠8只为正常对照组。治疗组给予替米沙坦10mg·kg-1·d-1灌胃给药,8周后处死动物,测量左心室心肌厚度并称重,计算左心室与体重比(LVW/BW);通过Van Gieson染色法观察左心室心肌胶原变化,对左心室心肌胶原容积分数(CVF)和血管周围胶原面积(PVCA)进行定性和半定量分析;电镜和HE染色观察左室心肌病理及超微结构。结果与WKY组相比,SHR空白对照组的尾动脉收缩压(SBP)、LVW/BW、左室壁厚度、CVF、PVCA、均显著增高(P<0.01);与SHR空白对照组相比,替米沙坦治疗组能有效降低SHR的SBP,改善左心室肥厚(P<0.01),减少心肌间质及心肌小动脉周围的胶原(P<0.01),组织病理及电镜显示,替米沙坦治疗能显著改善SHR左心室重塑。结论替米沙坦能有效降低SHR血压,改善左心室重塑。     

Impaired inotropic response to alpha 1- but not to beta-adrenoceptor stimulation in isolated hearts from spontaneously hypertensive rats.

OBJECTIVES: Hypertension in humans and experimental animals is known to be associated with an increase in left ventricular myocardial mass. The development of cardiac hypertrophy is not caused by increased blood pressure alone; the autonomic nervous system may also play an important role. DESIGN: The functional responses to the beta-adrenoceptor agonists isoprenaline, dobutamine, salbutamol and terbutaline, and the alpha 1-adrenoceptor agonists methoxamine, cirazoline and phenylephrine were studied in isolated (Langendorff) hearts from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls. The results were compared with data from radioligand binding experiments. RESULTS: There was no significant difference in the increase of left ventricular pressure induced by all beta-adrenoceptor agonists studied in SHR and WKY rat hearts. Although there was no significant difference in the response to phenylephrine, the inotropic responses to cirazoline and methoxamine proved to be significantly weaker in hearts from SHR than in those from WKY rats. Binding experiments with 3H-prazosin revealed no differences in density or affinity for cardiac tissues from SHR and WKY rats. CONCLUSIONS: Long-standing hypertension leads to an impaired response of the isolated heart to alpha 1-adrenoceptor stimulation, without changes in alpha 1-receptor density or affinity. It seems likely that changes in postreceptor events are responsible for the impaired inotropic response to alpha 1-adrenoceptor agonists in hearts from SHR.     

Transient AT1 receptor-inhibition in prehypertensive spontaneously hypertensive rats results in maintained cardiac protection until advanced age

OBJECTIVE: In young spontaneously hypertensive rats (SHR), transient angiotensin II type 1 receptor (AT1R) blockade decreases blood pressure for a prolonged period. We tested the hypothesis that transient AT1R blockade in SHR leads to cardiac protection until advanced age. METHOD: Wistar-Kyoto rats, SHR and transiently losartan-treated SHR (SHR-Los) (20 mg/kg per day; weeks 4-8 of age) were followed up until week 72 (n=9 each group), including repeated echocardiography, radiotelemetric investigations and 24-h urine collection. End-point measurements comprised left ventricular function parameters, left ventricular histomorphology and molecular biology (types I and III collagen, brain natriuretic peptide, AT1R mRNA) as well as renal morphology. RESULTS: Prehypertensive treatment with losartan, but not with the general vasodilator hydralazine, reduced blood pressure until age 48 weeks. In untreated SHR, the end-diastolic volume increased from week 36 and the left ventricular ejection fraction fell from week 48. In contrast, age-related changes in end-diastolic volume and ejection fraction were comparable in SHR-Los and Wistar-Kyoto rats up to age 60 weeks. At age 72 weeks, the ejection fraction was reduced in SHR-Los but higher than that in untreated SHR (ejection fraction: Wistar-Kyoto rats, 58 +/- 3%; SHR, 39 +/- 3%; SHR-Los, 46 +/- 3%; P < 0.01 and P < 0.05, respectively). The heart weight/body weight ratio (SHR-Los, 4.7 +/- 0.1 g/kg; SHR, 5.2 +/- 0.2 g/kg) and cardiac brain natriuretic peptide mRNA levels were improved by treatment. Left ventricular histomorphology and 24-h albuminuria were significantly improved in SHR-Los (41 +/- 5 mg/day; SHR, 80 +/- 22 mg/day; P < 0.05). CONCLUSION: In young SHR, transient AT1R blockade, not blood pressure lowering, attenuates the development of hypertension and exerts cardioprotective effects up to age 72 weeks.     

