Influence of spontaneous hypertension and cardiac hypertrophy on the severity of ischemic arrhythmias in the rat

Summary Cardiac hypertrophy (CH) and hypertension (HT) are major determinants of sudden cardiac death in patients with coronary artery disease. To investigate the hypothesis that CH and HT increase the incidence of severe ventricular arrhythmias in an animal model, we performed a 30-min period of coronary artery ligation in anesthetized spontaneously hypertensive rats (SHR), normotensive Wistar Kyoto (WKY) and Wistar (W) rats. The incidence and duration of ventricular fibrillation resulting from coronary artery occlusion were significantly (p<0.01) increased in hypertensive rats compared to normotensive animals. The calcium entry blocker nicardipine was administered orally to SHR either chronically for 8 weeks (20 mg·kg^–1 twice daily) or acutely as a single dose of 20 mg·kg^–1. After long-term treatment with nicardipine, left ventricular hypertrophy index and systolic blood pressure were significantly (p<0.001) reduced when compared to vehicle-treated SHR, whereas a single administration of nicardipine only decreased blood pressure without affecting cardiac mass. In the long-term nicardipine-treated SHR group, acute coronary artery ligation induced significantly less ventricular fibrillation (p<0.05) and mortality (p<0.001) than in acutely nicardipine-treated or untreated SHR groups. In conclusion, the data suggest that the severity and incidence of lethal ventricular arrhythmias are more elevated in hypertensive than in normotensive rats and this may be related to the myocardial hypertrophic state.     

Effects of chronic hypertension and left ventricular hypertrophy on the extent of infarct expansion in rats

Left ventricular hypertrophy is an adaptive response to long standing hypertension. However, the influence of left ventricular hypertrophy with hypertension on extent of infarct expansion has not been studied. We compared the effects of left ventricular hypertrophy with hypertension on infarct expansion in spontaneously hypertensive rats (SHR, n = 76), Wistar-Kyoto rats (WKY; n = 46) and spontaneously hypertensive rats treated with delapril, an angiotensin converting enzyme (ACE) inhibitor (SHRD; n = 39). The survival rates at 7 days after myocardial infarction were 41%, 24%, and 46% for WKY, SHR, and SHRD. The survival rate of SHR was significantly lower than those of both SHRD and WKY (P < .05). In the surviving rats (18 SHR, 19 WKY, 18 SHRD), both left ventricular cavity area (LCVA) and the infarct segment length per the noninfarct segment length (FW/IVS), measured as indices of left ventricular dilation, were significantly less in SHR and SHRD than in WKY, and the thickness of the left ventricular free wall (Wth), used as an index of left ventricular thinning, was significantly higher in both SHR and SHRD than in WKY (P < .01). However, there was no significant difference in FW/IVS, LCVA, and Wth between SHR and SHRD. Hemodynamic findings 1 week after coronary occlusion demonstrated that all rats were in heart failure, and there were no significant differences in hemodynamics among the three groups. In conclusion, our findings showed that hypertrophy with hypertension reduced infarct expansion, but that reduction of blood pressure by ACE inhibitor did not reduce infarct expansion more than hypertrophy did. However, this finding suggests that an ACE inhibitor may improve the rate of survival of patients with left ventricular hypertrophy with hypertension.     

Effects of duration and severity of arterial hypertension and cardiac hypertrophy on coronary vasodilator reserve

