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PubMed1983

Regression of cardiac hypertrophy. Experimental animal model.

Regression of cardiac hypertrophy has been proven to occur in experimental animals following some types of antihypertensive therapy. However, no direct and necessary correlation can be found between hypertension and cardiac hypertrophy. The effect of different antihypertensive drugs on regression of cardiac hypertrophy varies despite the same degree of reduction in arterial pressure in hypertensive control subjects. Therapy with alpha-methyldopa resulted in reversal of hypertrophy with effective blood pressure control, whereas treatment with vasodilators, namely hydralazine and minoxidil, either did not alter (hydralazine) degree of myocardial hypertrophy or increase it (minoxidil) despite normalization of blood pressure. The biochemical profile of the myocardium after regression of hypertrophy following antihypertensive therapy is not homogeneous; for example, reversal with alpha-methyldopa is associated with increased collagen content, whereas reversal with Captopril did not alter collagen content of the heart. Adrenergic factors seem to play an important role in the modulation of myocardial structure to variations in arterial pressure. Furthermore, in each type of hypertrophy in hypertension, a combination of different factors might be responsible, and it may not be correct to assume that the same factors must be involved in the regression of all types of myocardial hypertrophy.

Age Factors↗
PubMed1978

The ATPase activity of subfragment-1 from the hypertrophied heart.

Myosin and subfragment-1 were prepared from rabbit hearts hypertrophied secondary to pulmonary artery constriction. The Ca2+ -stimulated ATPase activity was reduced while the potassium/EDTA-stimulated ATPase activity was unchanged in both the myosin and subfragment 1 (S-1) from hypertrophied hearts. When hypertrophy myosin was mixed with an equal quantity of control myosin, the ATPase activity of the mixed protein fell halfway between control and hypertrophy values. Similar results were obtained with control and hypertrophy S-1. The actin-stimulated ATPase activity of hypertrophy S-1 was slightly depressed but unlike hypertrophy myosin this depression was not significant when compared to normal S-1. This suggests that papain cleavage may have removed part of the conformational difference that exists between control and hypertrophy myosins.

Actins↗
PubMed1990

Preload dependence of fiber shortening rate in conscious dogs with left ventricular hypertrophy.

Employing the new concept of systolic myocardial stiffness, this study addresses the questions of linearity of the end-systolic stress-strain relations in left ventricular hypertrophy and the preload dependence of fiber shortening rate. Pressure overload hypertrophy was induced in six puppies by banding the ascending aorta. Ultrasonic crystals were implanted for measurement of short axis and wall thickness in the six dogs with hypertrophy and in five control dogs. A pressure catheter was inserted through the apex for left ventricular pressure measurement. Load was altered by graded infusions of phenylephrine in the setting of beta-adrenergic blockade. Linearity of the end-systolic stress-strain relations was observed in all cases, and preload-corrected shortening rate-afterload relations were derived from these stress-strain relations. Without preload correction, mid wall and endocardial shortening rate were depressed (p less than 0.05 and p less than 0.005, respectively) in the hypertrophy group. However, with preload correction at 35 g/cm2, there was no significant difference in shortening rate between the control and hypertrophy groups at afterloads of 150, 200 and 250 g/cm2. Endocardial shortening rate at a preload of 25 versus 35 g/cm2 demonstrated a preload dependence in both the control (p less than 0.04) and the hypertrophy group (p less than 0.01). Mid wall shortening rate displayed a preload dependence only in the hypertrophy group (p less than 0.05). It is concluded that end-systolic stress-strain relations are linear in control conditions and in hypertrophy, fiber shortening rate is preload-dependent and, thus, shortening rate-afterload relations currently used to assess myocardial contractility need to be modified to account for these preload effects.

Animals↗
PubMed1992

Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension.

