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PubMed2004

Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development.

Mitochondrial dysfunction subsequent to increased oxidative stress and alterations in energy metabolism is considered to play a role in the development of cardiac hypertrophy and its progression to failure, although the sequence of events remains to be elucidated. This study aimed at characterizing the impact of hypertrophy development on the activity and expression of mitochondrial NADP+-isocitrate dehydrogenase (mNADP+-ICDH), a metabolic enzyme that controls redox and energy status. We expanded on our previous finding of its inactivation through posttranslational modification by the lipid peroxidation product 4-hydroxynonenal (HNE) in 7-wk-old spontaneously hypertensive rat (SHR) hearts before hypertrophy development (Benderdour et al. J Biol Chem 278: 45154-45159, 2003). In this study, we used 7-, 15-, and 30-wk-old SHR and Sprague-Dawley (SD) rats with abdominal aortic coarctation. Compared with age-matched control Wistar-Kyoto (WKY) rats, SHR hearts showed a significant 25% decrease of mNADP+-ICDH activity, which preceded in time 1) the decline in its protein and mRNA expression levels (between 10% and 35%) and 2) the increase in hypertrophy markers. The chronic and persistent loss of mNADP+-ICDH activity in SHR was associated with enhanced tissue accumulation of HNE-mNADP+-ICDH and total HNE-protein adducts at all ages and contrasted with the profile of changes in the activity of other mitochondrial enzymes involved in antioxidant or energy metabolism. Two-way ANOVA of the data also revealed a significant effect of age on most parameters measured in SHR and WKY hearts. The mNADP+-ICDH activity, protein, and mRNA expression were reduced between 25% and 35% in coarctated SD rats and were normalized by treatment of SHR or coarctated SD rats with renin-angiotensin system inhibitors, which prevented or attenuated hypertrophy. Altogether, our data show that cardiac mNADP+-ICDH activity and expression are differentially and sequentially affected in hypertrophy development and, to a lesser extent, with aging. Decreased cardiac mNADP+-ICDH activity, which is attributed at least in part to HNE adduct formation, appears to be a relevant early and persistent marker of mitochondrial oxidative stress-related alterations in hypertrophy development. Potentially, this could also contribute to the aetiology of cardiomyopathy.

Aldehydes↗
PubMed2004

Regulation of atrial contraction by PKA and PKC during development and regression of eccentric cardiac hypertrophy.

ANG II plays a major role in development of cardiac hypertrophy through its AT1 receptor subtype, whereas angiotensin-converting enzyme (ACE) inhibitors are effective in reversing effects of ANG II on the heart. The objective of this study was to investigate the role of PKA and PKC in the contractile response of atrial tissue during development and ACE inhibitor-induced regression of eccentric hypertrophy induced by aortocaval shunt. At 1 wk after surgery, sham and shunt rats were divided into captopril-treated and untreated groups for 2 wk. Then isometric contraction was assessed by electrical stimulation of isolated rat left atrial preparations superfused with Tyrode solution in the presence or absence of specific inhibitors KT-5720 (for PKA) and Ro-32-0432 (for PKC) and high Ca2+. Peak tension developed was greater in shunt than in sham hearts. However, when expressed relative to tissue mass, hypertrophied muscle showed weaker contraction than muscle from sham rats. In sham rats, peak tension developed was more affected by PKC than by PKA inhibition, whereas this differential effect was reduced in the hypertrophied heart. Treatment of shunt rats with captopril regressed left atrial hypertrophy by 67% and restored PKC-PKA differential responsiveness toward sham levels. In the hypertrophied left atria, there was an increase in the velocity of contraction and relaxation that was not evident when expressed in specific relative terms. Treatment with ACE inhibitor increased the specific velocity of contraction, as well as its PKC sensitivity, in shunt rats. We conclude that ACE inhibition during eccentric cardiac hypertrophy produces a negative trophic and a positive inotropic effect, mainly through a PKC-dependent mechanism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Altered coenzyme A and carnitine metabolism in pressure-overload hypertrophied hearts.

