Protective effects of N-(2-mercaptopropionyl)-glycine against ischemia–reperfusion injury in hypertrophied hearts

The beneficial effects of N-(2-mercaptopropionyl)-glycine (MPG) against ischemia–reperfusion injury in normotensive animals have been previously studied. Our objective was to test the action of MPG during ischemia and reperfusion in hearts from spontaneously hypertensive rats (SHR). Isolated hearts from SHR and age-matched normotensive rats Wistar Kyoto (WKY) were subjected to 50-min global ischemia (GI) and 2-hour reperfusion (R). In other hearts MPG 2 mM was administered during 10 min before GI and the first 10 min of R. Infarct size (IS) was assessed by TTC staining technique and expressed as percentage of risk area. Postischemic recovery of myocardial function was assessed. Reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and SOD cytosolic activity — as estimators of oxidative stress and MnSOD cytosolic activity — as an index of (mPTP) opening were determined. In isolated mitochondria H₂O₂-induced mPTP opening was also measured. The treatment with MPG decreased infarct size, preserved GSH levels and decreased SOD and MnSOD cytosolic activities, TBARS concentration, and H₂O₂ induced-mPTP opening in both rat strains. Our results show that in both hypertrophied and normal hearts an attenuation of mPTP opening via reduction of oxidative stress appears to be the predominant mechanism involved in the cardioprotection against reperfusion injury MPG-mediated.     

Expression and activity of the glutamate transporter EAAT2 in cardiac hypertrophy: implications for ischaemia reperfusion injury

The expression and activity of the glutamate transporter, excitatory amino acid transporter 2 (EAAT2), in cardiac hypertrophy were investigated with respect to glutamate’s potential as a cardioprotective agent. Sarcolemmal vesicles (SV) isolated from hypertrophic hearts of male spontaneously hypertensive rats (SHR) or normotrophic hearts from age-matched male Wistar Kyoto rats (WKY) were used to measure the relative level of EAAT2 expression by Western blotting and the initial rate of 0–0.3 mM l-[¹⁴C]glutamate uptake. The effects of 20-min global normothermic ischaemia ±0.5 mM glutamate on cardiac function were measured in isolated working SHR/WKY hearts. In a separate series of hearts, glutamate, lactate and ATP levels were measured. Both the level of EAAT2 expression and the V _max for sodium-dependent l-[¹⁴C]glutamate uptake were significantly greater in SHR SV compared to WKY SV. The reperfusion cardiac output (CO) of SHR hearts was significantly worse than that of the WKY hearts (24.3±2.2 ml/min vs 39.8±3.3 ml/min, n=7/9±SE, p<0.01). The addition of 0.5 mM l-glutamate improved the SHR reperfusion CO to 45.2±5 ml/min, (n=6±SE, p<0.01) but had no effect on WKYs (46.2±3.8 ml/min, n=6±SE). SHR with 0.5 mM l-glutamate had higher glutamate levels at the start of ischaemia, plus higher glutamate and ATP levels at the end of ischaemia compared to any other group. These results suggest that increased glutamate transporter expression and activity in the SHR hearts helped facilitate glutamate entry into the SHR cardiomyocytes leading to improved myocardial metabolism during ischaemia and better functional recovery on reperfusion.     

Transmural progression of morphologic changes during ischemic contracture and reperfusion in the normal and hypertrophied rat heart.

The purpose of this study was to compare the functional and morphologic changes that occur during ischemic contracture and reperfusion in the normal and hypertrophied heart. Hearts from Sprague-Dawley, spontaneously hypertensive (SHR), and normotensive Wistar-Kyoto rats were evaluated using a modified Langendorff perfusion apparatus. After obtaining control data, hearts were potassium-arrested, made ischemic, and studied at various time points. Regional coronary flow was assessed with the use of radiolabeled microspheres or Microfil dye infusion, and morphologic changes were evaluated by means of light and electron microscopy. Sarcomere length changes and qualitative morphologic changes during global ischemia demonstrate a transmural progression of ischemic damage starting at the endocardium and extending, with time, epicardially. The progression of ischemic changes in hypertrophied hearts of SHRs was similar to that of normal hearts; however, hypertrophied hearts developed ischemic contracture sooner than normal hearts. In addition, the development of contraction band change after ischemic contracture occurred only when hearts were reperfused and was related to the development of no-reflow.     