Regression of cardiomyocyte hypertrophy in SHR following chronic inhibition of the Na(+)/H(+) exchanger

OBJECTIVE: Experiments were performed to examine the effect of chronic inhibition of the Na(+)/H(+) exchanger isoform-1 (NHE-1) on cardiac hypertrophy of spontaneously hypertensive rats (SHR). METHODS: SHR were orally treated during 1 month with two different doses (0.3 and 3.0 mg/kg/day) of the NHE-1 inhibitor, cariporide, or nifedipine (10.0 mg/kg/day). RESULTS: The two doses of cariporide did not differ in their effects after 1 month of treatment, since both induced a slight decrease in systolic blood pressure (SBP) of approximately 6 mmHg and regression of the heart weight to body weight ratio (mg/g) from 3.28+/-0.05 to 3.04+/-0.05 (0.3 mg) and 2.99+/-0.10 (3.0 mg, P<0.05). Nifedipine, given for the same period, produced similar reduction in the hypertrophy index (3.03+/-0.05), but with a much greater decrease in arterial pressure (35.6+/-7.4 mmHg). Chronic treatment with cariporide induced a complete regression of the augmented cross sectional area of left ventricular myocytes without significant changes in collagen content, serum procollagen 1 propeptide levels or myocardial distensibility. CONCLUSIONS: NHE inhibition represents a novel approach to induce regression of pathological hypertrophy of the heart. The finding can be rationalized mechanistically by previous in vitro studies suggesting a role of the NHE in the development of myocardial hypertrophy.     

Selective effects of alpha-methyldopa on myocardial cell components independent of cell size in normotensive and genetically hypertensive rats

Alpha methyldopa has been shown to modify left ventricular mass and normalize mitochondria/myofibrils volume ratio in spontaneously hypertensive rats (SHR) when administered during the stage of developing cardiac hypertrophy (Tomanek et al., Cardiovas Res 23: 173, 1979). To evaluate the long-term effects of this antihypertensive agent, the drug was administered to SHR and normotensive (WKY) rats between the ages of 1 and 12 months. In another group of SHR and WKY, treatment was delayed until the age of 12 months and the animals were then treated for 3 months. Treatment with alpha-methyldopa had similar effects on systolic blood pressures in both SHR groups; group means (+/- SEM) were 151 +/- 1 in the long-term treatment group and 157 +/- 5 in the delayed treatment group compared to 178 +/- 4 and 176 +/- 3 for their respective controls. While left ventricular weight and cell size were significantly lower after early long-term treatment (compared to nontreated SHR), delayed treatment had no significant effect on these indices of left ventricular mass. Despite the effectiveness of early long-term treatment in modifying left ventricular mass, the relative volumes of mitochondria and myofibrils, as well as other cellular components (sarcoplasm), were not altered. In contrast, delayed treatment caused a significant increase (approximately twofold) in relative sarcoplasmic volume and a decrease in relative myofibrillar volume in both SHR and WKY. These findings indicate that shifts in the relative volumes of intracellular components after alpha-methyldopa are independent of cell size and blood pressure. Furthermore, the data suggest that the effects of alpha-methyldopa on the myocardial cell are dependent on or influenced by factors associated with the development or stabilization of hypertrophy and/or age.     