Cardiac hypertrophy is associated with a decrease in coronary reserve. However, factors which may modulate the interaction between myocardial growth and vascular proliferation, such as duration and severity of hypertrophy, have not been evaluated. We measured myocardial perfusion with microspheres in conscious, chronically instrumented. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats at 3, 7, and 15 months of age; and in SHR stroke-prone (SHR-SP) rats at 13-14 months of age. Myocardial perfusion was measured with microspheres in awake rats at rest and during maximal coronary dilation produced by dipyridamole infusion (2.0 mg/kg per min, iv). Arterial pressure was significantly elevated (P less than or equal to 0.05) in all hypertensive groups (vs. age-matched WKY), both at rest and during dipyridamole infusion. Left ventricular mass in the SHR rats was increased significantly (P less than or equal to 0.05) by 14%, 28%, and 29% at 3, 7, and 15 months, respectively. Left ventricular mass in the SHR-SP group was increased by 50% (P less than or equal to 0.05) compared to the 15-month-old WKY. Left ventricular minimal coronary vascular resistance (per gram) was significantly greater (P less than or equal to 0.05) in SHR at 7 months, and in the SHR-SP group (66% and 60%, respectively). Right ventricular minimal coronary vascular resistance was significantly greater (P less than or equal to 0.05) in SHR at 7 and 15 months (50%), and in the SHR-SP group (122%), compared to 15-month-old WKY. The results indicate the following: (1) the increase in minimal coronary vascular resistance between SHR and WKY rats was greatest when left ventricular hypertrophy peaked (7 months) and was no longer present after left ventricular hypertrophy had stabilized. (2) In 14-month-old SHR-SP rats, with more severe left ventricular hypertrophy and hypertension, minimal coronary vascular resistance was considerably higher than in SHR of approximately the same age. (3) Long-term arterial hypertension was associated with a higher right ventricular minimal coronary vascular resistance. Resistance appeared to change in proportion to the severity of hypertension, and the changes were independent of the presence of right ventricular hypertrophy.     

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.     

Reflex cardiovascular responses to somatic stimulation in spontaneously hypertensive rats

OBJECTIVES: This study aimed to test whether the cardiovascular responses to somatic stimulation in spontaneously hypertensive rats (SHR) were enhanced compared with those in normotensive Wistar-Kyoto (WKY) rats, and to examine any role of the impaired baroreflex function in the hypertensive rats. METHODS: Experiments were done in anaesthetized SHR (n = 34) and WKY (n = 31). Baroreceptor reflexes were assessed by continuous infusion of incremental doses (5-30 microg/kg per min) of phenylephrine over a 3 min infusion period. Cardiovascular responses to sciatic nerve stimulation (5 s trains, 1 ms pulse duration, 400 microA intensity) were studied before and after baroreceptor deactivation. The latter was achieved either by carotid occlusion and cutting the vagi and aortic nerves (SHR, n = 28 and WKY rats, n = 27), or by complete baroreceptor denervation (SHR, n = 6 and WKY rats, n = 4). RESULTS: We confirmed that baroreceptor sensitivity was significantly lower in SHR (0.40 +/- 0.05 ms/mmHg) than in WKY rats (0.90 +/- 0.04 ms/mmHg). Sciatic nerve stimulation elicited significantly greater increases in mean arterial pressure (MAP) and in heart rate in SHR than in WKY rats (+32.5 +/- 1.9 mmHg versus +20.2 +/- 1.1 mmHg and +13.5 +/- 1.5 bpm versus +8.0 +/- 1.1 bpm, respectively). Following baroreceptor deactivation, the responses to the same sciatic nerve stimulation of MAP and heart rate in SHR (+38.5 +/- 2.4 mmHg and +15.5 +/- 1.5 bpm) were still significantly greater than those in WKY rats (+29.5 +/- 1.3 mmHg and +11.6 +/- 1.2 bpm). CONCLUSIONS: These results show that cardiovascular responses to sciatic nerve stimulation are increased in SHR compared to WKY rats, and that this increased reactivity to somatic stimuli in hypertensive rats does not depend upon the impairment in baroreflex function demonstrated in this strain.     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Effects of a protocol of ischemic postconditioning and/or captopril in hearts of normotensive and hypertensive rats