Changes in the total content and acylation state of coenzyme A (CoA) and carnitine in the heart result in alterations in fatty acid metabolism that may be associated with ventricular dysfunction. The present study was undertaken to determine whether abnormal myocardial CoA and carnitine metabolism occur in pressure-overload hypertrophy and congestive heart failure. Right ventricular hypertrophy was induced in cats by pulmonary artery (PA) banding. Total tissue CoA was reduced by 50% in the hypertrophied right ventricle and 25% in the nonhypertrophied left ventricle of PA-banded cats in the presence or absence of heart failure. No alterations were observed in long-chain fatty acyl CoA levels in either ventricle of PA-banded cats. In addition, a 20% reduction in total CoA was also observed in hypertrophied hearts of rats subjected to aortic banding. Although the CoA content was reduced in hypertrophied cat hearts, myocardial tissue levels of its precursor, pantothenic acid, were unaltered. Total tissue carnitine and long-chain fatty acyl-carnitine levels were unchanged in both ventricles of PA-banded cats; however, total carnitine was reduced by 25% in hypertrophied rat hearts. This study establishes a marked reduction in myocardial CoA content in pressure-overload hypertrophy.

Animals↗
PubMed1987

Active force during hypoxia of hypertrophied rabbit right ventricular trabeculae.

Hypertrophy is often accompanied by increased myocardial oxygen demand, but any unique effects of hypoxia on contraction in hypertrophy are unknown. Trabeculae from normal [n = 9; 0.119 +/- 0.014 mm2 (means +/- SE) cross-sectional area] and hypertrophied (pulmonary artery constriction; n = 7; 0.108 +/- 0.028 mm2) rabbit right ventricles were subjected to graded hypoxia (Krebs-Ringer solution, 28 degrees C, 1 Hz stimulus frequency). During normoxia, peak active isometric (Pmax) and resting stress (Prest) at optimum length and peak rate of stress development (dP/dt) in hypertrophy were the same as normal and time to peak stress was longer than normal. Time to peak stress and dP/dt decreased with hypoxia, but time to peak stress remained longer than normal in hypertrophy; Prest was unchanged. The ratio of peak active stress (P) during hypoxia to Pmax decreased linearly with superfusate PO2, but the hypertrophy relationship (y = 4.00 X 10(-3) x + 0.084) is the same as normal (y = 3.70 X 10(-3) x + 0.154; p greater than 0.05). Therefore, a normal level of P was preserved in hypertrophied myocardium and prolonged time to peak stress might have been important for that preservation.

Animals↗
PubMed1988

Calcium currents in normal and hypertrophied isolated feline ventricular myocytes.

The magnitude and kinetics of the slow inward calcium current (Isi) were compared in single right ventricular myocytes that were isolated from normal cats and cats with right ventricular hypertrophy. Peak inward current density was greater in hypertrophy than normal myocytes (-20.4 +/- 15.3 vs. -10.4 +/- 8.8 microA/cm2, P less than 0.05). When we blocked early outward currents with intracellular CsCl, however, the peak magnitude of Isi was shown to be similar in hypertrophy and normal myocytes (-16.4 +/- 11.2 vs. -12.7 +/- 3.0 microA/cm2, P = NS). The increased net inward current in hypertrophy was thus due to a decrease in Cs-sensitive early outward current rather than an increase in the magnitude of Isi. The fast component of inactivation of Isi was similar in hypertrophy and normal myocytes, but the slow component was delayed in hypertrophy (slow time constant; tau slow = 75.9 +/- 14.7 ms vs. tau slow = 60.6 +/- 4.9 ms, P less than 0.05). These abnormalities of Isi may contribute to the prolonged duration of the action potential and of contraction in hypertrophied myocardium, but a defect in excitation-contraction coupling distal to Isi appears to produce the diminished magnitude of contraction.

Action Potentials↗
PubMed1990

Differential effects of caffeine on skinned fibers from control and hypertrophied ferret hearts.

The effects of caffeine on the mechanical properties of detergent-skinned fibers from control and pressure-overloaded ferret hearts have been compared. Right ventricle hypertrophy was studied 6 wk after pulmonary artery ligation, an intervention that increased the right ventricular weight-body weight ratio by 60%. Although no changes were observed in the Ca sensitivity of contraction between control [pCa for one-half-maximal activation (pCa50) = 5.80 +/- 0.05] and hypertrophied (pCa50 = 5.85 +/- 0.02) muscles, the leftward shift of the force-pCa relationship induced by caffeine was more pronounced in hypertrophied fibers than in control; pCa50, was 5.86 +/- 0.02, 5.94 +/- 0.01, 6.03 +/- 0.01 in control and 5.97 +/- 0.03, 6.10 +/- 0.03, 6.24 +/- 0.01 in control and 5.97 +/- 0.03, 6.10 +/- 0.03, 6.24 +/- 0.03 in hypertrophied fibers for 2, 5, 10 mM caffeine, respectively. This was accompanied in the hypertrophied muscles by a decrease in the Hill coefficient. On the other hand, maximal force was not affected by 10 mM caffeine. From these results it is possible that the site of action of caffeine in myofibrillar proteins is the thin filament. The increased responsiveness of hypertrophied fibers to caffeine may be mediated by a pressure overload-induced change in the thin filament regulatory proteins. Moreover, inotropic agents may act differently in hypertrophied than in control myocardium.

