自发高血压大鼠左心室心肌胶原含量与舒张功能的相关性研究

目的测定自发高血压大鼠(SHR)左心室心肌胶原含量和舒张功能的参数,探讨二者的相关性,并揭示它们的增龄性改变。方法雄性SHR共30只(8、14周和20周各8只,32周6只),行组织多普勒成像(TDI)检测左心室舒张功能。处死后取左心室心肌,用羟脯氨酸试剂盒测定羟脯氨酸含量;反转录-聚合酶链反应(RT-PCR)检测Ⅰ型和Ⅲ型胶原的mRNA表达。结果 TDI显示,二尖瓣环舒张早期速度(Ea)随增龄减低(P0.05),二尖瓣环舒张早期与晚期速度比值(Ea/Aa)32周比8周时减低(P0.01),左心室等容舒张时间(TVRT)随增龄延长(P0.05),Tei指数随增龄增加(P0.05)。心肌羟脯氨酸含量、Ⅰ型和Ⅲ型胶原的mRNA表达随增龄均增加(均为P0.05)。羟脯氨酸含量、Ⅰ型和Ⅲ型胶原mRNA表达与TDI指标Ea、Ea/Aa均早负相关(r=-0.713～-0.431,P0.001～0.05),与IVRT均呈正相关(r=0.427～0.721,P0.001～0.01),与Tei指数均呈正相关(r=0.413～0.576,P0.001～0.01)。结论 SHR左心室心肌胶原含量呈增龄性增加,舒张功能呈增龄性降低,二者具有相关性。     

Effects of antihypertensive therapy on cardiac sodium/hydrogen ion exchanger activity and hypertrophy in spontaneously hypertensive rats

BACKGROUND: Sodium/hydrogen ion exchange is hyperactive in hypertension. Myocardial sodium/hydrogen ion exchange hyperactivity accompanies the regression of cardiac hypertrophy in spontaneously hypertensive rats (SHR) after long term control of blood pressure with enalapril. Objectives: To explore whether this effect is shared by other antihypertensive agents or is specific to angiotensin-converting enzyme inhibition. ANIMALS AND METHODS: SHR and normotensive Wistar Kyoto (WKY) rats were treated for five weeks with enalapril (20 mg/kg/day), nifedipine (10 mg/kg/day) or losartan (40 mg/kg/day). Sodium/hydrogen ion exchange activity was estimated in terms of both steady intracellular pH in HEPES buffer and the rate of intracellular pH recovery from intracellular acid loads in isolated superfused 2'-7'-bis(2-carboxyethyl)-5,-(and-6)-carboxyfluorescein, acetoxymethyl ester form-loaded papillary muscles. RESULTS: Enalapril, nifedipine and losartan decreased systolic blood pressure in SHR to about the same value (140 3, 140 2 and 146 3 mmHg, respectively, at the end the treatment). However, the index of cardiac hypertrophy (heart weight to body weight ratio) was decreased to a smaller value with losartan than with nifedipine or enalapril (2.66 0.09, 3.06 0.05 and 2.86 0.04 mg/g respectively; P<0.05 ANOVA). For the untreated SHR, the index of cardiac hypertrophy was 3.30 0.04 mg/g. Myocardial sodium/hydrogen ion exchange hyperactivity in SHR was normalized by all treatments. CONCLUSIONS: The three treatments regressed cardiac hypertrophy and normalized sodium/hydrogen ion exchange exchange activity in SHR, and losartan was the most effective treatment for reversing cardiac hypertrophy, despite producing effects on blood pressure and sodium/hydrogen exchange activity similar to that of other antihypertensive drugs.     

盐酸埃他卡林对脑卒中易感型自发性高血压大鼠心功能的影响

目的研究盐酸埃他卡林（Ipt）对大鼠无创心功能参数的影响。方法利用清醒无创心功能血流动力学计算机监测系统,对比研究Ipt对正常血压大鼠和脑卒中易感型自发性高血压大鼠（SHRsp）心率、心脏收缩、舒张和泵血功能的影响。结果Ipt0.5mg/kg静注可降低SHRsp心率、室缩波、抑制心肌收缩力指数,延长左室射血期和心肌电机械收缩时间,降低心输出量,延长左室舒张期。Ipt相同剂量对正常血压大鼠心功能参数却无明显影响。结论Ipt可抑制SHRsp大鼠心脏收缩和泵血功能,延长左室舒张期时间,但不影响正常血压大鼠心脏功能,提示Ipt对心功能的影响与血压状态密切相关。     