Influence of Parathyroidectomy on Blood Pressure and Vascular Reactivity in Spontaneously Hypertensive Rats

We investigated the influence of parathyroidectomy (PTX) on blood pressure (BP) and hindlimb vascular reactivity to noradrenaline (NA) and vasopressin (AVP) in male spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKR). Three groups of SHR and WKR, respectively, were investigated: Sham-operated (SO) rats on a normal calcium intake (0.95%), SO rats on moderately elevated calcium intake (1.6% calcium diet) and PTX rats on the 1.6% calcium diet. At the end of the experiment (3 months), directly or indirectly measured BP was significantly lower in the PTX-SHR group on the 1.6% calcium diet than in SO-SHR on the same diet. In WKR groups, no changes of BP were recorded. Hindlimb perfusion with oxygenated Tyrode's     

厄贝沙坦对SHR左心室肥厚和心肌纤维化的影响

目的 探讨厄贝沙坦对自发性高血压大鼠(SHR)左心室肥厚(LVH)和心肌纤维化的影响。方法 16只16周龄雄性SHR,随机分为厄贝沙坦治疗组和SHR空白对照组;另设同源的WKY大鼠8只为正常对照组。治疗组予厄贝沙坦15 mg/（kg·d）灌胃给药,8周后处死动物,测量左心室心肌厚度并称质量,计算左心室质量/体质量比(LVM/BM);通过Van Gieson染色法观察左心室心肌胶原变化,对左心室心肌胶原容积分数(CVF)和血管周围胶原面积(PVCA)进行定性和半定量分析;HE染色光镜观察左心室心肌病理变化。结果 与WKY组相比,SHR对照组的尾动脉收缩压(SBP)、LVM/BM、左心室壁厚度、CVF、PVCA、均显著增高(P<0.01);与SHR对照组相比,厄贝沙坦治疗组能有效降低SHR的SBP,改善LVH(P<0.01),减少心肌间质及心肌小动脉周围的胶原(P<0.01)。结论 厄贝沙坦可有效降低SHR血压,减轻心肌纤维化和LVH。     

Cilnidipine improves spontaneously hypertensive rat coronary hemodynamics without altering cardiovascular mass and collagen

OBJECTIVE : The present study was designed to determine the effects of prolonged treatment with cilnidipine, a novel dihydropyridine calcium antagonist which blocks both L-type and N-type calcium channels, on systemic, regional and coronary hemodynamics, cardiovascular mass and collagen content in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. METHODS : Male 23-week-old WKY and SHR rats were divided into two groups for each strain. One group received cilnidipine (10 mg/kg per day), whereas their respective controls were given no therapy. Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic mass, and hydroxyproline concentration were determined after 12 weeks treatment. RESULTS : The data demonstrated that cilnidipine neither affected systemic hemodynamics nor cardiovascular mass and collagen content in WKY rats. The same treatment in the SHR reduced arterial pressure and total peripheral resistance without changes in heart rate and cardiac index. Ventricular and aortic mass indices as well as ventricular collagen content remained unchanged. There were no differences in organ blood flows between two SHR groups, whereas renal, liver and left ventricular coronary vascular resistances were reduced by cilnidipine. After dipyridamole infusion left ventricular minimal coronary vascular resistance decreased further in cilnidipine-treated SHR as compared with control SHR rats. CONCLUSION : These data suggest that cilnidipine, an L- and N- type calcium channel antagonist, exerted beneficial effects on coronary hemodynamics without altering cardiovascular mass or collagen content in SHR.     

