Role of the native kidney in experimental post-transplantation hypertension

In experimental renal transplantation studies using several animal models of primary hypertension, including stroke-prone spontaneously hypertensive rats (SHRSP) and their normotensive Wistar-Kyoto controls (WKY), single transplanted kidneys from genetically hypertensive but not normotensive donors elicited post-transplantation hypertension in bilaterally nephrectomized genetically normotensive recipients. The underlying mechanisms are presently unclear. The present study was designed to investigate the effects of a remaining native kidney on post-transplantation blood pressure, plasma renin activity and plasma angiotensin II concentration in (WKY×SHRSP) F₁ hybrid recipients of a WKY or SHRSP kidney. The presence of a native kidney markedly reduced, but did not prevent, post-transplantation hypertension in recipients of an SHRSP kidney. WKY kidney grafts did not significantly alter blood pressure in bilaterally or unilaterally nephrectomized recipients. Plasma renin activity was lower in bilaterally than in unilaterally nephrectomized recipients, regardless of the source of the graft. The plasma angiotensin II concentration was similar in all groups. Renal graft function as assessed by ^99mtechnetium-mercaptoacetyltriglycine scintigraphy was well preserved. These data suggest that post-transplantation hypertension in recipients of an SHRSP kidney may be partly due to the failure of the graft to eliminate a hypertensinogenic substance or to produce a blood pressure lowering agent. Received: 21 July 1995 /Received after revision: 6 November 1995 /Accepted: 21 November 1995     

SHR心肌细胞内钙离子浓度改变与左室肥厚和功能的关系

目的:探讨自发性高血压大鼠(SHR)心肌细胞内钙离子浓度的动态演变规律及其与左室肥厚和功能的相互关系。方法:应用Ca²⁺荧光指示剂Fura-2/AM分别测定了10周龄、22周龄、34周龄SHR心肌细胞内Ca²⁺浓度以及导管法测定了大鼠心功能,并以同龄京都-Wistar(WKY)大鼠作对照。结果:各周龄SHR收缩压(SBP)、心肌细胞内Ca²⁺浓度([Ca⁺]_i)、左室重量/体重(LVM/BW)均明显高于同龄正常血压WKY大鼠,22周龄SHR左室压力最大下降速率(-dp/dt_max)低于、左室松弛时间常数(τ)长于同龄WKY大鼠,34周龄SHR±dp／dt_max和左室收缩指数均显著低于同龄WKY大鼠,τ进一步延长;心肌细胞内[Ca⁺]_i与大鼠LVM/BW、SBP-dp／dt_max、τ呈显著正相关(r=0.47-0.83,P＜0.01),与dp／dt_max和收缩指数呈显著负相关(r=-0.46,P<0.05和-0.81,P<0.01)。结论:SHR心肌细胞内钙离子超负荷不仅介导了心肌肥厚的形成,还导致了心肌的收缩和舒张功能障碍。     

Angiotensin converting enzyme inhibition prevents polyploidization of cardiomyocytes in spontaneously hypertensive rats with left ventricular hypertrophy

Polyploidization of cardiomyocyte nuclei is a physiological phenomenon that increases in pathological conditions such as myocardial hypertrophy. The purpose of this study was to evaluate the potential benefit of the angiotensin converting enzyme (ACE) inhibitor quinapril in reversing the polyploidization of cardiomyocyte nuclei in spontaneously hypertensive rats (SHR) with established left ventricular hypertrophy (LVH). Sixteen week-old male SHR were treated with oral quinapril (average dose 10 mg/kg per day) for 20 weeks. Sixteen- and 36-week-old untreated SHR and 16- and 36-week-old normotensive Wistar-Kyoto (WKY) rats were used as controls. Nuclear polyploidization was determined by DNA flow cytometry of frozen tissues from the left ventricle, at least 20 000 nuclei being measured in each sample. The rates of tetraploidy in the 16- and 36-week-old SHR groups were 2·8 per cent (range 2·16-3 per cent) and 5·4 per cent (range 4·9–5·9 per cent), respectively. Treated SHR had a similar rate of DNA tetraploidy to the 16- and 36-week-old WKY rat groups: 1·8 per cent (range 1·5–2·3 per cent), 1·55 per cent (range 1·5–1·6 per cent), and 1·5 per cent (range 1·4–1·6 per cent), respectively. The differences in the percentage of tetraploid cardiomyocytes between the SHR untreated groups and the SHR treated group were statistically significant (P<0·05). Regression of LVH and normalization of blood pressure were observed in treated rats. These results indicate that DNA tetraploidy in the myocardium of SHR increases with hypertrophy and decreases on quinapril treatment. It is suggested that ACE inhibition modifies nuclear processes involved in myocyte growth in arterial hypertension.     

