Myocardial function during chronic food restriction in isolated hypertrophied cardiac muscle

BACKGROUND: The effect of food restriction (FR) on myocardial performance has been studied in normal hearts. Few experiments analyzed the effects of undernutrition on hearts subjected to cardiac overload. The aim of this study was to determine whether chronic FR promotes more significant changes in hypertrophied hearts than in normal hearts. METHODS: Myocardial performance was studied in isolated left ventricular papillary muscle from young male spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY) submitted to FR or to control diet. The animals subjected to FR were fed 50% of the amount of food consumed by control groups for 60 days. Isolated muscles were studied while contracting isometrically and isotonically. RESULTS: FR decreased the body weight and the left ventricular weight in both groups. FR increased the left ventricular weight-to-body weight ratio in the WKY rats and tended to decrease this ratio in SHR (P = 0.055). The arterial systolic pressure was greater in SHR than in WKY groups and did not change with FR. In the animals with normal diet, myocardial performance was better in SHR than in WKY. FR increased time to tension to fall from peak to 50% of peak tension and time to peak tension in the WKY rats and time to peak tension in the SHR. CONCLUSIONS: FR for 60 days has a trend to attenuate the development of cardiac hypertrophy and does not promote more mechanical functional changes in the hypertrophied myocardium than in the normal cardiac muscle.     

Effects of hypertrophy and allylamine-induced fibrosis on mechanical properties of isolated rat heart muscles with references to the pumping function of the intact heart in the same models

To examine the effects of hypertrophy and fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 6-month-old male SHR and allylamine-fed rats. In SHR, the peak developed tension (DT) and the maximum rate of tension development (dT/dt) were higher compared to control male Wistar-Kyoto rats (WKY). With 15 min of hypoxia, the DT and the dT/dt declined similarly in both groups and the ratios of DT and dT/dt to their prehypoxic values after 15 min of hypoxia were not different in the two groups. From allylamine-fed rats, only 4 papillary muscles had more than 25% interstitial fibrosis by point-counting (AL-B group), but 9 muscles had no fibrotic involvement and their left ventricular hydroxyproline concentration was normal (AL-A group). The myocardial diameters, the passive stiffness constant and the duration of isometric contractions at Lmax were increased in AL-B group, but the resting tension, the DT at Lmax and the force-velocity relations did not differ from controls. The mechanical properties of the AL-A group muscles were not different from controls. However, when pumping function was examined in the intact heart from the AL-A group, the LVEDP was increased and the peak cardiac output normalized by body weight was decreased. Thus, hypertrophied muscle from SHR shows hyperfunction without an increase in susceptibility to hypoxic stress. Even if fibrosis progresses, hypertrophy can compensate for the reduction in contractile component up to a certain degree.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneously occurring hypertrophic cardiomyopathy in the rat. I. Pathologic features

The gross anatomic and microscopic appearance of the hearts of young and adult WKY/NCrj rats was examined in comparison with that of normotensive Wistar and SHR/NCrj rats. In a substantial number of the WKY rats, the heart weight and thickness of ventricular septum were much greater than those of the Wistar and SHR rats. The ventricular septum to left ventricular free wall thickness ratio was greater than 1.3 in about one sixth of the WKY rats. In most of the hypertrophied WKY hearts, the transverse area of the left ventricular cavity was smaller in relation to the wall area than in the Wistar and SHR rat hearts, although in a few it was greater. Abnormal fiber arrangement, myocyte hypertrophy, and myocardial fibrosis were far more prominent in the hypertrophied myocardium of the WKY rats compared with the Wistar or SHR rats. Intramural arteries with marked wall thickening existed frequently in the hypertrophied and dilated hearts. Electron microscopic examination revealed marked disarrangement of bundles of myofilaments and widened Z-bands in the hypertrophied myocardium. Blood pressure was not elevated in the rats with cardiac hypertrophy. These findings show that a disease of the myocardium with the pathologic features similar to those of hypertrophic cardiomyopathy in man occurs spontaneously in rats.     

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.     