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。     

Hämodynamische Wirkungen von Disopyramid auf postischämisches und normales Myokard

Summary The acute effects of i.v. disopyramide (1.5 mg/kg) on the hemodynamics of postischemic hearts were investigated in comparison to normal ventricles. Infusion (7 min) was started in rats 20 min after 3×4 min of global ischemia during the period of stable postischemic dysfunction. 15 minutes after disopyramide i.v. (vs. NaCl control data) the cardiac output was reduced to 82±4% (vs. 101±5%;p<0.01) anddp/dt _max to 77±5% (vs. 83±3%). The maximum isovolumic pressure generating capacity as load-independent index of myocardial contractility was reduced to 89±2% (vs. 95±2%;p<0.05). In contrast to the results on postischemic myocardium no measureable change of the hemodynamics was detectable after the identical dose in normal animals without left ventricular dysfunction. Our results indicate an increased sensitivity of postischemic myocardium with modestly reduced contractile function to the hemodynamic effects of disopyramide, especially to the negative-inotropic effects.

Mit Unterstützung der Deutschen Forschungsgemeinschaft, Bonn (HO 1003-2)     

Lipid peroxidation and myocardial vulnerability in hypertrophied SHR myocardium.

In a comparison using age-matched Wistar-Kyoto rats (WKY), 16-week-old male spontaneously hypertensive rat (SHR) hearts were examined histologically and biochemically on the first and fourth day after administration of 20 mg/kg doxorubicin in order to examine whether membrane abnormalities in hypertrophied SHR myocardium are caused by lipid peroxidation. Morphological examination of the SHR revealed focal myocytolysis on the first day and severe cardiomyopathy involving diffuse myocytolysis and vacuolar degeneration in the left ventricle on the fourth day. The activity of a membrane-related enzyme, Na+/K(+)-ATPase, was already lower in control SHR than that of control WKY and was lower in both SHR and WKY than in the respective saline groups on the first day after administration, whereas the enzyme activity in the doxorubicin-treated SHR was not significantly different from that of the treated WKY. A thiobarbituric acid-reactant substance, a lipid peroxidation marker, was significantly higher in treated SHR than it was in the treated WKY on the first day. Furthermore, in comparison with WKY, alpha-tocopherol in the left ventricle in SHR was significantly lower on the fourth day after administration. These results show that a proneness to lipid peroxidation in the membrane system is closely associated with severity of doxorubicin-induced cardiomyopathy in SHR and suggests that membrane lipid peroxidation may cause a higher degree of vulnerability in hypertrophied SHR myocardium.     

Albumin decreases hydrogen peroxide and reperfusion injury in isolated rat hearts

Perfusion with human serum albumin decreased myocardial hydrogen peroxide (H₂O₂) levels (as assessed by inactivation of myocardial catalase activities following ammotriazole pretreatment) and increased myocardial ventricular developed pressures (DP), contractility (+dP/dt) but not relaxation rate (-dP/dt) in isolated crystalloid perfused rat hearts subjected to normothermic global ischemia (20 min) and then reperfusion (40 min). Albumin also decreased H₂O₂ concentrations in vitro. The findings support the possibility that albumin may act as a protective O₂ metabolite scavenger in vivo.     

Cellular distribution of calcium current is unaltered during compensated hypertrophy in the spontaneously hypertensive rat

Changes in cellular calcium (Ca²⁺) handling are thought to underlie the altered contraction that occurs during cardiac hypertrophy and failure. Recent work has highlighted the importance of t-tubules in the control of intracellular Ca²⁺. The present study was performed to investigate whether changes in the distribution of I _Ca between the surface and t-tubule membranes might contribute to the altered Ca²⁺ handling observed during compensated hypertrophy in the spontaneously hypertensive rat (SHR). Experiments were performed on ventricular myocytes isolated from 5-month-old SHR and normotensive Wistar-Kyoto (WKY) control rats. Osmotic shock using formamide was used to disrupt the t-tubular system and the whole-cell patch clamp technique used to monitor I _Ca in the presence and absence of t-tubules. Membrane capacitance and I _Ca were greater in control SHR than WKY myocytes; following detubulation, cell capacitance and I _Ca both decreased and were no longer significantly different in the two cell types. The density of I _Ca was not significantly different in control SHR and WKY cells or in detubulated myocytes from the two species. These data suggest that the distribution of I _Ca is unchanged in SHR myocytes compared to WKY controls; I _Ca density in the t-tubules was 1.2-fold greater than in the sarcolemma in both strains. These data also imply that the increase in surface area in SHR myocytes is due principally to an increase in t-tubular area, which is accompanied by an approximately equivalent increase in I _Ca, so that the density of I _Ca at the cell surface and in the t-tubules remains the same. These changes would be expected to retain cell function and synchronicity of Ca²⁺ release in the SHR at this stage of compensated hypertrophy.     