Immobilization stress induces vasodepressor and altered neuroendocrine responses in the adult stroke-prone spontaneously hypertensive male rat

The effects of acute (1 h) and daily repeated immobilization stress (14 days, twice-daily, 1 h) were studied on arterial blood pressure and heart rate and on the blood levels of several hormones in the adult (5 months old) stroke-prone spontaneously hypertensive rat (SHRSP) and in the age-matched normotensive Wistar-Kyoto (WKY) rat. The major result was the development of a long-lasting vasodepressor response in the SHRSP, while the same acute or repeated immobilization stress in the WKY rat led to the development of a prolonged vasopressor response. Differential changes to stress were also observed in practically all neuroendocrine axes with the exception of the pituitary-adrenal axis. The vasodepressor response to immobilization stress in SHRSP may be related to an exaggerated defence-like reaction causing an enhanced vasodilation in the skeletal muscle beds associated with a tachycardia similar to that in the normotensive control rats.     

Reactivity of intrarenal arteries to vasoconstrictor and vasorelaxant polypeptides in adult stroke-prone spontaneously hypertensive rats.

The reactivity of intrarenal arteries to vasoconstrictor and vasodilator polypeptides was examined in adult stroke-prone spontaneously hypertensive rats (SHRSP). The contraction response to endothelin-1 (ET-1) was greater in SHRSP than in age-matched Wistar-Kyoto rats (WKY), and so was the pD2 estimate (8.05+/-0.03 in SHRSP, and 7.73+/-0.06 in WKY; n=5, P < 0.05). The contraction response to, and the pD2 estimate of, vasopressin were comparable in SHRSP and WKY. Neuropeptide Y did not contract the intrarenal arteries. In norepinephrine-precontracted arteries with intact endothelium, substance P and neurokinin A did not relax the arteries of either SHRSP or WKY, while calcitonin gene-related peptide (CGRP) induced a profound relaxation response. Relaxation response to CGRP was significantly greater in SHRSP than in WKY. Atrial, brain, and C-type natriuretic peptides (ANP, BNP, CNP), vasoactive intestinal polypeptide (VIP), and peptide histidine isoleucine (PHI) all caused relaxation responses, with a greater extent of relaxation to ANP, BNP, and VIP and a less extent to CNP and PHI. However, there were no significant differences in these relaxation responses between SHRSP and WKY. The current results revealed the character of heterogeneity of rat intrarenal arteries in response to vasoconstrictor and vasodilator peptides, and showed an enhanced reactivity to ET-1 and to CGRP in SHRSP.     

The renal kallikrein-kinin system in spontaneously hypertensive rats

In male spontaneously hypertensive rats (SHRSP) of the stroke prone strain (Okamoto) and in normotensive Wistar-Kyoto rats (WKY) urinary kallikrein excretion was investigated at different age and at drug-induced diuresis.In rats of both strains from 7th till 19th week of age urinary kallikrein excretion increased with age. In SHRSP of 7th till 11th week of age kallikrein excretion was higher than in WKY rats, while it was lower in the 48-week-old SHRSP. No correlation was found between urinary kallikrein excretion and systolic blood pressure.In SHRSP and WKY rats a similar daily rhythm of kallikrein excretion in urine was found being high in the early morning and low in the afternoon. Kallikrein excretion correlated significantly with urine volume.The loop diuretic bumetanide (4 and 40 mg/kg) induced diuresis and natriuresis in both strains, however more marked in the WKY rats than in the SHRSP. Urinary kallikrein excretion, however, showed in both strains the same biphasic course with a short lasting increase and a secondary decrease. Thus, in the average urinary kallikrein excretion was not effected by the drug.Prolonged treatment with furosemide over 5 days (125 mg/kg) resulted in an increase in kallikrein excretion in urine, more pronounced in the WKY rats than in the SHRSP.The observed results suggest that renal kallikrein-kinin system is not involved in the development of spontaneous hypertension as a pathogenetic factor, but rather is influenced by other factors like hormone interactions, i.e. mineralocorticoids and catecholamines, as well as renal function and acute changes in urine flow.Herrn Professor Dr. med. W. Kaufmann zum 60. Geburtstag     

Hemodynamic, Morphometric and Autonomic Patterns in Hypertensive Rats - Renin-Angiotensin System Modulation

BACKGROUND:

Spontaneously hypertensive rats develop left ventricular hypertrophy, increased blood pressure and blood pressure variability, which are important determinants of heart damage, like the activation of renin-angiotensin system.