Compensated function in hypertrophied ventricles of Wistar Kyoto and spontaneously hypertensive rats

STUDY OBJECTIVE--The aim of the study was to compare the compensatory nature of left ventricular hypertrophy in models of normal and increased peripheral resistance. DESIGN--Peak left ventricular performance was compared in normotensive Wistar Kyoto (WKY) rats, in a subset of this strain with biventricular hypertrophy associated with volume overload (WKY-CH), and in spontaneously hypertensive rats (SHR), all studied at one year of age (ie, long term hypertrophy). SUBJECTS--8 WKY-CH rats with biventricular hypertrophy were compared with 8 WKY (normal right and left ventricular weights). These groups were then compared with 9 SHR rats. All were maintained under identical conditions. MEASUREMENTS AND MAIN RESULTS--Left ventricular to body weight ratios (mg:g) were as follows: WKY-CH 2.78(SEM 0.09); SHR 2.90(0.09); WKY 2.10(0.09). Systolic blood pressures (mm Hg) were normal in WKY-CH [104(9)] and WKY [111(9)], but raised in SHR [163(8)]. Left ventricles from WKY and WKY-CH had normal histology and no fibre disorientation, fibrosis, or other morphological abnormalities. Peak cardiac index (ml.min-1.body weight-1) measured during rapid volume expansion with Tyrode's solution was higher in WKY-CH [427(33)] than in WKY [315(33)] and SHR [349(31)] (p less than 0.05). When peak stroke volume was expressed per mg left ventricular weight there were no significant differences between the groups. Peripheral resistance (mean arterial pressure divided by cardiac output) at peak cardiac output was higher in SHR [1.20(0.12)] than in either WKY-CH [0.57(0.08)] or WKY [0.74(0.08)]. CONCLUSIONS--These data show that both types of hypertrophy enhance peak left ventricular performance. In WKY-CH, which have normal peripheral resistance, the larger ventricle allows a higher peak cardiac index compared to WKY with no left ventricular hypertrophy. In SHR, the higher left ventricular mass is used to overcome an increased peripheral resistance and thereby provide a normal peak cardiac index.     

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.     

Cardiac mechanical dysfunction induced by ischemia-reperfusion in perfused heart isolated from stroke-prone spontaneously hypertensive rats

We investigated the difference in mechanical function after ischemia and reperfusion between Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) or stroke-prone SHR (SHRSP) using the isolated working heart model, in order to examine postischemic mechanical dysfunction in the severely hypertrophied heart. Systolic blood pressure of SHRSP was higher than that of SHR and WKY, and the left ventricular wall in SHRSP was thicker than in WKY. Mechanical dysfunction of the heart during reperfusion following ischemia (11 min) in SHRSP was severer than that in SHR and WKY, and recovery of the cardiac energy charge potential (ECP) level in SHRSP was lower than that in SHR and WKY. Twenty-five, 12 and 11 min-ischemia in WKY, SHR and SHRSP, respectively, caused a similar level of cardiac mechanical damage. Also, the ECP levels were almost equivalent among them at the end of 20 min reperfusion following each time of ischemia. Under each ischemic condition, a Ca2+-channel blocker, diltiazem, and an adenosine potentiator, dilazep, produced a beneficial effect on the post-ischemic dysfunction in SHR and WKY. However, neither cardioprotective drug led to recovery of the mechanical dysfunction of the heart during reperfusion following ischemia in SHRSP. Thus, the severely hypertrophied heart such as that in SHRSP was more susceptible to cardiac reperfusion dysfunction, than the moderately hypertrophied heart such as that in SHR. These results suggest that the cardioprotective effects of drugs may be deteriorated in severe hypertrophied hearts.     

Cardiac Mechanical Dysfunction Induced by Ischemia‐reperfusion in Perfused Heart Isolated from Stroke‐prone Spontaneously Hypertensive Rats

We investigated the difference in mechanical function after ischemia and reperfusion between Wistar‐Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) or stroke‐prone SHR (SHRSP) using the isolated working heart model, in order to examine postischemic mechanical dysfunction in the severely hypertrophied heart. Systolic blood pressure of SHRSP was higher than that of SHR and WKY, and the left ventricular wall in SHRSP was thicker than in WKY. Mechanical dysfunction of the heart during reperfusion following ischemia (11 min) in SHRSP was severer than that in SHR and WKY, and recovery of the cardiac energy charge potential (ECP) level in SHRSP was lower than that in SHR and WKY. Twenty‐five, 12 and 11 min‐ischemia in WKY, SHR and SHRSP, respectively, caused a similar level of cardiac mechanical damage. Also, the ECP levels were almost equivalent among them at the end of 20 min reperfusion following each time of ischemia. Under each ischemic condition, a Ca^{2 +}‐channel blocker, diltiazem, and an adenosine potentiator, dilazep, produced a beneficial effect on the post‐ischemic dysfunction in SHR and WKY. However, neither cardioprotective drug led to recovery of the mechanical dysfunction of the heart during reperfusion following ischemia in SHRSP. Thus, the severely hypertrophied heart such as that in SHRSP was more susceptible to cardiac reperfusion dysfunction, than the moderately hypertrophied heart such as that in SHR. These results suggest that the cardioprotective effects of drugs may be deteriorated in severe hypertrophied hearts.     