The effect of alkaline pH and transmural pressure on arterial constriction and membrane potential of hypertensive cerebral arteries

These studies were undertaken to examine the effect of alkalosis to modify pressure-induced activation of isolated cerebral arteries from spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. At pH 7.4 andPCO₂ of 34 torr elevation of transmural pressure from 0–140 mm Hg resulted in myogenic activation preceeded by membrane depolarization in both SHR and WKY. The degree of developed myogenic tone in SHR was elevated above WKY. Aklalosis (pH 7.4–7.7) depolarized and activated SHR cerebral arteries to a greater extent than WKY. Furthermore, both the electrical and mechanical responses to elevation in transmural pressure were exaggerated in SHR compared to WKY at pH 7.7 (PCO₂ constant at 34 torr).Manipulation ofPCO₂ at constant pH of 7.4 had similar effects on pressure-induced myogenic tone in both SHR and WKY. Thus, cerebral arteries from both SHR and WKY depolarize and develop myogenic tone in response to increasing transmural pressure. This response is augmented in SHR, but to a much greater extent upon elevation of extracellular pH, whilePCO₂ is maintained within normal limits. The implications of these findings are discussed.D. R. Harder is an Established Investigator of the American Heart Association and a Research Career Scientist of the Veterans Administration. This study supported by NIH grants 33833 and 31871 and the Veterans Adminstration.     

Losartan抗高血压左室肥厚的细胞学机制研究

目的:探讨细胞增殖与细胞凋亡在高血压左室肥厚中的作用及血管紧张素Ⅱ1型受体(AT₁受体)拮抗剂在体干预对其影响。方法:选用成年12及24周龄SHR和WKY大鼠,干预组SHR自12周龄起每日胃管灌饲losartan(15mg·kg^-1·d^-1)至24周龄止。称重法测量左室肥厚指数,免疫组化法检测PCNA的蛋白表达,TUNEL法原位检测细胞凋亡,半定量RT－PCR法检测fas mRNA表达。结果:SHR左室肥厚指数、心肌细胞凋亡率显著多于同龄WKY(P＜0.01),心肌成纤维细胞凋亡率显著低于同龄WKY(P＜0.05)。12周龄SHR心肌细胞PCNA阳性率显著高于同龄WKY(P＜0.05),心肌成纤维细胞阳性率在两组间无显著差异。24周龄WKY和干预组SHR无PCNA阳性细胞检出,24周龄SHR偶见阳性心肌细胞。干预组左室肥厚指数、心肌细胞凋亡率显著低于同龄SHR组,成纤维细胞凋亡率显著高于同龄SHR组。各组大鼠心肌组织中fasmRNA表达量与细胞凋亡率呈正相关(r=0.52,P＜0.05)。结论:成年SHR左室肥厚的细胞学变化表现为心肌细胞的增殖/凋亡的失衡,以及心肌成纤维细胞凋亡的减少。losartan抗成年SHR左室肥厚的机制可能与改变这种异常的细胞群体变化及调节fas基因的表达有关。     

Anaerobic chemical changes and mechanical output during isometric tetani of rat skeletal muscle in situ

The time course was examined of the energy-rich phosphate usage and exerted isometric tetanic force in electrically stimulated rat quadriceps muscle. The maximal rate of energy-rich phosphate usage was calculated from the changes in the intramuscular concentrations of phosphocreatine, lactate, ATP and inosine monophosphate (IMP) and was somewhat higher than those calculated on the basis of exercise in vivo. The IMP concentration increased directly from the onset of the contraction until after about 11 s it remained constant. The increase in the IMP concentration coincided with a decrease in the ATP concentration. The relationship between mechanical output and energy usage was examined in two wasy (i) by calculating the ratio time integral of the force (FTI) and the total energy-rich usage (P _tot) and (ii) by calculating the ratio Force (F _t) to the energy flux (dP _tot/dt) at a certain timet.Whereas the ratio FTI/P _tot showed a hyperbolic relationship, the ratioF _t/(dP _tot/dt) showed a parabolic relationship From the latter finding and from the results described in the literature it is concluded that the ratio mechanical output/energy-rich phosphate usage depends on the conditions under which exercise is carried out. Recovery under aerobic conditions from a maximal tetanic isometric contraction sustained for 15 s was slow compared to results of experiments in vivo.     