Animals↗
PubMed1994

Antioxidant changes in hypertrophied and failing guinea pig hearts.

Hypertrophy and heart failure were induced by placing a mildly constrictive band around the ascending aorta in young guinea pigs. Based on heart weight, left ventricular wall thickness, hemodynamic data, and other clinical signs, these animals were found to have physiological hypertrophy at 10 wk and congestive heart failure (CHF) at 20 wk. Hearts from these two groups of animals were examined for superoxide dismutase (SOD), glutathione peroxidase (GSHPx), and catalase activities as well as lipid peroxidation and glutathione [reduced glutathione (GSH)/oxidized glutathione (GSSG)] levels. There was an age-dependent increase in SOD activity and GSH content in sham controls. SOD activity was 28% higher in the 10-wk-hypertrophy group and 46% lower in the CHF group than in respective sham controls. GSHPx activity increased significantly in the hypertrophied hearts, whereas in the failing hearts, the activity was not different from the 20-wk controls but was significantly lower than in the hypertrophied hearts. Catalase activity did not change at either stage. GSH content in the hypertrophied hearts was significantly higher compared with sham controls. In the CHF group, GSH content was significantly lower and GSSG content was significantly higher than in sham controls. Lipid peroxidation, as indicated by malondialdehyde content, was significantly decreased in the hypertrophy group but increased toward control levels in the failure group. It is proposed that a relative deficit in myocardial antioxidant capacity as well as in the redox state may play a role in the pathogenesis of cardiac failure.

Animals↗
PubMed1994

Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts.

The contribution of glycolysis and oxidative metabolism to ATP production was determined in isolated working hypertrophied hearts perfused with Krebs-Henseleit buffer containing 3% albumin, 0.4 mM palmitate, 0.5 mM lactate, and 11 mM glucose. Glycolysis and glucose oxidation were directly measured by perfusing hearts with [5-3H/U-14C]glucose and by measuring 3H2O and 14CO2 production, respectively. Palmitate and lactate oxidation were determined by simultaneous measurement of 3H2O and 14CO2 in hearts perfused with [9,10-3H]palmitate and [U-14C]lactate. At low workloads (60 mmHg aortic after-load), rates of palmitate oxidation were 47% lower in hypertrophied hearts than in control hearts, but palmitate oxidation remained the primary energy source in both groups, accounting for 55 and 69% of total ATP production, respectively. The contribution of glycolysis to ATP production was significantly higher in hypertrophied hearts (19%) than in control hearts (7%), whereas that of glucose and lactate oxidation did not differ between groups. During conditions of high work (120 mmHg aortic afterload), the extra ATP production required for mechanical function was obtained primarily from an increase in the oxidation of glucose and lactate in both groups. The contribution of palmitate oxidation to overall ATP production decreased in hypertrophied and control hearts (to 40 and 55% of overall ATP production, respectively) and was no longer significantly depressed in hypertrophied hearts. Glycolysis, on the other hand, was accelerated in control hearts to rates seen in the hypertrophied hearts. Thus a reduced contribution of fatty acid oxidation to energy production in hypertrophied rat hearts is accompanied by a compensatory increase in glycolysis during low work conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1996

Impaired Ca2+ handling is an early manifestation of pressure-overload hypertrophy in rat hearts.

Both cytosolic free Ca2+ ([Ca2+]i) decline and myocardial relaxation are slowed in severe hypertrophy and heart failure. However, it is not certain whether this occurs in mild to moderate hypertrophy. Therefore, we tested the hypotheses that slowing of [Ca2+]i decline 1) occurs in mild to moderate hypertrophy, 2) occurs in the absence of slowed relaxation, and 3) is related to the degree of hypertrophy. Experiments were performed on isolated rat hearts subjected to pressure overload. Indo 1 fluorescence was used as an index of [Ca2+]i. [Ca2+]i decline and myocardial relaxation were assessed by the time constant of exponential [Ca2+]i decline (tau Ca) and left ventricular (LV) pressure decline (tau p), respectively. Mean tau Ca was significantly increased in hearts from banded rats compared with sham-operated rats (59 +/- 13 vs. 45 +/- 5 ms, P = 0.03). In contrast, there was no difference in mean tau p (28 +/- 3 vs. 29 +/- 5 ms, P = not significant). There was a linear relationship between tau Ca and LV dry weight (r = 0.79). In summary, slowing of the [Ca2+]i transient decline occurred in mild to moderate hypertrophy. However, LV relaxation was unaffected. Furthermore, slowing of the [Ca2+]i transient decline was closely related to the degree of LV hypertrophy. These data suggest that slowing of [Ca2+]i decline is an early manifestation of pressure-overload hypertrophy that precedes slowing of relaxation.