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.     

Mechanical and morphological properties of arterial resistance vessels in young and old spontaneously hypertensive rats.

We studied alterations in structural and mechanical properties of mesenteric arterial resistance vessels from young (6-week) and old (50-week) spontaneously hypertensive (SHR)and matched normotensive Wistar-Kyoto (WKY) rats. Emphasis was placed upon relating the active tension capabilities of these vessels to their smooth muscle cell content. Cylindrical segments, 0.7 mm long with internal diameters of 150 micrometer, were mounted in a myograph capable of recording circumferential vessel wall tension and dimensions. Comparisons of vessel morphology and mechanics were performed at a normalized internal circumference, L1,where active tension (delta T1) is near maximum. Arterial wall and medial hypertrophy were observed in young and old SHR. Since the percent smooth muscle cells within the media for SHR was similar to that of WKY, both increased smooth muscle cell and connective tissue content account for the medial hypertrophy. These differences in SHR vessels were reflected directly in their passive and active mechanical properties. Fully relaxed vessels from SHR were less compliant, and upon activation at L1 (high potassium depolarization), delta T1 was not different for young SHR and WKY, but values for old SHR were 35% greater (P less than 0.05) than for WKY. When relating the active force generation of the vessel to the actual smooth muscle cell area, values for smooth muscle cell stress (force/area) were similar for SHR and WKY at both ages. In addition, similarities were observed for active dynamic mechanical measurements of Young's modulus and half response time. Genetic hypertension in rats therefore appears to be associated with the development of increased vessel contractility determined by a greater number of smooth muscle cells which possess contractile properties similar to those of normotensive vessels.     

Immunoreactive atrial natriuretic peptide in ventricles, atria, hypothalamus, and plasma of genetically hypertensive rats

To evaluate the role of extra-atrial atrial natriuretic peptide (ANP) in volume and blood pressure regulation, the plasma, atrial, ventricular, and hypothalamic levels of immunoreactive atrial natriuretic peptide (IR-ANP) were measured simultaneously in the spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at the ages of 2, 6, and 12 months. Plasma IR-ANP in the 12-month-old, conscious SHR was significantly higher than that of the WKY (300 +/- 18 versus 200 +/- 20 pg/ml, p less than 0.05, n = 9), while no differences in plasma IR-ANP levels were found between the strains in younger rats. Acute volume expansion with saline (1.1 ml/100 g body wt) in hypertensive as well as in normotensive rats resulted in marked increases in right atrial pressure and plasma IR-ANP concentration. The older SHR had attenuated ANP release to volume loading as shown by the shift of the ANP versus right atrial pressure curve to the right. Right auricular IR-ANP concentration decreased, while that of left auricle increased with increasing age in both strains. No substantial differences were noted in auricular ANP concentration between SHR and WKY. However, the total atrial IR-ANP content (micrograms/atria) was consistently lower in SHR compared with WKY. In both ventricles, IR-ANP concentrations and contents increased with increasing age in WKY and SHR, but the ventricular levels of ANP were reduced in ventricles of the SHR heart compared with normotensive controls. The depletion of total ventricular IR-ANP was greatest in SHR with greatest ventricular hypertrophy and coincided with the attenuated ANP release to acute volume load. The increase of left but not right ventricular weight occurring secondary to 6 weeks minoxidil treatment was accompanied by higher ANP concentration in both strains. In contrast to the ventricles, the hypothalamic IR-ANP concentration was significantly increased in SHR compared with that of WKY and decreased in both strains after 6 weeks' treatment with antihypertensive drugs. Thus, ventricular and hypothalamic, as well as atrial, ANP respond to increased pressure overload in genetically hypertensive rats. Our results suggest that chronic stimulation of ANP release from ventricles is associated with depleted stores of ANP from both ventricles and reduced response to acute volume load. Our findings that ventricular ANP increased with increasing weight and in response to a hypertrophic stimulus in WKY and was decreased in SHR with severe ventricular hypertrophy suggest that ANP may locally have an inhibitory effect on the development of cardiac hypertrophy.     