Brief periods (a few seconds) of cyclic coronary occlusions applied early in reperfusion induce a cardioprotection against infarct size, called postconditioning (PostC) in which B₂-bradykinin receptors play a pivotal role. Since angiotensin-converting enzyme (ACE) inhibitors reduce degradation of kinins, we studied the effects of PostC on infarct size and postischemic myocardial dysfunction in both normotensive (WKY) and spontaneously hypertensive rats (SHR) acutely or chronically treated with the ACE inhibitor Captopril. Isolated hearts from SHR and WKY rats were subjected to the following protocols: (a) ischemia for 30- and 120-min reperfusion (I/R); (b) I/R + PostC protocol (5-cycles 10-s I/R); (c) pretreatment with Captopril for 4-weeks before to subject the hearts to I/R with or without PostC maneuvers. Some SHR hearts were treated with Captopril during the 20- or 40-min early reperfusion with or without PostC maneuvers. Cardiac function was assessed in vivo with echocardiography. Left ventricular pressure and infarct size were measured ex vivo. Chronic Captopril significantly reduced left ventricular hypertrophy in SHR, and reduced infarct size in both WKY and SHR hearts. PostC maneuvers significantly reduced infarct size in WKY, but not in SHR hearts. Yet, PostC slightly improved postischemic systolic function in untreated SHR. Captopril given in reperfusion was unable to limit I/R injury in SHR hearts. Data show that PostC protection against infarct size is blunted in SHR and that PostC is unable to add its protective effect to those of chronic Captopril, which per se reduces cardiac hypertrophy and heart susceptibility to I/R insult.     

Increase in G(i alpha) protein accompanies progression of post-infarction remodeling in hypertensive cardiomyopathy

Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.     

Impaired nitric oxide production and enhanced autoregulation of coronary circulation in young spontaneously hypertensive rats at prehypertensive stage.

In the current study, we investigated the NO-generation pathway in response to mechanical stimuli in SHR at the prehypertensive stage. To examine the role of NO in coronary autoregulation, we evaluated the effects of L-NAME on the coronary flow in SHR at both the prehypertensive and hypertensive stages. Isolated perfused hearts from 5- and 15-week-old SHR and from age-matched Wistar-Kyoto rats (WKY) were used. After stabilization at 60 mmHg, perfusion pressure was immediately raised to 90 mmHg to record the change in coronary flow for 10 min without (control) or with NO synthesis blockade by Nomega-nitro-L-arginine methyl ester (L-NAME). NOx- (nitrite/nitrate) was measured in coronary effluent. At 5 weeks of age, SHR did not have hypertension, while the coronary autoregulation was enhanced. L-NAME did not affect this enhanced autoregulation in 5-week-old SHR. At perfusion pressures of both 60 and 90 mmHg, 5-week-old SHR showed less coronary NOx- production than age-matched WKY. At 15 weeks, SHR showed a higher blood pressure than WKY. The coronary autoregulation in SHR remained higher than that in WKY, but was below that in 5-week-old SHR. NOx- production in 15-week-old SHR recovered to the level of age-matched WKY. These results indicate that NOx- production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the prehypertensive stage, which may have enhanced coronary autoregulation. An impaired nitric oxide production may precede the onset of hypertension in SHR.     

Comparative effects of candesartan and enalapril on augmented vasoconstrictive responses to endothelin-1 in coronary vessels of spontaneously hypertensive rats

BACKGROUND: The aim of this study was to compare the effect of angiotensin type-1 receptor blockade (ARB) on augmented vasoconstrictive response to endothelin-1 (ET-1) in coronary vessels of hypertensive hearts with angiotensin converting enzyme (ACE) inhibitor, candesartan cilexetil (CAN) or enalapril was administered for 3 weeks in spontaneously hypertensive rats (SHR). METHODS: We used SHR (9 to 12 weeks old, n = 18) and Wistar-Kyoto (WKY) rats (n = 6). Systolic blood pressure was measured once a week. Spontaneously hypertensive rats were divided into three groups. Enalapril malate (10 mg/day) or CAN (10 mg/day) was administered orally in each of six SHR in each group receiving treatment for 3 weeks. The control group (n = 6) received no treatment. At the end of this experiment, the hearts were isolated. Isolated hearts mounted on a Langendorff apparatus after weighing were then perfused with modified Krebs-Henseleit buffer at constant pressure (75 mm Hg). The coronary perfusion pressure and coronary flow were measured during perfusion of isolated hearts. Coronary vascular resistance (CVR; mm Hg/mL/min/100 g) was calculated. RESULTS: The ET-1 elicited increases in CVR dose-dependently in both normotensive and hypertensive rat hearts. However, the responses were significantly greater in SHR than in WKY rat. Chronic treatment with enalapril or candesartan inhibited the development of hypertension and cardiac hypertrophy equally in SHR. Augmented vasoconstrictive responses to ET-1 were significantly reduced in treated SHR. There was no difference in these effects between enalapril and candesartan. CONCLUSION: These findings suggest that both ACE inhibitors and ARB can equally inhibit augmented coronary vascular response to ET-1 in hypertensive hearts.     