Regression of structural cardiovascular changes by antihypertensive therapy in spontaneously hypertensive rats

Trophic adrenergic influences may in part potentiate the pressure dependent development of structural cardiovascular changes in hypertension. Regression of such changes by antihypertensive treatment should therefore be most successful if adrenergic blocking drugs are used. In the present study spontaneously hypertensive rats (SHR) received either alpha-methyldopa, metoprolol, felodipine, a new vasodilating Ca2+-antagonist, or metoprolol and felodipine in combination for 10 weeks. Their left ventricles were weighed and resistance vessel design was analysed using a haemodynamic technique. Arterial pressure (MAP) was equally reduced by metoprolol and felodipine. Despite their different modes of action cardiovascular design was also equally affected. The combined regimen reduced average MAP more than either drug alone. It also caused more pronounced regression of cardiovascular structural changes. Methyldopa lowered MAP less than either metoprolol or felodipine and had only modest effects on cardiovascular design. Thus, the extent of MAP reduction, regardless of which therapeutic regimen is used to induce it, determines the extent of regression of structural cardiovascular changes during antihypertensive treatment.     

A comparative study of cardiac function in transgenic hypertensive rats, in spontaneously hypertensive rats and in normotensive rats

Left ventricular hypertrophy (LVH) entails numerous functional and molecular changes that ultimately lead to cardiac insufficiency. The renin-angiotensin system and adrenergic receptor signalling pathway have both been implicated in LVH progression and interactions between these factors may precipitate contractile dysfunction. We therefore investigated cardiac function in hypertensive rats transgenic for the human renin and angiotensinogen genes (TGR) having a genetic activation of the renin-angiotensin system, stroke-prone spontaneously hypertensive rats (SHR) and normotensive controls (CTR) aged 6 weeks. The isolated perfused heart model was used and the effect of isoproterenol (0.1-1000 nmol/L on cardiac function was studied. Cardiac protein and gene expression was studied by Western blot and RNase protection assay. TGR had 75 mmHg higher blood pressure and a 24% higher cardiac/body weight ratio than CTR; blood pressure in SHR was 17 mmHg higher without heart weight difference (p < 0.05). Basal Pmax, +dP/dt and -dP/dt were higher in TGR and SHR compared with CTR hearts. Isoproterenol stimulated these parameters by a maximum factor 6-8 in CTR and SHR but had almost no effect in TGR (p < 0.05). Basal CF per g heart weight was similar in all experimental groups. Isoproterenol produced a significantly smaller vasodilation in TGR compared with CTR or SHR. beta 1 and beta 2 receptor and Gs alpha proteins were similar in TGR, SHR and CTR. Gi alpha was increased in TGR hearts (p < 0.05). Converting enzyme and atrial natriuretic factor mRNA expression was increased (p < 0.01) while beta 1 receptor, adenylyl-cyclase V, SERCA2a and phospholamban mRNA expression was unchanged in TGR compared with CTR. Thus, LVH in TGR is characterised by early adrenergic dysfunction and beta 1 receptor signalling abnormalities indicating progressive functional deterioration. The data may serve as support for an early preventive intervention in angiotensin-II dependent cardiac hypertrophy and may have also implications for patients with genetic alterations of the renin-angiotensin system.     

Influence of intracoronary nifedipine on left ventricular function, coronary vasomotility, and myocardial oxygen consumption.

The effect of intracoronary nifedipine on regional and global left ventricular performance, coronary vasomotility, and myocardial oxygen consumption is reported. Left ventricular pressures and volume indices of contractility and relaxation were simultaneously recorded in five patients without coronary artery disease. In these patients, nifedipine in the left main coronary artery not only delayed (+115 ms) anterior wall contraction but also slowed (3.5 vs 1.9 cm/s) and depressed it (-26%), resulting in a depression of global left ventricular ejection. This asynchrony and depression of regional contraction is considered to be responsible for the slowed isovolumic contraction and relaxation of the whole ventricle. In 10 other patients with coronary artery disease, coronary sinus blood flow and myocardial oxygen consumption were measured before and after intracoronary nifedipine. The observed decrease in myocardial oxygen consumption (-28%) depended primarily on a decrease in contractility and left ventricular performance. In a third study group of 12 patients with coronary artery disease, the effects of intracoronary nifedipine on the coronary vasomotility of 40 coronary segments (normal, prestenotic, stenotic, poststenotic) were quantitatively determined. Left ventricular haemodynamics and coronary sinus saturation were monitored while the cineangiograms were recorded before and after nifedipine. Nifedipine provoked vasodilatation of the normal (+10.3%), prestenotic, stenotic (+4 to 30%), and poststenotic (+16.4%) coronary segments, which persisted after the disappearance of its direct effects on the myocardium. This transient regional "cardioplegic" effect of nifedipine, associated with an increase in coronary blood flow, a reduction in myocardial oxygen consumption, and a vasodilatation of the epicardial vessels is likely to be beneficial during temporary coronary occlusion such as occurs in spasm or transluminal angioplasty.     