Nuclear DNA content and nucleation patterns in rat cardiac myocytes from different models of cardiac hypertrophy.

Nuclear DNA content and number of nuclei were examined in cardiac myocytes isolated from controls and rats with volume and pressure overload hypertrophy to determine if haemodynamic overload alters these nuclear parameters. The experimental groups were comprised of normotensive (WKY) and Spontaneously Hypertensive rats (SHR). Additionally, Sprague-Dawley rats with aortic constriction (AC), pulmonary stenosis (PS), myocardial infarction (MI), and 5 month arteriovenous fistulas (F) were studied along with appropriate shams for each of these groups. Nuclear DNA content was measured from DAPI-stained nuclei using an image analysis microdensitometry system. Myocyte volume was measured with a Coulter Channelyzer system. Approximately 83% of the left ventricular myocytes from the SHR and WKY groups contained a diploid DNA content with the remainder being tetraploid. The remaining experimental and sham groups, all female Sprague-Dawley rats (SD), were approximately 93% diploid. The nucleation patterns differed slightly between rat strains with the SHR/WKY expressing approximately 85% binucleation, 14% mononucleation and 5% tri- or tetranucleation. All SD groups, control and hypertrophied, showed approximately 89% binucleation, and 10% mononucleation with the remainder being tri- or tetranucleated. In summary: (1) cardiac myocytes from SHR/WKY strains are predominantly diploid but to a lesser degree than myocytes from SD; (2) nuclear number follows the same pattern with SHR/WKY showing a smaller percentage of binucleated myocytes than SD myocytes; (3) neither the duration, severity, or type of overload caused a significant change in the extent of polyploidy in overloaded hearts from SD rats; and (4) the extent of polyploidy in cardiac myocytes from both the right and left ventricles of SHR and WKY animals does not differ statistically.     

The role of the renin-angiotensin and cardiac sympathetic nervous systems in the development of hypertension and left ventricular hypertrophy in spontaneously hypertensive rats.

To elucidate the relationship between the development of left ventricular hypertrophy (LVH) in hypertension and the development of both the cardiac sympathetic nervous and renin-angiotensin systems, as measured by norepinephrine and angiotensin II levels, respectively. In this longitudinal study, we compared blood pressure (BP), left ventricular weight, and norepinephrine (NE) and angiotensin II (Ang II) concentrations, in Spontaneously Hypertensive Rats (SHR) and age-matched Wistar-Kyoto (WKY) rats at 5, 10, 15, 20, and 28 wk of age. Blood pressure, plasma and ventricular Ang II and tissue NE were measured by the tail-cuff method, radioimmunoassay, and high-performance liquid chromatography (HPLC), respectively. At 5 wk, systolic blood pressure was the same in both strains. But the left ventricular plus septum weight to body weight (LVSW/BW) ratio was higher in SHR than in WKY rats (p < 0.01), which finding may have been related to the increased cardiac tissue NE concentration, and this increase tended to parallel the rise in blood pressure. Both left ventricle and forelimb muscle NE concentrations were significantly higher in SHR than in WKY rats at 5, 10, and 15 wk of age (p < 0.01, respectively), and were similar at 20 and 28 wk of age. The heart and plasma Ang II levels decreased with age, which results were in keeping with the known developmental tendencies of the biological aging progress. There was no significant difference in plasma Ang II levels between the two strains from 5 to 20 wk, whereas these levels were remarkably higher in WKY than in SHR rats at 28 wk (p< 0.01). Otherwise, the left ventricular tissue Ang II concentrations were significantly higher in SHR than in WKY rats at the late stage (from 15 to 28 wk), which may have contributed to the late-stage cardiac hypertrophy. These results suggested that the sympathetic nervous system (SNS) and the renin-angiotensin-system (RAS) in SHR may contribute to the pathogenesis of hypertension and LVH at the early and late stages, respectively.     

Cosegregation analysis in genetic crosses suggests a protective role for atrial natriuretic factor against ventricular hypertrophy.