复方降压片对高血压大鼠冠状动脉壁肥厚和储备力下降的影响

目的 研究复方降压片对高血压大鼠冠状动脉壁肥厚和储备力下降的影响。方法 4w大鼠设4组：分别为自发性高血压大鼠(SHR)组、SHR口服复方降压片组、SHR口服卡托普利组和正常血压大鼠(WKY)组，饲养12w。冠脉最大血流量用离体心脏灌注法测定。结果 复方降压片能显著降低SHR收缩压、冠状动脉横截面积，提高最大冠状动脉流量，与卡托普利相似。复方降压片能降低SHR的左心室重与体重比，但仍然显著高于WKY组和口服卡托普利组。结论 复方降压片能预防SHR冠状动脉壁肥厚、储备力下降，减轻左心室肥厚；冠状动脉血流储备力的损害程度和左心室肥厚程度不平行。     

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

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

Potentiation of the baroreceptor-heart rate reflex by sympathectomy in conscious rats

In both animals and humans, stimuli leading to sympathetic activation are accompanied by an impairment of the baroreceptor-heart rate reflex. To determine whether sympathetic activity normally interferes with this reflex function we examined in conscious Wistar-Kyoto (WKY) rats the effect of chemical sympathectomy by 6-hydroxydopamine on the bradycardic response to baroreceptor stimulation induced by raising blood pressure via intravenous phenylephrine boluses; control rats received vehicle. Spontaneously hypertensive rats were also studied because in these animals there is both a baroreceptor reflex impairment and a sympathetic overactivity. Baroreceptor reflex sensitivity, calculated as the ratio of the peak increase in pulse interval to the peak increase in mean arterial pressure, was 75% greater in sympathectomized WKY rats than in control WKY rats (1.28 +/- 0.15 versus 0.73 +/- 0.10 msec/mm Hg, mean +/- SEM; p less than 0.01). The sympathectomy-induced increase in sensitivity was even larger in spontaneously hypertensive rats (SHR) (1.26 +/- 0.12 versus 0.44 +/- 0.06 msec/mm Hg in sympathectomized SHR versus control SHR, +186%; p less than 0.01) so that the impaired baroreceptor reflex sensitivity observed in control SHR as compared with control WKY rats (-40%, p less than 0.01) was no longer detectable in the sympathectomized groups. To establish whether the sympathectomy-induced potentiation of the reflex was due to an increase in cardiac responsiveness to vagal stimuli, we subjected separate groups of anesthetized, vagotomized SHR and WKY rats to graded electrical stimulation of the right efferent vagus. The bradycardic effects of vagal stimulation, however, were similar in sympathectomized and control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Short-Term Treatment of SHR With the Novel Calcium Channel Antagonist Mibefradil on Function of Small Arteries