AIMS:

To investigate the effects of the time-course of hypertension over 1) hemodynamic and autonomic patterns (blood pressure; blood pressure variability; heart rate); 2) left ventricular hypertrophy; and 3) local and systemic Renin-angiotensin system of the spontaneously hypertensive rats.

METHODS:

Male spontaneously hypertensive rats were randomized into two groups: young (n=13) and adult (n=12). Hemodynamic signals (blood pressure, heart rate), blood pressure variability (BPV) and spectral analysis of the autonomic components of blood pressure were analyzed. LEFT ventricular hypertrophy was measured by the ratio of LV mass to body weight (mg/g), by myocyte diameter (μm) and by relative fibrosis area (RFA, %). ACE and ACE2 activities were measured by fluorometry (UF/min), and plasma renin activity (PRA) was assessed by a radioimmunoassay (ng/mL/h). Cardiac gene expressions of Agt, Ace and Ace2 were quantified by RT-PCR (AU).

RESULTS:

The time-course of hypertension in spontaneously hypertensive rats increased BPV and reduced the alpha index in adult spontaneously hypertensive rats. Adult rats showed increases in left ventricular hypertrophy and in RFA. Compared to young spontaneously hypertensive rats, adult spontaneously hypertensive rats had lower cardiac ACE and ACE2 activities, and high levels of PRA. No change was observed in gene expression of Renin-angiotensin system components.

CONCLUSIONS:

The observed autonomic dysfunction and modulation of Renin-angiotensin system activity are contributing factors to end-organ damage in hypertension and could be interacting. Our findings suggest that the management of hypertensive disease must start before blood pressure reaches the highest stable levels and the consequent established end-organ damage is reached.     

Enhanced oxidative stress and impaired thioredoxin expression in spontaneously hypertensive rats

As oxidative stress plays a crucial role in the development and pathogenesis of hypertension, we analyzed the redox (reduction/oxidation) status in tissues from Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP). Expressions of 8-hydroxy-2'-deoxyguanosine, a marker for oxidative stress-induced DNA damage, and protein carbonylation, a marker for oxidation status of proteins, were enhanced in aorta, heart, and kidney from SHR and SHRSP compared with WKY. The expression of redox regulating protein, thioredoxin (TRX), estimated by immunohistochemistry and western blot, and expression of TRX gene estimated by real-time RT-PCR were markedly suppressed in those tissues from SHR and SHRSP compared with WKY. Induction of TRX was impaired after angiotension II treatment in peripheral blood mononuclear cells isolated from SHR and SHRSP compared with those isolated from WKY. Although previous reports have shown that TRX is induced by a variety of oxidative stress in tissues, the present study shows the impaired induction of TRX in tissues from genetically hypertensive rats despite the relative increment of oxidative stress. Redox imbalance in essential organs may play a crucial role in the development and pathogenesis of hypertension.     

Elastin and elastase-like enzyme change in aorta of rat with malignant hypertension

In order to study the role of elastin in arteries with respect to hypertension and hypertensive arterial disease, aortic elastin content and elastase-like enzyme activity were examined and compared in stroke-prone spontaneously hypertensive rats (SHRSP), which show malignant hypertension, and Wistar-Kyoto normotensive rats (WKY). The elastin content was lower, whereas the elastase-like activity was higher at 20 weeks of age in SHRSP than in WKY, so that the aortic elastin/enzyme ratio of SHRSP was lower than that in WKY. These differences were not found at 6 weeks of age (prehypertensive stage). For SHRSP anti-hypertensive treatment resulted in lowering the elastase-like activity and in increasing the elastin content in comparison to untreated animals. The subcellular distribution of the elastase-like activity closely correlated with that of 5'-nucleotidase activity, a plasma membrane marker enzyme. The results indicate involvement of a smooth muscle plasmalemmal elastase-like enzyme in vascular connective tissue metabolism in health and possibly also its participation in hypertensive arterial diseases.     