In most rat models studied to date, increased ventricular mass is associated with high ventricular expression of the atrial natriuretic factor (ANF) gene. However, it is unknown whether ANF plays a beneficial or detrimental role in the course of left ventricular hypertrophy or whether ANF gene expression could be genetically linked to cardiac mass. To address such questions, we performed a cosegregation analysis in genetic crosses of inbred strains of rats. To select strains with the appropriate phenotypic characteristics, we first compared the ventricular abundance of ANF mRNA to ventricular mass (corrected for body weight) in 2 recombinant inbred strains derived from Wistar-Kyoto (WKY)/spontaneously hypertensive rat (SHR) hybrid crosses, ie, WKY-derived hyperactive (WKHA) and WKY-derived hypertensive (WKHT) rats, as well as in their parental inbred strains. In the 2 such strains that were normotensive, we observed that ventricular mass was higher in WKHA than in WKY rats, yet ventricular ANF mRNA was less abundant in WKHA than in WKY rats. Within a segregating population of F2 animals generated from a cross between WKY and WKHA genitors, the abundance of ventricular ANF mRNA and peptide correlated inversely with left ventricular mass, in contrast to the positive correlation observed with beta-myosin heavy chain mRNA. Finally, in the equally hypertensive SHR and WKHT strains, we found that ventricular mass was higher in SHR than in WKHT, yet ventricular ANF mRNA was less abundant in SHR than in WKHT. These results demonstrate for the first time that low ventricular ANF gene expression can be linked genetically to high cardiac mass independently of blood pressure and are consistent with a protective role for ANF against left ventricular hypertrophy.     

Differential development of vascular and cardiac hypertrophy in genetic hypertension. Relation to sympathetic function

We compared blood pressure, hindquarter vascular resistance properties, left ventricular weight, and norepinephrine kinetics, in spontaneously hypertensive rats (SHR) and weight-matched normotensive Wistar-Kyoto (WKY) rats at 4, 9, 14, 20, 30, and 50 weeks of age. At 4 weeks, systolic and mean blood pressure measurements were the same in both strains, but the vascular resistance of the fully dilated hindquarter bed was significantly higher in SHR than in WKY rats, with a much larger difference during maximum constriction. Plots of resistance at maximum dilatation and at maximum constriction against body weight suggest that a component of the increase in vascular muscle mass in SHR occurred in the neonatal period preceding hypertension followed by a later component related to the rise in blood pressure. By contrast, left ventricular hypertrophy was minimal at 4 weeks and most of its development paralleled the rise in blood pressure. Sympathetic activity, assessed by norepinephrine fractional rate constant, was higher in SHR than in WKY rats in the left ventricle and kidney through most of the period between 4 and 50 weeks, but was similar in both strains in the muscle bed. This pattern of sympathetic activity will accentuate hypertension once cardiac and vascular hypertrophy are fully established. In all regions, norepinephrine tissue concentration was higher in young SHR and could potentiate the trophic effects of growth factors in early vascular hypertrophy. We suggest that the initial (primary) component of vascular hypertrophy precedes the rise in blood pressure and may be critical in the pathogenesis of hypertension. Possible reasons for the short delay in the rise in blood pressure in young SHR, once the vascular "amplifier" has been established, include high vascularity, immaturity of smooth muscle, and delay in the development of left ventricular hypertrophy.     

Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats

OBJECTIVE: To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. RESULTS: Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. CONCLUSIONS: Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.     

原癌基因c—myc,c—fos在自发性高血压大鼠左心室的表达

目的 探讨ＳＨＲ左心室肥厚时原癌基因ｃ－ｍｙｃ，ｃ－ｆｏｓ表达的变化及其意义。 方法 １６周龄的雄性ＳＨＲ在测量收缩压和体重后处死，年龄、性别和数量配对的正常血压的ＷＫＹ为对照组。取左心室称重，异硫氰酸胍酸－酚氯仿一步法提取组织总ＲＮＡ，用＾３２Ｐ标记的ｃ－ｍｙｃ，ｃ－ｆｏｓ ｃＤＮＡ探针行Ｎｏｒｔｈｅｒｎ杂交，同时取左心室组织制备蛋白抽提物进行法提取组织总ＲＮＡ，用＾３２Ｐ标记的ｃ－ｍｙｃ，ｃ－     

Effect of Long-Term Treatment with Diltiazem on Atrial Natriuretic Peptides in Spontaneously Hypertensive Rats