Effect of antihypertensive therapy upon myosin isozyme distribution in spontaneously hypertensive rats.

INTRODUCTION: Myosin isozymes have been known to become altered during the development and regression of myocardial hypertrophy, but the mechanism by which the shifting takes place is not known. The present paper describes the effects of antihypertensive drugs, with a known mechanism of action, upon myocardial mass, blood pressure and myosin isoforms in spontaneously hypertensive rats (SHR). METHODS: SHR were treated with antihypertensive drugs and their blood pressure, myocardial mass and myosin isoforms determined. RESULTS: A shift of myosin isoform from the V3 to the V1 type and normalization of myocardial hypertrophy were seen in rats treated with captopril but not in those treated with diuretics. Clonidine and guanethidine increased the V3 form in association with moderate control of blood pressure and no change in myocardial mass. Treatment with a beta-blocker regressed hypertrophy, controlled hypertension but increased the V3 form. Treatment with minoxidil normalized blood pressure, increased cardiac mass and increased the V3 type. CONCLUSIONS: Treatment with different antihypertensive drugs does not cause similar types of shifts in myosin isoform and has divergent effects upon blood pressure and heart weight. Furthermore, there is no correlation between myocardial mass, blood pressure and myosin isozyme shifts. We conclude that factors other than blood pressure, myocardial mass and catecholamines modulate the shifting of myosin isoforms. Since captopril had a greater remedial effect upon myosin isoforms in our study than the more commonly used agents, we recommend that the current criteria for selection of antihypertensive drugs and the relation between those drugs and cardiac function be re-evaluated.     

Chronic antisense therapy for angiotensinogen on cardiac hypertrophy in spontaneously hypertensive rats

OBJECTIVE: We examined the effect of the suppression of plasma angiotensinogen (AGT) by the intravenous injection of antisense oligodeoxynucleotides (ODNs) against AGT targeted to the liver on cardiac remodeling in spontaneously hypertensive rats (SHR). The ODNs against rat AGT were coupled to asialoglycoprotein (ASOR) carrier molecules, which serve as an important method for regulating liver gene expression. METHODS: Male SHR (n = 18), and age-matched male Wistar-Kyoto rats (WKY, n = 6) were used for this study. At 10 weeks of age, the SHR were divided into three groups (each group n = 6), and the systolic blood pressure (SBP) did not significantly change among them. The control SHR and WKY groups received saline, the sense SHR group was injected with the sense ODNs complex and the antisense SHR group was injected with the antisense ODNs complex, from 10 to 20 weeks of age. ASOR-poly(L)lysine-ODNs complex was injected via the tail veins twice a week. RESULTS: At the end of the treatment, a reduction of hepatic AGT mRNA, cardiac angiotensin II type 1 receptor mRNA and the plasma AGT concentration was only observed in the antisense-injected SHR but not in the other groups of SHR and WKY. This antisense therapy did not significantly change the mRNA expression for angiotensin converting enzyme, angiotensin II type 2 receptor and AGT in the left ventricle (LV) among all three groups. Although the plasma angiotensin II (Ang II) concentration significantly decreased to the level of WKY after the antisense therapy, the SBP, LV to body weight ratio and % collagen volume fraction also showed a reduction, however, these findings were still larger than in the WKY than in either the sense-injected SHR or control SHR. CONCLUSION: The plasma AGT is considered to play a role in the development of cardiac hypertrophy in SHR, but it has not a complete effects on cardiac remodeling even if the plasma Ang II levels are inhibited because of an insufficient suppression of hypertension.     

Relative importance of cardiac output and arterial pressure in determining myocardial oxygen consumption and coronary blood flow

Oxygen consumption and coronary blood flow were measured in anesthetized dogs while cardiac work was altered by changing arterial pressure or by opening an aorta to left atrial shunt. When oxygen consumption during pressure work was compared with that during flow work, at a constant heart rate, it was found that flow work increased oxygen consumption as much, or more, than did increasing pressure work. Coronary blood flow, but not A-V oxygen difference, was correlated with oxygen consumption. The highest correlation with oxygen consumption, however, was obtained for left ventricular end-diastolic pressure, which was even more highly correlated than was cardiac work. The conclusion is that it may be the initial stretch of the myocardial fiber, rather than the arterial pressure or the cardiac output, that is the primary determinant of myocardial oxygen consumption at a constant heart rate.     