High plasmatic angiotensin-converting enzyme (ACE) activity is not correlated with training-induced left ventricular growth in ACE congenic rats

Aim: The aim of this study was to determine the influence of angiotensin‐converting enzyme (ACE) genotype on left ventricular growth after endurance training, in ACE congenic rats with plasma ACE activity twice as high as the donor strain (LOU), thus mimicking the ACE I/D polymorphism observed in humans. Methods: LOU and congenic rats (n = 12) were submitted to an endurance training on a treadmill for 7 weeks, while similar LOU and congenic rats (n = 10) constituted the control groups. Blood pressure, skeletal muscle citrate synthase activity, plasma and left ventricular ACE activity were assessed, and echocardiography was performed before and after the training. Results: Angiotensin‐converting enzyme plasmatic activity of congenic rats (188.2 ± 26.6 in controls and 187.1 ± 22.6 IU in trained rats respectively) was twofold that of the LOU strain (91.9 ± 23.3 in controls, and 88.3 ± 18.1 IU in trained rats respectively). After training, congenic and LOU rats showed a similar significant increase in citrate synthase activity (P < 0.05), and in the left ventricular mass/body mass ratio × 10³: 3.7 ± 0.3 and 3.6 ± 0.6 in the trained congenic and LOU groups, respectively, vs. 3.0 ± 0.1 and 2.9 ± 0.2 in the control congenic and LOU groups respectively (P < 0.05). There was no significant correlation between ACE plasma activity and left ventricular mass in trained or untrained congenic rats. Conclusion: We conclude that training‐induced left ventricular growth is not associated with plasma ACE activity in congenic rats.     

Hypertension and impairment of endothelium-dependent relaxation of arteries from spontaneously hypertensive and L-NAME-treated Wistar rats.

Effects of chronic treatment of normotensive Wistar rats with N(omega)-nitro-L-arginine methyl ester (L-NAME) on blood pressure and on endothelium-dependent relaxation of the aorta, carotid and iliac arteries were studied. The endothelium-dependent relaxation was compared in arteries from normotensive Wistar Kyoto rats (WKY) and genetically hypertensive rats (stroke-prone spontaneously hypertensive rats, SHRSP). Chronic treatment of normotensive Wistar rats with L-NAME caused an elevation of blood pressure. The elevated blood pressure at 15 weeks of age was significantly higher in these animals than that of untreated Wistar rats, but lower than that of SHRSP. Endothelium-dependent relaxation of the arteries induced by acetylcholine (ACh) was almost abolished by chronic treatment with L-NAME. The remaining small relaxation in arteries from L-NAME-treated rats was completely inhibited by application of L-NAME (10(-4) M). In such preparations, higher concentrations of ACh induced a contraction, which was abolished by removal of the endothelium or by an application of indomethacin (10(-5) M). Endothelium-independent relaxation induced by sodium nitroprusside was similar between preparations from untreated and L-NAME-treated Wistar rats. Endothelium-dependent relaxation was significantly impaired in preparations from SHRSP, when compared with that in those from WKY. However, the impairment was less prominent in preparations from SHRSP than in those from L-NAME-treated rats. These results suggest that the impairment of endothelium-dependent relaxation in the arteries from L-NAME-treated rats is not due to the elevated blood pressure resulting from the chronic treatment, and that impairment of NO synthesis by the endothelium does not play a major role in the initiation of hypertension in SHRSP.     

Natural biventricular hypertrophy in normotensive rats. I. Physical and hemodynamic characteristics.

The Wistar-Kyoto strain of normotensive rats (WKY) is being used as a control animal for studies involving the spontaneously hypertensive rats (SHR). A subset of the WKY demonstrating an inheritable transmission of biventricular cardiac hypertrophy (BVH) has been identified. The cardiac enlargement is pronounced, with right and left ventricular weights greater than twice normal in some animals. This natural development of BVH appears to be in response to an increased cardiac output. Blood pressure is normal and, therefore, peripheral resistance is reduced. Left ventricular injection of 15-micrometer radioactively labeled microspheres demonstrated that WKY with BVH had a substantial shunt fraction of their cardiac output (45 +/- 7% radioactivity recovered in the lungs vs. 3 +/- 2% in normal WKY). This subset of WKY with BVH provides a natural model of volume-load hypertrophy. In addition, investigators using the WKY for comparison with SHR should exclude animals with BVH.     