ABSTRACT

The present study was designed to examine the possible effect of long-term treatment with diltiazem on plasma and atrial concentrations of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR). Diltiazem treatment reduced blood pressure and ventricular weight in SHR. Plasma ANP concentration in untreated SHR was higher than Wistar-Kyoto rats (WKY). Diltiazem treatment decreased plasma ANP concentration in SHR near to the level of WKY; moreover, plasma ANP concentration was correlated with blood pressure and ventricular weight in treated and untreated SHR. Left atrial ANP concentration in untreated SHR was lower than WKY. Diltiazem treatment increased left atrial ANP concentration in SHR, but this effect was not noted in WKY. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that the prevention of an increase in plasma ANP by diltiazem treatment may be, in part, attributed to the improvement of cardiac overload induced by reductions in blood pressure and cardiac hypertrophy.     

Differential regulation of IGF-I, its receptor and GH receptor mRNAs in the right ventricle and caval vein in volume-loaded genetically hypertensive and normotensive rats.

It has been suggested, mainly by in vitro findings, that cardiovascular tissue in the spontaneously hypertensive rat (SHR) should be more prone to proliferate/hypertrophy than that of the Wistar-Kyoto rat (WKY). The present study tests the hypothesis that the tissue of the low-pressure compartment in SHR, being structurally similar to that of the WKY, shows an increased growth response due to activation of the GH-IGF-I system. An aortocaval fistula (ACF) was induced in 64 SHR and WKY male rats and 44 rats served as controls. They were all followed for 1, 2, 4 and 7 days after surgery. In separate groups of SHR (n=4) and WKY (n=3), central venous pressure was measured by telemetry recordings prior to opening of the fistula and for up to 16 h post-surgery. Systolic blood pressure was measured during the week post-surgery. The right ventricular (RV) and the caval vein IGF-I mRNA and RV IGF-I receptor and GH receptor mRNAs were quantitated by means of solution hybridisation assay. In rats with ACF the systolic blood pressure decreased, approximately 29% in SHR and 16% in WKY between 1 and 7 days post-surgery (P<0.05, n=5-6 in each group). SHR with ACF showed a transient elevation in central venous pressure vs WKY. Within the week following fistula induction both strains showed a similar, pronounced increase in RV hypertrophy. SHR with ACF showed a smaller, or even blunted, overall response with respect to activation of the GH-IGF-I system compared with WKY, the latter showing clear-cut elevation of gene expressions. Two days after shunt opening in SHR, RV and caval vein IGF-I mRNA increased by 57% and 108% (P<0.05 for both, n=5-6 in each group) respectively, and these expressions were then turned off, whereas RV GH receptor and IGF-I receptor mRNA expression remained unaffected compared with WKY rats. WKY rats showed on average a later and a greater response of GH-IGF-I system mRNA expression vs SHR. The present in vivo study suggests that the SHR requires less activation of the GH-IGF-I system for creating a given adaptive structural growth response.     

Ventricular performance in spontaneously hypertensive rats (SHR) with reduced cardiac mass

Summary This study was designed to investigate the effect of 4 weeks of captopril treatment on cardiac mass and performance in spontaneously hypertensive rats (SHR). Left (LV) and right (RV) ventricular mass of SHR and normotensive WKY rats was reduced (p<0.01). Mean arterial pressure (MAP) and total peripheral resistance index (TPRI) in the treated SHR and WKY were reduced; cardiac (CI) and stroke (SI) indices remained unaltered in SHR but increased in WKY. Ventricular performance (i.e., cardiac pumping ability), assessed by rapid blood infusion, did not differ between untreated SHR and WKY, and between treated and untreated WKY rats. However, the ventricular performance curves for the treated SHR shifted down and to the right from the untreated SHR (p<0.01). Moreover, when MAP of treated SHR (with regressed LV mass) was elevated to their pretreatment levels, cardiac performance curves shifted further rightward and downward. In contrast, the performance curves of treated WKY whose MAP was also elevated to the level of untreated WKY were no different from those of untreated WKY. These data demonstrate that captopril treatment (at doses used in this study) reduced MAP in SHR through decreased TPRI while decreasing biventricular mass. Furthermore, the cardiac-pumping ability of previously hypertrophied SHR hearts was reduced, suggesting that certain antihypertensive agents that diminish cardiac mass could produce impaired cardiac function when called upon to increase performance (e.g., when MAP is suddenly raised).