Increased sodium-dependent D-glucose transport in the jejunal brush-border membrane of spontaneously hypertensive rat

The current studies explore the effect of hypertension on D-glucose transport into jejunal brush-border membrane vesicles (BBMV). Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, as a control group, were used. The purity of the BBMV from both groups of animals was validated by the finding that the specific activity of brush-border enzyme marker, sucrase, was severalfold greater in membrane vesicles compared with corresponding values in mucosal homogenate. D-glucose uptake was Na⁺ dependent in both groups of animals, with a transient increase in the intravesicular concentration of D-glucose. However, the initial rate and the magnitude of the accumulation of Na⁺-dependent D-glucose was significantly higher in SHR compared with WKY rats. In order to investigate the mechanism(s) for the increase in Na⁺-dependent D-glucose transport in SHR, several experiments were performed: (1) an experiment that indicated ²²Na uptake, as an indicator for Na⁺ permeability, was similar between SHR and WKY rats, (2) kinetic studies that indicated that V _max values of SHR were significantly greater that those of WKY rats. In contrast, similar K _m values for glucose were found between SHR and WKY rats, (3) Na⁺-dependent phlorizin binding measurements that were not altered by hypertension and (4) a study of the brush-border membrane lipid composition that showed a significant increase in the free cholesterol/phospholipid ratio in SHR. We conclude that altered membrane cholesterol content and consequently altered lipid fluidity could be, at least in part, responsible for the observed increase in Na⁺-dependent D-glucose transport in SHR. Received: 27 October 1995/Received after revision and accepted: 23 January 1996     

Adrenal α2-adrenergic receptors in the aging normotensive and spontaneously hypertensive rat

This study investigates α₂-adrenergic receptor (α₂AR) mediated feedback inhibition of catecholamine release from the adrenal medulla of adult (52 weeks) and old (98 weeks) spontaneously hypertensive rats (SHR) and normotensive controls Wistar Kyoto (WKY) rats. Adrenal epinephrine content as well as the spontaneous and the nicotinic-evoked release of epinephrine were similar between adult SHR and WKY rats. Aging produced a significant reduction in epinephrine synthesis in WKY rats. In contrast, in SHR aging produced a significant increase in epinephrine release without significant changes in epinephrine synthesis. The α₂AR agonist medetomidine abolished (80–90% inhibition) the nicotinic-evoked release of epinephrine in adult SHR and WKY rats. With aging, this effect was unaltered in WKY rats but was significantly decreased in SHR (30% inhibition). Adrenal α_2AAR mRNA levels were significantly reduced in old SHR compared with age matched WKY rats. In conclusion, in aging the α₂AR mediated feedback inhibition of epinephrine release from the adrenal medulla is preserved in WKY rats but compromised in SHR, resulting in increased epinephrine release.     

Augmented aftercontractions in papillary muscles from rats with cardiac hypertrophy.

Paired-pulse stimulation induced larger aftercontractions in papillary muscles from spontaneously hypertensive rats (SHR) than from normotensive Wistar-Kyoto rats (WKY). To determine whether aftercontraction exaggeration is a general characteristic of hypertrophied cardiac muscle, three models were examined: SHRs, deoxycorticosterone acetate (DOCA)-treated rats, and aorta-constricted rats. Responses of pipillary muscles from hypertrophied hearts tested under conditions conducive to aftercontraction generation were compared to pipillary muscles from WKY or sham-treated controls, respectively. Field-stimulated papillary muscles mounted in an oxygenated temperature-controlled physiologic salt solution were exposed to calcium concentrations of 2.5 and 5.0 mM, and temperatures of 27 degrees C and 17 degrees C. Although testing conditions influenced the contractile responses to single stimuli, there was no difference in active tension, time to peak tension, or one-half relaxation time between the three experimental groups and their respective controls. Paired-pulse stimulation induced aftercontractions that were enhanced in high-calcium and low-temperature solutions. Under these conditions, papillary muscles from hypertrophied hearts developed larger aftercontractions than did their respective controls.     