Animals↗
PubMed1975

Myocardial transcapillary exchange in the hypertrophied heart of the dog.

Myocardial transcapillary exchange was investigated in control hearts and in two types of hypertrophied hearts: exercise hypertrophy and pathological hypertrophy due to tricuspid insufficiency. Using the single-injection indicator diffusion method (6, 28), myocardial extractions (E), capillary clearances (C), and permeability surface area products (PS) of urea, sucrose, and inulin were measured in intact, pump-perfused, working hearts of anesthetized dogs. Both types of cardiac hypertrophy were associated with a decreased coronary vascular resistance. Myocardial E, C, and PS values from the exercised group were not significantly different from control. Dogs with pathological hypertrophy exhibited increased central venous pressures, RVEDP's, and heart rates which were greater than control values. The E, C, and PS values from the pathologically hypertrophied hearts were significantly greater than control. These increases in myocardial transcapillary exchange can be explained either by increasing the equivalent pore radius of myocardial capillary membranes from a control value of 70 to 100 A or by assuming that pathologically hypertrophied hearts have a myocardial capillary surface area available for exchange which is twice that of control hearts.

Animals↗
PubMed2004

Mechanisms of blood pressure variability-induced cardiac hypertrophy and dysfunction in mice with impaired baroreflex.

Enhanced blood pressure variability contributes to left ventricular hypertrophy and end-organ damage, even in the absence of hypertension. We hypothesized that the greater number of high-blood pressure episodes associated with enhanced blood pressure variability causes cardiac hypertrophy and dysfunction by activation of mechanosensitive and autocrine pathways. Normotensive mice were subjected to sinoaortic baroreceptor denervation (SAD) or sham surgery. Twelve weeks later, blood pressure variability was doubled in SAD compared with sham-operated mice. Blood pressure did not differ. Cardiac hypertrophy was reflected in greater heart/body weight ratios, larger myocyte cross-sectional areas, and greater left ventricular collagen deposition. Furthermore, left ventricular atrial and brain natriuretic peptide mRNA expression was greater in SAD than in sham-operated mice. SAD had higher left ventricular end-diastolic pressures and lower myocardial contractility indexes, indicating cardiac dysfunction. Cardiac protein content of phosphorylated p125 focal adhesion kinase (p125 FAK) and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) was greater in SAD than in sham-operated mice, indicating activation of mechanosensitive pathways of cardiac hypertrophy. Furthermore, enhanced cardiac renin and transforming growth factor-beta1 (TGFbeta1) protein content indicates activation of autocrine pathways of cardiac hypertrophy. Adrenal tyrosine hydroxylase protein content and the number of renin-positive glomeruli were not different, suggesting that sympathetic activation and the systemic renin-angiotensin system did not contribute to cardiac hypertrophy. In conclusion, more frequent blood pressure rises in subjects with high blood pressure variability activate mechanosensitive and autocrine pathways leading to cardiac hypertrophy and dysfunction even in the absence of hypertension.

Adrenal Glands↗
PubMed2001

Attenuation of inhibitory effect of CNP on the secretion of ANP from hypertrophied atria.

It has been shown that atrial natriuretic peptide (ANP) influences proliferation of cardiac cells. To define the possible role of C-type natriuretic peptide (CNP) in cardiac hypertrophy, the influence of CNP on the secretion of ANP was studied with the use of perfused nonbeating atria from monocrotaline-treated rats. Increases in atrial volume caused proportional increases in ANP secretion that were markedly suppressed by CNP (10(-6) M) in nonhypertrophied left atria and control right atria but not in hypertrophied right atria. However, increases in atrial volume and mechanically stimulated extracellular fluid (ECF) translocation by CNP were similar to those in the control group. Therefore, the secretion of ANP in terms of ECF translocation was decreased by CNP in nonhypertrophied left and control right atria but not in hypertrophied atria. However, the inhibitory effect of 8-bromo-cGMP on the secretion of ANP was observed in both atria. The cGMP productions from perfused hypertrophied atria and their membranes exposed to CNP were significantly lower than those from nonhypertrophied atria. No significant difference in natriuretic peptide receptor-B transcript was found. Therefore, attenuation of the inhibitory effect of CNP on the ANP secretion in hypertrophied atria may be due to lack of cGMP production. The results showing the relief of CNP-induced negative inhibition of ANP secretion by atrial hypertrophy suggest that CNP may be a contributing factor to delay the development of cardiac hypertrophy.