Effect of phosphodiesterase inhibition on myocardial oxygen consumption and coronary blood flow

The phosphodiesterase inhibitors (amrinone, milrinone and enoximone) can cause major improvement in the performance of the failing heart without increasing myocardial oxygen consumption. This appears to be the result of a reduction in left ventricular systolic wall stress due to peripheral arteriolar vasodilatation, which offsets the increase in myocardial oxygen consumption that would otherwise result from an enhanced inotropic state. In comparison, catecholamine agents such as dobutamine, given at doses that achieve the same level of inotropic enhancement or improved left ventricular performance, produce less associated arteriolar vasodilatation and a significant (approximately 30%) increase in myocardial oxygen consumption. This difference between the phosphodiesterase inhibitors and the conventional catecholamine agents may be of clinical importance in patients with limited coronary flow reserve due to severe congestive heart failure.     

Effects of regression of left ventricular hypertrophy following atenolol or bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats.

The effects of regression of left ventricular hypertrophy following atenolol and bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats (SHR) were studied. Atenolol (50 mg/kg/day) and bunazosin (5 mg/kg/day) were administered to SHR from 19 to 26 weeks of age, whereas tap water was given to control SHR and normotensive Wistar-Kyoto rats (WKY). Both atenolol and bunazosin significantly decreased arterial blood pressure and significantly decelerated the increase in left ventricular weight in SHR. At the end of the long-term treatment, hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The pressure-rate product and the extent of recovery of the coronary flow after reperfusion following 30 min of ischemia in the bunazosin-treated SHR were significantly higher than those in the control SHR and the atenolol-treated SHR. The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were significantly lower than those in the reperfused WKY. Both atenolol and bunazosin improved the restoration of ATP and CrP in SHR after reperfusion following 30 min of ischemia. In conclusion, antihypertensive therapy with either atenolol or bunazosin was effective in preventing cardiac hypertrophy and ischemic damage caused by different mechanisms. Factors resulting from stimulation of the cardiac alpha 1 adrenoceptor may play an important role in the development of hypertensive cardiac hypertrophy, just as factors resulting from stimulation of the beta 1-adrenoceptor do.     

Effects of triiodothyronine in spontaneously hypertensive rats. Studies on cardiac metabolism,function, and heart weight

Summary We have studied the effects of triiodothyronine (T₃) on heart function,on the myocardial oxidative pentose phosphate pathway, and on heart weight in spontaneously hypertensive (SHR) rats. Another aim was to examine whether these T₃-effects may be reversible. T₃ was administered daily (0.2 mg/kg s. c.) for 14 days. Compared to the untreated SHR controls, T₃ induced an increase in heart rate (beast/min) from 357±10 (n=17) to 553±10 (n=17), in the pressure-rate-product (mm Hg/min) from 78400±4500 (n=15) to 113700±4800 (n=15), and in the heart weight/body weight ratio (mg/g) from 4.2±0.2 (n=20) to 5.8±0.2 (n=19). The activity of myocardial glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the oxidative pentose phosphate pathway (units/g protein), was clevated from 4.2±0.2 (n=9) to 7.0±0.6 (n=9) after 14 days of T₃-treatment while the activity of 6-phosphogluconate dehydrogenase, one of the following enzymes in the pathway, was not altered appreciably. These changes returned to the respective control values when T₃-treatment was discontinued for 14 days. Our results demonstrate that T₃ had a positive chronotropic effect and induced an additional heart enlargement in an animal model with already established cardiac hyperfunction and hypertrophy. The effects on heart function and weight, which were fully reversible, were not as pronounced as in normal Sprague-Dawley rats.     

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.     