Treatment of spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) for at least 12 weeks with calcium channel antagonists is associated with regression of structural hypertensive changes in the heart and in conduit and small arteries. To establish whether structural or functional changes of small arteries could be corrected with shorter periods of specific antihypertensive treatment, SHR and WKY were treated for 4 weeks with the novel calcium channel blocker mibefradil. Blood pressure rise was significantly reduced by mibefradil treatment in SHR to 165 ± 1 mm Hg compared to a systolic blood pressure of 183 ± 2 mm Hg in untreated SHR (P < .01). Aortic hypertrophy in SHR was slightly reduced by treatment, but small artery hypertrophy in 4 vascular beds (mesenteric, renal, coronary, and femoral) was unaffected by administration of mibefradil for 4 weeks. Mibefradil treatment resulted in normalization of endothelium-dependent relaxation in mesenteric small arteries, with disappearance of acetylcholine-induced contractions, although hypertrophy and remodeling of these small arteries were not significantly affected by treatment. In WKY rats, treatment had no effect on either structure or function of small arteries. These results demonstrate that treatment with the calcium antagonist mibefradil may induce an improvement in altered endothelial function even before regression of cardiovascular hypertrophy and remodeling takes place under treatment, indicating that normalization of abnormal small artery endothelial function in SHR under antihypertensive therapy may be independent of correction of altered small artery structure.     

Early,Short-Term Treatment with Captopril Permanently Attenuates Cardiovascular Changes in Spontaneously Hypertensive Rats

The purpose of the current study was to determine if early, short-term treatment of spontaneously hypertensive rats (SHR) with captopril would cause a persistent attenuation of the structural alterations of the heart, aorta, and coronary arteries that are commonly seen in adult SHR. Therefore, mating pairs of SHR were treated with captopril and the pups were kept on captopril (SHRC) or were taken off captopril at two months (SHROC). Untreated SHR and Wistar-Kyoto (WKY) rats were mated and served as controls. At 8–10 months of age, heart weight and left ventricular weight/body weight ratios were increased in SHR compared to WKY, SHRC, and SHROC. Aortic medial areas of SHR and SHROC were similar and were larger than WKY and SHRC. Nuclear density in SHR and SHROC was less than WKY and SHRC suggesting hypertrophy of the medial wall. In coronary vessels, medial thickness was greatest in SHR, while there was no difference among WKY, SHRC, SHROC. These data suggest that early, short-term treatment of SHR with captopril permanently attenuated the structural alterations in the heart and coronary vessels that are commonly seen in adult SHR.     

Reduced left ventricular hypertrophy following long-term water deprivation in the young spontaneously hypertensive rat

Biochemical and physical parameters of cardiac hypertrophy accompanying hypertension were studied in water deprived versus non-deprived immature spontaneously hypertensive rats (SHR) and their normotensive progenitor strain, Wistar Kyoto (WKY). A 23.5 hour/day water deprivation schedule was maintained from 5 to 13 weeks of age in 23 SHR and 8 WKY rats to compare the non-deprived animals (16 SHR and 8 WKY controls). Water deprived SHR had lower left ventricular weight, lower total protein and hydroxyproline and the same total DNA as the non-deprived SHR. DNA concentration was higher in the deprived SHR than in the non-deprived SHR. No differences were found among the four groups in right ventricular weight or DNA concentration. Left to right ventricular weight ratio was significantly lower and left to right ventricular DNA concentration ratio significantly higher in the deprived SHR relative to non-deprived SHR. These data indicate that the water deprived SHR, which was less hypertensive than the non-deprived SHR, had less hypertrophy of their left ventricles. While water deprivation lowered mean arterial pressure in the WKY, also, there was no effect on left ventricular weight or biochemical indices of left ventricular cell size and cell number.     

The characteristics of renal hemodynamics in diabetic spontaneously hypertensive rats in comparison with diabetic Wistar-Kyoto rats

Diabetic Sprague-Dawley (SD) rats are known to exhibit renal hyperfiltration and hyperperfusion accompanied by renal hypertrophy. We examined whether such characteristics of renal hemodynamics in diabetic SD rats are also observed in diabetic spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. SHR and WKY rats were divided into four groups: D-S, diabetic SHR; N-S, nondiabetic SHR; D-W, diabetic WKY rats; and N-W, nondiabetic WKY rats. Streptozotocin (STZ), 90 mg, was intraperitoneally injected to induce diabetes. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate and insulin, respectively, 7–12 days after diabetes induction. In D-S and D-W, there was no increase in the kidney weight and RBF, in spite of significant increases in GFR and fasting blood sugar levels. These results indicate that, in both WKY and SHR, diabetes does not always produce renal hypertrophy and does not result in an increase in RBF.     