Animals↗
PubMed2004

Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload.

BACKGROUND: Rapamycin is a specific inhibitor of the mammalian target of rapamycin (mTOR). We recently reported that administration of rapamycin before exposure to ascending aortic constriction significantly attenuated the load-induced increase in heart weight by approximately 70%. METHODS AND RESULTS: To examine whether rapamycin can regress established cardiac hypertrophy, mice were subjected to pressure overload (ascending aortic constriction) for 1 week, echocardiography was performed to verify an increase in ventricular wall thickness, and mice were given rapamycin (2 mg x kg(-1) x d(-1)) for 1 week. After 1 week of pressure overload (before treatment), 2 distinct groups of animals became apparent: (1) mice with compensated cardiac hypertrophy (normal function) and (2) mice with decompensated hypertrophy (dilated with depressed function). Rapamycin regressed the pressure overload-induced increase in heart weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and 41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular end-systolic dimensions, fractional shortening, and ejection fraction in mice with decompensated cardiac hypertrophy. Rapamycin also altered the expression of some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase. CONCLUSIONS: Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.

Adaptation, Physiological↗
PubMed2004

Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes.

BACKGROUND: Obesity is a major risk factor for the development of cardiovascular disease. Emerging evidence indicates that leptin, a protein encoded by the obesity gene, is linked with cardiac hypertrophy in obese humans and directly induces cardiomyocyte hypertrophy in vitro. However, the mechanisms by which leptin induces cardiomyocyte hypertrophy are poorly understood. METHODS AND RESULTS: This study investigated how leptin contributes to cardiomyocyte hypertrophy. Cultured neonatal rat cardiomyocytes were used to evaluate the effects of leptin on hypertrophy. Both endothelin-1 (ET-1) and reactive oxygen species (ROS) levels were elevated in a concentration-dependent manner in cardiomyocytes treated with leptin for 4 hours compared with those cells without leptin treatment. ET-1 stimulated ROS production in a concentration-dependent manner in cardiomyocytes. The augmentation of ROS levels in cardiomyocytes treated with both leptin and ET-1 was reversed by a selective ET(A) receptor antagonist, ABT-627, and catalase, a hydrogen peroxide-decomposing enzyme. After treatment for 72 hours, leptin or ET-1 concentration-dependently increased total RNA levels, cell surface areas, and protein synthesis in cardiomyocytes, all of which were significantly inhibited by ABT-627 or catalase treatment. CONCLUSIONS: These findings indicate that leptin elevates ET-1 and ROS levels, resulting in hypertrophy of cultured neonatal rat cardiac myocytes. The ET-1-ET(A)-ROS pathway may be involved in cardiomyocyte hypertrophy induced by leptin. ET(A) receptor antagonists and antioxidant therapy may provide an effective means of ameliorating cardiac dysfunction in obese humans.

Animals↗
PubMed2000

Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy.

BACKGROUND: Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin. METHODS AND RESULTS: We showed that calcineurin enzymatic activity is increased 3. 2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy. CONCLUSIONS: These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.

Animals↗
PubMed1981

Hypertrophic cardiomyopathy with unusual locations of left ventricular hypertrophy undetectable by M-mode echocardiography. Identification by wide-angle two-dimensional echocardiography.