Impact of antihypertensive treatments on erectile responses in aging spontaneously hypertensive rats

OBJECTIVE: We previously demonstrated that brief, aggressive antihypertensive therapy recovered erectile function in 40-week-old spontaneously hypertensive rats (SHR). The present study examined the impact of antihypertensive and testosterone treatments on erectile function in aging SHR. DESIGN AND METHODS: Centrally initiated erections were determined in response to apomorphine throughout. At 30 and 49 weeks, SHR were treated for 2 weeks with enalapril or hydralazine. A third more aggressive treatment (68 weeks) involved enalapril or losartan plus a low salt diet or a triple therapy (hydralazine, nifedipine, hydrochlorothiazide). In a separate study, cross-over kidney transplantations were performed between untreated and losartan-treated SHR. Arterial pressure was assessed post-transplantation using radio-telemetric transducers. RESULTS: There was an age-related decrease in erections between 30 and 68 weeks (3.1 +/- 0.79 versus 0.2 +/- 0.38) that was not improved by testosterone administration. Early treatment with enalapril or hydralazine did not prevent this decline, although the second treatment resulted in significant improvements (enalapril, 0.8 +/- 0.70; hydralazine, 0.8 +/- 0.41 versus control, 0.3 +/- 0.60). A 2-week aggressive antihypertensive treatment at 68 weeks increased erections approximately two-fold, with the previously treated rats receiving triple therapy having markedly improved erectile responses (0.2 +/- 0.53 versus 1.1 +/- 1.67). In the transplantation study, previously losartan-treated SHR given an untreated kidney had higher arterial pressure but twice the number of erections in comparison with the SHR with lower arterial pressure resulting from transplanting a treated kidney. CONCLUSIONS: Aggressive antihypertensive treatments may be more beneficial in improving erectile function in aged SHR, via an effect that appears to be tissue specific, and not based on changes in blood pressure.     

Effect of antihypertensive treatment on peripheral nerve vasculature in spontaneously hypertensive rats

The influence of hypertension and of treatment with the dihydropyridine-type Ca+2 antagonist nicardipine on peripheral nerve vasculature were investigated in spontaneously hypertensive rats (SHR). Male SHR were treated from the 16th to the 26th week of age with vehicle (control group), with nicardipine, at the hypotensive dose of 3 mg/kg/day, or at the nonhypotensive dose of 0.1 mg/kg/day or with an equihypotensive dose (10 mg/kg/day) of the nondihydropyridine-type vasodilator hydralazine. Age-matched normotensive Wistar-Kyoto (WKY) rats were left untreated and used as normotensive reference animals. In SHR a significant increase of systolic pressure values accompanied by sciatic nerve microvascular changes, involving primarily interfascicular arteries and to a lesser extent intrafascicular arteries, was observed. Treatment with the hypotensive dose of nicardipine countered hypertension-dependent microvascular changes occurring in both interfascicular and intrafascicular arteries. The nonhypotensive dose of nicardipine and hydralazine displayed a modest activity on interfascicular arteries, but significantly countered hypertension-related changes involving intrafascicular arteries. The above findings indicate the occurrence of hypertension-related changes of peripheral nerve microvasculature and of positive effects induced by appropriate pharmacological treatment. Further work is in progress to identify the functional relevance of microanatomical observations of the present study.     

Short- and long-term determinants of baroreceptor function in aged normotensive and spontaneously hypertensive rats

In a variety of animal models, baroreceptor resetting during chronic hypertension has been correlated to vessel wall hypertrophy and decreased distensibility. In one possible mechanism of chronic resetting, termed the splinting hypothesis here, it has been suggested that a stiffer vessel wall might increase the minimum pressure required for activation of these mechanoreceptors (pressure threshold) and decrease suprathreshold pressure sensitivity. Lower vessel distensibility would alter baroreceptor function by preventing equivalent pressures from producing equivalent vessel distensions and, thus, receptor distortions. Recent studies have also suggested that the pressure threshold is strongly influenced by the most recent (minutes) history of blood pressure exposure during a process termed rapid resetting. Hypertension and advanced aging are associated with distensibility changes. The present study examines pressure and equivalent mechanical response characteristics of aortic baroreceptors from aged normotensive Wistar-Kyoto and spontaneously hypertensive rats. An in vitro aortic arch-aortic nerve preparation was used to assess the discharge properties from a number of baroreceptors and the pressure-diameter relationship of each aorta. Both control and rapid resetting protocols were used to study the baroreceptor characteristics. Aged Wistar-Kyoto rats were normotensive and averaged 115 weeks of age. Aged spontaneously hypertensive rats had systolic tail pressures of 187 mm Hg and averaged 76 weeks of age. Although aortic distensibility of aged WKYs was much lower than previously found in younger animals, the pressure threshold was unchanged. Aged spontaneously hypertensive rat receptors were chronically reset in proportion to their blood pressure. Decreased distensibility did not alter the rapid resetting process. It is concluded that baroreceptor pressure sensitivity is more closely related to aortic distensibility under several conditions altering vessel stiffness, whereas, the pressure threshold may be regulated additionally by mechanisms independent of distensibility. The results are inconsistent with the splinting hypothesis.