HSP 70.2:新的高血压致病相关基因?

目的探讨HSP70·2基因是否是新的高血压致病相关基因。方法从13周龄的自发性高血压大鼠(SHR)和正常血压(WKY)大鼠的阻力血管(肠系膜动脉第二、三级分支)和肾脏组织中提取总RNA,与含10000个基因及EST片断的SBC-R-RC-100-13大鼠表达芯片进行杂交,找出差异表达的基因,并经RT-PCR和real-timeRT-PCR初步筛选出高血压新的相关基因。结果基因芯片在SHR组中发现19个上调基因,另外也发现19个基因表达下调,其中涉及细胞周期,直接参与代谢的酶,细胞信号转导及核转录因子等基因。RT-PCR和定量RT-PCR证实HSP70·2基因在SHR组中表达上调2·1倍(P<0·01)。结论HSP70·2基因可能和高血压相关,深入研究HSP70·2基因及其功能为进一步了解高血压病的分子机制提供新的思路和线索。     

Cardiac aging, calcium overload, and arrhythmias

The effect of aging was tested on experimental ventricular arrhythmias in isolated heart preparations from normal Wistar rats (NWR), Wistar Kyoto rats (WKY), and spontaneously hypertensive rats (SHR). Delayed afterdepolarizations and triggered activity induced by high-calcium perfusion (16 mM) in isolated papillary muscles were more frequent in the 24-month-old than in 6-month-old NWR. Reperfusion-VA were more severe in 14-month-old SHR than in WKY. The authors have previously shown that: (1) reperfusion- and reoxygenation-induced VA, in the isolated Langendorff perfused heart, were significantly more severe and frequent in 24-month-old than in 6-month-old NWR; (2) no age-related difference in the incidence of programmed electrical stimulation (PES, train of stimuli + 1 or 2 extrastimuli)-induced VA was observed in isolated NWR hearts during control perfusion, after coronary artery ligation or during hypoxia; (3) on the contrary, the incidence of PES-induced VA was significantly higher in isolated hearts from 14-month-old SHR than from 3-month-old SHR, and 3-month-old and 14-month-old WKY. It was concluded that "physiological" aging is associated with a higher propensity to calcium-related VA, while "pathological" aging characterized by hypertension of long duration increases the incidence of PES-induced VA, probably caused by myocardial fibrosis, which could facilitate reentry.     

Improved myocardial efficiency in the working perfused heart of the spontaneously hypertensive rat

We assessed the relationship between determinants of myocardial oxygen demand--wall stress, peak rate of change of pressure and heart rate--and measured myocardial oxygen consumption over a range of loading conditions in the perfused, working heart of 6-month-old spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY). Two isolated heart preparations, an aortic-ejecting heart and an isovolumically contracting preparation with and without isoproterenol (10(-7)M) added, were employed. Under a constant perfusion pressure of 110 mm Hg, the heart rate, developed wall stress, and peak rate of change of pressure were not different between the two groups, but coronary flow and myocardial oxygen consumption were significantly lower in the SHR. Systolic values of myocardial high energy phosphate compounds (adenosine 5'-triphosphate, phosphocreatine) and myocardial lactate in the two preparations were not significantly different between SHR and WKY. Following adenosine infusion at maximum developed pressure (isovolumic preparation), both SHR and WKY demonstrated preservation of coronary reserve. These results indicate that cardiac hypertrophy represents a compensatory adaptation with improved mechanical efficiency in the 6-month-old SHR when maximally stressed and may be related to the shift from V1 to V2 and V3 isomyosin phenotypes that was observed in the hypertensive animals.