Twenty-one patients without evidence of hypertrophy by M-mode echocardiography were studied by wide-angle two-dimensional echocardiography to determine if they had a form of hypertrophic cardiomyopathy that could not be detected by conventional M-mode echocardiography. Each patient was suspected clinically of having hypertrophic cardiomyopathy because of a distinctly abnormal ECG and either a family history of hypertrophic cardiomyopathy or cardiac symptoms. Patients were 5-49 years old (mean 16 years) and 16 of the 21 had no functional limitation. The most common electrocardiographic abnormalities were deep Q waves, T-wave inversion and right ventricular hypertrophy. Using wide-angle two-dimensional echocardiography to reconstruct the geometry of the left ventricular wall, 16 of the 21 patients (76%) were shown to have prominent but unusually located regions of left ventricular wall hypertrophy. In each instance, the hypertrophy involved regions of the left ventricular wall through which the M-mode ultrasound beam does not usually pass, i.e., posterior ventricular septum (seven patients), anterior or lateral left ventricular free wall (seven patients) and ventricular septum near the apex (two patients). There was no echocardiographic or hemodynamic evidence of left ventricular outflow tract obstruction in any patient. Hence, some patients with hypertrophic cardiomyopathy may have substantial hypertrophy present in unusual locations of the left ventricular wall. Although electrocardiographic abnormalities suggested the presence of myocardial disease, conventional M-mode echocardiography (performed from standard parasternal positions) did not reliably identify such sites of hypertrophy, which were limited to regions of the left ventricle not accessible to the M-mode beam. Only wide-angle two-dimensional echocardiography permits definitive identification of these unusually located regions of cardiac hypertrophy and confirmation of the diagnosis of hypertrophic cardiomyopathy.

Adolescent↗
PubMed1990

Incidence of sudden cardiac death associated with coronary artery occlusion in dogs with hypertension and left ventricular hypertrophy is reduced by chronic beta-adrenergic blockade.

Because beta-adrenergic blockade has as one of its many effects altered electrophysiological abnormalities after dogs with left ventricular hypertrophy have been subjected to coronary occlusion, we tested the hypothesis that metoprolol (200-400 mg/day) would reduce mortality rates in dogs with one-kidney, one clip left ventricular hypertrophy while a similar reduction in arterial pressure with enalapril (20-40 mg/day) would not. Dogs with left ventricular hypertrophy were given metoprolol or enalapril for 5-7 days before a 3-hour coronary occlusion. Infarct size and risk area were measured with triphenyltetrazolium chloride stain and barium angiography, respectively. For control (n = 15), left ventricular hypertrophy (n = 17), left ventricular hypertrophy plus metoprolol (n = 12), and left ventricular hypertrophy plus enalapril (n = 15) groups, mean arterial pressure, ratio of infarct size to risk area, and dogs experiencing sudden death were 110 +/- 4, 142 +/- 4, 121 +/- 7, and 120 +/- 3 mm Hg; 44 +/- 5%, 65 +/- 5%, 44 +/- 7%, and 30 +/- 4%; and 27%, 65%, 17%, and 53%, respectively. Thus, the excessive increase in early mortality occurring when dogs with hypertension and left ventricular hypertrophy undergo coronary occlusion is interrupted with beta-blockade, possibly via electrophysiological effects rather than by changes in arterial pressure or infarct size.

Adrenergic beta-Antagonists↗
PubMed1994

Effects of enalapril versus losartan on regression of volume overload-induced cardiac hypertrophy in rats.

BACKGROUND: The role of nonhemodynamic cardiac trophic mechanisms differs not only between different models of cardiac hypertrophy but also within the same model for development versus maintenance of cardiac hypertrophy. Our previous studies pointed to a major role for the renin-angiotensin system (RAS) as a cardiac trophic stimulus in the remodeling of the heart in response to volume overload by aortocaval shunt or minoxidil treatment. METHODS AND RESULTS: In the present study, we evaluated the effects of blockade of the RAS by the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor blocker losartan on left ventricular (LV) and right ventricular mass and LV dilation in relation to changes in central hemodynamics during the maintenance of minoxidil and aortocaval shunt-induced cardiac hypertrophy. Both blockers similarly decreased LV end-diastolic pressure (LVEDP) and LV peak systolic pressure, whereas cardiac output remained unchanged in both models of volume overload. This suggests a major contribution of improved LV performance and decreased afterload to the decrease in cardiac preload by the two blockers rather than decreased venous return. Both blockers reversed LV hypertrophy in parallel to their effects on LVEDP in both models of volume overload. In minoxidil-treated rats, the extent of reversal in LV mass and dilation by the two blockers was similar to "spontaneous regression" after discontinuation of minoxidil treatment. CONCLUSIONS: These results indicate that in contrast to the development phase of cardiac hypertrophy, the RAS does not contribute to the maintenance of volume overload-induced cardiac hypertrophy in these two models via direct cardiac trophic effects. The RAS, however, maintains cardiac hypertrophy indirectly by contributing to the persistence of high filling pressures.

Animals↗