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive Wistar-Kyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDA-treated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke.Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension,¹ match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis,² and protect against ischemia.^3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids.⁵ In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke,⁶ and this association could be related to modifications in SEH activity, and thus epoxide catabolism.⁷ An alternative strategy that has been used to increase EETs systemically is SEH inhibition.¹We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.⁸ Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO) without decreasing blood pressure.⁸ Although blood pressure is an important variable in controlling infarct size in the SHRSP, the cerebrovasculature is also a key determinant of increased sensitivity to cerebral ischemia and thus infarct size.^9,10 Our study provided preliminary evidence that AUDA protection in the SHRSP involved changes in vascular structure.⁸ More recently, a report suggested that administration of AUDA-butyl ester protects against cerebral ischemic reperfusion injury in normotensive mice by mechanisms that may involve neural protection rather than vascular protection.¹¹ As a result, the contribution of vascular and neural protection to the cerebral protective effects of SEH inhibition during states of hypertension and normotension are unclear and require further investigation. The present study tested the hypothesis that SEH inhibition provides cerebral protection via different mechanisms in normotensive WKY and hypertensive SHRSP rats.     

Development of SHR hypertension and cardiac hypertrophy during prolonged beta blockade.

Spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were treated with beta-adrenergic receptor inhibiting drugs (either propranolol or timolol) from conception until 12 weeks of age to determine if this therapy would alter the development of systemic hypertension or left ventricular hypertrophy. Therapy (propranolol or timolol, 500 mg/liter drinking water) was initiated with breeding parents and continued throughout the pregnancy, nursing, and postweaning periods. Although the heart rates of beta-adrenergic receptor inhibited WKY and SHR rats were consistently reduced with respect to their respective tap-water controls, this therapy did not alter body growth. Hemodynamic studies demonstrated reduced central venous pressure, cardiac index, and maximum acceleration of aortic flow in the beta-adrenergic inhibited rats. In spite of these findings, the arterial pressure of the treated rats and the degree of left ventricular hypertrophy of the SHR were unaltered by treatment. Thus, administration of the beta-adrenergic receptor blocking agents, propranolol or timolol, from conception through the developmental stage of SHR hypertension, failed to alter either the progressive rise in arterial pressure or the development of hypertensive vascular disease and left ventricular hypertrophy.     

Transmural distribution of biochemical markers of total protein and collagen synthesis,myocardial contraction speed and capillary density in the rat left ventricle in angiotensin ll-induced hypertension

The effect of angiotensin II-induced hypertension on selected biochemical parameters was studied in Sprague-Dawley rats. Angiotensin II infusion at rates of 41.7 μg h^-1 kg^-1 and 12.5 μg h^-1 kg^-1 for 2, 5, 10 and 15 days elevated the systolic blood pressure from 143 ± 7 mmHg to 215–230 mmHg (P < 0.001) and 185–195 mmHg (P < 0.001), respectively. The left ventricular weight/body weight ratio increased 10–14% (P < 0.05) and 23–32% (P < 0.001) after 2–15 days in rats treated at the lower and higher infusion rates, respectively. Prolyl 4-hydroxylase (PH) activity, a marker of collagen synthesis, was evenly distributed in the left ventricle. PH activity increased by about 100% in both subendocardial and subepicardial layers of the left ventricular wall after angiotensin II infusion for 10 days at 41.7 γ h^-1 kg^-1, but remained unaltered at 12.5 μg h^-1 kg^-1. No change was observed in hydroxyproline concentration. Myosin isoenzymes (V₁-V₃), which reflect myocardial contractility, were unevenly distributed in the left ventricular wall: the proportion of the fast-turnover isoenzyme (V₁) was smaller in the subendocardial layer than in the subepicardial layer. The proportion of V_l decreased after treatment in both layers. Alkaline phosphatase activity, a marker of capillary density, was evenly distributed transmurally in the left ventricular wall. Angiotensin II caused a slight decrease in this activity in both myocardial layers. The results suggest that the elevation of blood pressure leads to transmurally evenly distributed changes in biochemical parameters reflecting collagen synthesis, capillary density and contractile properties of the myocardium.     