Diminished toxicity of ouabain in the hypertrophied rat heart

The responsiveness to ouabain of hypertrophied rat hearts has been investigated either in vivo using an isolated Langendorff rat heart perfused at various external calcium concentrations, or in vitro on purified sarcolemma vesicles. (i) The physiological study shows that at 0.25 mM CaCl₂, the positive inotropic effect of 10^–5 M ouabain was diminished in hypertrophied hearts (p<0.02). At 0.5 mM CaCl₂, the drug has no effect in controls, but it has a slight positive inotropic effect in hypertrophied hearts. At 2.50 mM CaCl₂, ouabain has a negative inotropic effect accompanied by extrasystoles in controls, but in hypertrophied hearts it still has a positive inotropic effect and is not arrhythmogenic. (ii) After the pretreatment of the hearts with 2.5 mM CaCl₂, the responsiveness of the (Na⁺, K⁺)-ATPase activity to ouabain was studied: the sarcolemma from hypertrophied heart contains half as many low affinity forms of (Na⁺, K⁺)-ATPase for ouabain (35%±6) than in controls (80%±2). Assuming that the low affinity forms are responsible for the toxic effect, these data correlate well with some of the physiological findings and suggest that the diminished toxicity for ouabain in hypertrophied hearts rather reflects a modification of the properties of the (Na⁺, K⁺)-ATPases than a change in the myocardial calcium metabolism.Supported by a grant from Caisse Nationale d'Assurances Maladie des Travailleurs Salariés (1986)     

Non-steady-state calcium handling in failing hearts from the spontaneously hypertensive rat

It is generally agreed that changes in Ca²⁺ cycling are often associated with heart failure, yet the impact of these changes on a beat-to-beat basis remains unclear. Measurements of isometric force and [Ca²⁺]_i were made at 37°C in left ventricular trabeculae from failing spontaneously hypertensive rat (SHR) hearts, and their normotensive Wistar–Kyoto (WKY) controls. At 1 Hz, peak stress was reduced in SHR (14.5?±?2.4 mN mm^?2 versus 22.5?±?6.7 mN mm^?2 for WKY), although the Ca²⁺ transients were bigger (peak [Ca²⁺]_i 0.60?±?0.08 μM versus 0.38?±?0.03 μM for WKY) with a slower decay of fluorescence (time constant 0.105?±?0.005 s versus 0.093?±?0.002 s for WKY). To probe dynamic Ca²⁺ cycling, two experimental protocols were used to potentiate force: (1) an interval of 30 s rest, and (2) a 30-s train of paired-pulses, and the recirculation fraction (RF) calculated for recovery to steady-state. No difference was found between rat strains for RF calculated from either peak force or Ca²⁺, although the RF was dependent on potentiation protocol. Since SR uptake is slower in SHR, the lack of change in RF must be due to a parallel decrease in trans-sarcolemmal Ca²⁺ extrusion. This view was supported by a slower decay of caffeine-induced Ca²⁺ transients in SHR trabeculae. Confocal analysis of LV free wall showed t-tubules were distorted in SHR myocytes, with reduced intensity of NCX and SERCA2a labelling in comparison to WKY.     

Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function: essential role of the proteasome

This study examined the hypothesis that postischemic levels of oxidized and/or ubiquitinated proteins may be predictive of functional recovery as they may be indicative of activity of the 20S and/or 26S proteasomes, respectively. Subjecting isolated rat hearts to 15 min of ischemia had no effect on 20S- and 26S-proteasome activities; however, both were significantly (p < 0.05) decreased by 70% and 54%, respectively, following 30 min of ischemia and 60 min of reperfusion, changes associated with increased levels of protein carbonyls and ubiquitinated proteins. Preischemic treatment of hearts with the proteasome inhibitor, MG132, resulted in dose-dependent decreases (p < 0.05) in recovery of postischemic function [MG132 (microM), heart rate x pressure product: 0, 11,158 +/- 2,423; 6, 11,400 +/- 3,009; 12, 5,513 +/- 2,225; 25, 2,325 +/- 992] and increased accumulation of ubiquitinated proteins. Preconditioning with repetitive ischemia (IP) or preischemic treatment with nicorandil (Nic) resulted in a significant increase in postischemic 20S-proteasome activity after 60 min of reperfusion (control, 95 +/- 4; IP, 301 +/- 65; Nic, 242 +/- 61 fluorescence units). Only Nic had similar effects on 26S-proteasome activity. These results support the conclusion that a correlation exists between eventual recovery of postischemic function and levels of oxidized and/or ubiquitinated proteins, a phenomenon that may be dependent on activity of the 20S and 26S proteasomes.     

Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis

This study determined whether exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial and apoptosis-associated genes. We used spontaneously hypertensive rats (n=15, non-exercise SHR), exercise-trained SHR (n=15, treadmill exercise for 12 weeks), and sedentary Wistar-Kyoto (WKY) rats (n=15). Exercise-trained SHR expressed adaptive changes such as reduced body weight, heart rate, blood pressures, left ventricle wall thickness, lipid profiles, and homocysteine level. The mRNA expression of angiotensin converting enzyme, endothelin-1, and brain natriuretic peptides in the heart was lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR, whereas mRNA expression of caveolin-3 and eNOS in the heart was higher. Bcl-2 protein was higher in the exercise-trained SHR than in the WKY and the non-exercise SHR. In contrast, Bax protein levels were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. Furthermore, the levels of the active forms of caspase-3 (20 kDa) were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. These findings suggest that exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial genes and that it interferes with a signal transduction pathway of apoptosis secondary to the pathological cardiac hypertrophy.     

Variations in arterioles in spontaneously hypertensive rats

Summary In the present study, the diameters of afferent and efferent arterioles of kidneys from spontaneously hypertensive rats (SHR) were evaluated and compared with those from Wistar Kyoto rats (WKY) using a vascular cast model. At 4 weeks of age, the blood pressure was slightly higher in SHR than in WKY (124±1 vs 116±7 mmHg, ns). The diameters of afferent arterioles in SHR were smaller than those in WKY (10.3±0.6 vs 12.3±0.7 µm,P<0.001), whereas the diameters of efferent arterioles were comparable in the two strains. At 20 weeks of age, the blood pressure was markedly elevated in SHR than in WKY (192±5 vs 140±4 mmHg,P<0.001). The diameters of afferent arterioles in SHR at this age were much smaller than those in WKY (14.3±0.5 vs 17.1±0.6 µm,P<0.01). The diameters of efferent arterioles in SHR were, however, larger than those in WKY (15.4±l.2 vs 12.9±0.4 µm,P< 0.05). The net effect of these changes in arteriolar size helps to maintain normal intraglomerular pressure and to protect glomeruli from damage due to hypertension.     

Increased plasma calcitonin levels in young spontaneously hypertensive rats: role in disturbed phosphate homeostasis

In young spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto controls (WKY) several parameters of phosphate and calcium homeostasis were determined. At 6 and 8 weeks, blood analysis revealed a significant hypophosphatemia (p<0.001) in SHR and twice as high plasma calcitonin levels in SHR than in WKY controls. At 8 weeks, 1,25-dihydroxycholecalciferol concentration was 20% higher in SHR (p<0.02) while 25-hydroxycholecalciferol was unaltered (p<0.51). In addition total immunoreactive PTH, iPTH, was slightly increased (p<0.07) but intact PTH (1–84) (p>0.90) was not significantly different from age matched WKY controls. Also at 8 weeks, a slightly reduced serum ionized Ca²⁺ concentration (p<0.001) with no change in total serum calcium was found in SHR (p>0.39). Balance studies at 6 and 8 weeks of age revealed no significantly different balances for phosphate (F=2.5,p>0.10) and for calcium (F=2.6,p>0.09), although a tendency for slightly more positive balaces existed in SHR when compared to WKY. However, SHR excreted significantly less phosphate in the urine than WKY control (F=0.2,p<0.0009). Bone analysis was performed on femora of SHR and WKY of 6 weeks of age. Femora were significantly shorter in SHR (20.54±0.35 vs. 21.50±0.05 mm in WKY), whereas bone dry weight (127±6 vs. 107±2mg), bone ash weight (79±4 vs. 66±1 mg) and bone volume (0.196±0.007 vs. 0.165±0.004 cm³) were significantly greater in SHR. Calcium content per femur (717±35 vs. 617±11 mol Ca/femur) and phosphate content per femur (512±23 vs. 447±8 mol P/femur) were also significantly higher in SHR. It is discussed that the disturbances in phosphate homeostasis may be secondary to the strikingly increased plasma calcitonin levels present in young SHR.