Myocardial collagen and mechanics after preventing hypertrophy in hypertensive rats

To determine if a remodeling of the collagen matrix would occur in the absence of hypertrophy and cell necrosis and if such a remodeling could alter active and passive stiffness of the intact myocardium, five rats with genetic hypertension (SHR) were treated (SHRT) with hydralazine for 32 weeks, beginning at four weeks of age, and compared to six age- and sex-matched SHR and seven Wistar-Kyoto genetic control rats (WKY). Left ventricular (LV) weight of SHRT was 17% lower (P less than .001) than that of SHR and 19% higher (P less than .01) than that of WKY. Collagen volume fraction of SHR (13.7 +/- 3.2%) and SHRT (9.9 +/- 1.8%) were greater (P less than .01) than WKY (5.0 +/- 1.9%). Diastolic and systolic stress-strain relations were determined in the isolated heart. A comparison of these relations revealed: 1) a 24% increase in passive stiffness for SHR and SHRT; and 2) a reduced zero-strain intercept (41% to 54%) and slope (36% to 48%) of the developed stress-strain relation for the SHRT. Thus, in SHR, collagen remodeling occurred in the absence of hypertrophy which suggests that the muscular and collagenous compartments of the myocardium are under separate controls. The excess accumulation of collagen in SHR and SHRT leads to abnormal passive stiffness, and the prevention of hypertrophy with hydralazine reduces active stiffness.     

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.     

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)     

Noninvasive characterization of myocardial blood flow in diabetic, hypertensive, and diabetic-hypertensive rats using spin-labeling MRI

OBJECTIVE: Microvascular alterations in the diabetic and hypertensive heart are likely to contribute to heart failure. In this work, myocardial blood flow and left ventricular function were measured in vivo in diabetic, hypertensive, and diabetic-hypertensive rats using MRI methods. METHODS: An 8-week-duration type 1 diabetes was induced by streptozotocin (STZ) in 8 Wistar-Kyoto (WKY) rats (STZ) and in 11 spontaneously hypertensive (SHR) rats (STZ-SHR). Fourteen WKY and 12 SHR served as control and hypertensive groups. Myocardial blood flow quantification was performed using an arterial spin-labeling MRI method. Left ventricular morphology and function were assessed during the same experiment using cine-MRI. RESULTS: Respective myocardial blood flow values for each group were 6.4 +/- 1.1 (WKY), 6.0 +/- 1.9 (STZ), 5.5 +/- 1.3 (SHR), and 4.3 +/- 0.9 mL. g(-1). min(-1) (STZ-SHR). Myocardial blood flow was significantly decreased in STZ-SHR rats compared with the other groups (p <.05, STZ-SHR vs. all groups). Cine-MRI showed morphological alterations in all pathological groups. No alteration of the ejection fraction was observed in the pathological groups. CONCLUSION: Myocardial blood flow is altered in vivo before any sign of heart failure when rats have type 1 diabetes and hypertension simultaneously. When only one of the pathologies occurs, MBF does not vary significantly.     

Extracellular matrix gene expression in the left ventricular tissue of spontaneously hypertensive rats.

The aim of this study was to investigate the extracellular matrix gene expression in the hypertrophied left ventricular tissue of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at early and mature ages. Interestingly, with age, a marked increase (+85% and +187% at 25 and 30 weeks of age, respectively, p < 0.01, vs 5 weeks) in matrix metalloproteinase-1 (MMP-1) mRNA levels in SHR and a progressive decrease (-50%, -70%, -78%, -70% at 10, 15, 25 and 30 weeks, respectively, p < 0.01, vs 5 weeks) in WKY were seen. Moreover, mRNA levels were significantly lower in SHR at 5 weeks. The analysis of mRNA expression for the tissue inhibitor of metalloproteinase-1 (TIMP-1) showed a significant increase in WKY (+44% and +44%, vs 15 and 25 weeks, respectively, p < 0.05), whereas there were no significant changes in SHR with development. At 30 weeks TIMP-1 mRNA levels were significantly reduced in SHR. Temporal trends of procollagen alpha1(I) and procollagen alpha1(III) mRNA levels were similar in both strains, but lower levels for procollagen alpha1(III) were found in SHR at 5 and 30 weeks. Although no significant differences were measured between the strains, mRNA levels for fibronectin were found decreased in WKY and increased in SHR with age. The results of the present study suggest an altered balance between collagen deposition and collagen degradation with development in this model of left ventricular hypertrophy and hypertension.