Functional and stereologic estimations of myocardial capillary exchange capacity in treated and untreated spontaneously hypertensive rats

Myocardial capillary exchange capacity was investigated by stereologic and functional techniques in parallel during pressure-overload cardiac hypertrophy and after long-term antihypertensive therapy with the vasodilator felodipine. In 26-week-old female spontaneously hypertensive rats (SHR) blood pressure increased by 25 % and left ventricular weight (LVW/BW) increased by 18% compared to Wistar-Kyoto rats (WKY). Myocardial capillary surface and volume densities normalized for organ weight were similar in both ventricles for both strains. Moreover, capillary surface density was higher sub-epicardially (EPI) than in the subendocardium (ENDO) in the left ventricle of SHR. Thirteen weeks of felodipine-therapy (SHR-Felo) normalized blood pressure without affecting LVW/BW although a transition from concentric to eccentric hypertrophy is known to occur. Myocardial capillary surface and volume densities and the left ventricular ENDO-EPI-gradient in surface density were similar to untreated SHR. However, felodipine-treatment increased right ventricular weight and capillary volume density. Functional capillary exchange was estimated in terms of permeability surface area products (PS) for Cr-EDTA and vitamin B₁₂ and normalized for organ weight. PS_cr-EDTA, PS_B12 and the ratio PS_cr-EDTA/PS_B12 (an index of capillary permeability) were similar in SHR and WKY. Furthermore, the relation between functional and stereological indices of exchange capacity was investigated in a multiple linear regression analysis. However, no significant correlation between PS and neither capillary surface nor volume density was found. In conclusion, myocardial capillary exchange capacity was well adapted to the pressure overload cardiac hypertrophy present in female SHR. Despite induction of right ventricular hypertrophy, felodipine-treatment did not affect capillary exchange capacity. Furthermore, when functional and stereologic estimates were performed in parallel, the importance of dynamic factors for myocardial capillary exchange capacity (e.g. heterogeneity) was illustrated.     

Left ventricular hypertrophy improves cardiac performance in spontaneously hypertensive rats

Cardiac function was studied in spontaneously breathing, adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY). By rapid intravenous blood infusion, the relation between left ventricular end-diastolic pressure (LVEDP) and stroke volume (SV) was determined while the cardiac nervous control was pharmacologically blocked. Since SV is greatly influenced by the level of afterload (mean arterial pressure, MAP), SV was also determined at increased MAP (constriction of abdominal aorta) and at decreased MAP (vasodilation by hydralazine). At low LVEDP levels, a righward shift of the Frank-Starling relationship was observed in SHR. This rightward shift seems mainly to depend on the increased MAP present in SHR since it was less prominent if MAP was lowered to normotensive levels in SHR. Maximal SV during volume infusion was similar in SHR and WKY, despite a much higher MAP in SHR. When peak SV was instead compared at similar MAP levels for both (either at ‘normotensive’ or ‘hypertensive’ levels) it was always significantly greater in SHR, and was increased largely in proportion to their increased left ventricular weight. This indicates that the left ventricular hypertrophy present in SHR is, at least at this stage, a physiological adaptation of the heart to increase its performance, in order to maintain a normal SV and hence cardiac output, despite an increased arterial pressure.     

氯沙坦逆转高血压大鼠心肌重塑的实验研究

目的探讨氯沙坦对自发性高血压大鼠(SHR)心肌重塑的影响。方法16周龄雄性SHR20只,随机分为氯沙坦治疗组和SHR对照组。同龄雄性WKY鼠10只作为正常对照组。给予氯沙坦每天30mg/kg溶于饮水灌胃治疗17周。测定动脉收缩压、左心室壁的厚度、左心室重量与体重之比(LVW/BW)。透射电镜评估左心室肥厚(LVH)的程度。用真彩色图像分析系统计算左心室胶原容积分数。结果氯沙坦治疗组血压、LVW/BW、左室壁厚度与SHR对照组相比明显降低,但与WKY相比有所升高。透射电镜下氯沙坦治疗组心肌的超微结构与WKY相似,SHR的结构有异常改变。与SHR对照组相比,氯沙坦治疗组左心室胶原容积分数下降。结论氯沙坦能有效地降低SHR的血压、逆转高血压左室重塑。     

脑内ACE2基因过表达对高血压前期大鼠血压进展和氧化应激的影响

目的:观察下丘脑室旁核内血管紧张素转换酶2(angiotension-converting enzyme 2,ACE2)基因过表达对高血压前期大鼠血压进展和中枢氧化应激的影响,并探讨ACE2基因中枢降压的分子机制.方法:ACE2基因以慢病毒为载体,载体上携带增强型绿色荧光蛋白(enhanced green fluore...