The spectrum of left ventricular geometric adaptation to hypertension was investigated in 165 patients with untreated essential hypertension and 125 age- and gender-matched normal adults studied by two-dimensional and M-mode echocardiography. Among hypertensive patients, left ventricular mass index and relative wall thickness were normal in 52%, whereas 13% had increased relative wall thickness with normal ventricular mass ("concentric remodeling"), 27% had increased mass with normal relative wall thickness (eccentric hypertrophy) and only 8% had "typical" hypertensive concentric hypertrophy (increase in both variables). Systemic hemodynamics paralleled ventricular geometry, with the highest peripheral resistance in the groups with concentric remodeling and hypertrophy, whereas cardiac index was super-normal in those with eccentric hypertrophy and low normal in patients with concentric remodeling. The left ventricular short-axis/long-axis ratio was positively related to stroke volume (r = 0.45, p less than 0.001), with cavity shape most elliptic in patients with concentric remodeling and most spheric in those with eccentric hypertrophy. Normality of left ventricular mass in concentric remodeling appeared to reflect offsetting by volume "underload" of the effects of pressure overload, whereas eccentric hypertrophy was associated with concomitant pressure and volume overload. Thus, arterial hypertension is associated with a spectrum of cardiac geometric adaptation matched to systemic hemodynamics and ventricular load. Concentric left ventricular remodeling and eccentric hypertrophy are more common than the typical pattern of concentric hypertrophy in untreated hypertensive patients.

Adaptation, Physiological↗
PubMed1996

Cardiac hypertrophy in the Dahl rat is associated with increased tyrosine phosphorylation of several cytosolic proteins, including a 120 kDa protein.

Because of the well established role that tyrosine phosphorylation (tyr phos) plays in growth factor signalling and regulating cell growth, we hypothesized that cardiac hypertrophy might be associated with altered tyr phos of certain cellular proteins in the heart. Furthermore, we hypothesized that angiotensin II (ang II), a putative growth factor for cardiac cells, might be useful as a probe to highlight any differences in intracellular signalling between normal and hypertrophied hearts. The heart and, for comparison, skeletal muscle, from Dahl S rats, which are predisposed to cardiac hypertrophy, and Dahl R rats, which are not, were examined. Antiphosphotyrosine immunoprecipitation and immunoblotting of heart cell extracts revealed the presence of a constitutively tyr phos 120 kDa cytosolic protein. Hearts from Dahl R rats on a high salt diet displayed a smaller amount of constitutive tyr phos of this protein. In the hearts of both Dahl R and S rats maintained on low salt diets there was little evidence of constitutive tyr phos of this protein. Ang II induced tyr phos of this protein in Dahl S rats on a low salt diet and Dahl R rats on a high salt diet, both of which show mild cardiac hypertrophy. In contrast, the markedly hypertrophied ventricle showed a minimal response to Ang II. Thus the severity of cardiac hypertrophy correlated directly with the tyr phos level of this protein. In an attempt to identify this protein, immunoblotting was carried out with antibodies to the signal transducing proteins rasGAP, JAK2 iNOS, p125FAK, and the Src substrate, pp120, but all proved negative. Ang II also stimulated an increase in tyr phos of proteins with apparent molecular masses of 42, 55, and 69 to 85 kDa in hearts from Dahl S rats on high salt diet. By comparison, there was no 120 kDa tyr phos protein in skeletal muscle even in response to Ang II. Silver stained sodium dodecyl sulfate gels demonstrated that this 120 kDa tyr phos protein is present in substantial amounts in the ventricles of rats fed high salt diets. Thus cardiac hypertrophy is characterized by an abundant 120 kDa cytosolic tyr phos protein, which is apparent with Ang II stimulation in milder degrees of cardiac hypertrophy, and is most likely an as yet uncharacterized protein.

Angiotensin II↗
PubMed2004

Atrial natriuretic peptide inhibits cardiomyocyte hypertrophy through mitogen-activated protein kinase phosphatase-1.

Cardiac hypertrophy is formed in response to hemodynamic overload. Although a variety of factors such as catecholamines, angiotensin II (AngII), and endothelin-1 (ET-1) have been reported to induce cardiac hypertrophy, little is known regarding the factors that inhibit the development of cardiac hypertrophy. Production of atrial natriuretic peptide (ANP) is increased in the hypertrophied heart and ANP has recently been reported to inhibit the growth of various cell types. We therefore examined whether ANP inhibits the development of cardiac hypertrophy. Pretreatment of cultured cardiomyocytes with ANP inhibited the AngII- or ET-1-induced increase in the cell size and the protein synthesis. ANP also inhibited the AngII- or ET-1-induced hypertrophic responses such as activation of mitogen-activated protein kinase (MAPK) and induction of immediate early response genes and fetal type genes. To determine how ANP inhibits cardiomyocyte hypertrophy, we examined the mechanism of ANP-induced suppression of the MAPK activation. ANP strongly induced expression of MAPK phosphatase-1 (MKP-1) and overexpression of MKP-1 inhibited AngII- or ET-1-induced hypertrophic responses. These growth-inhibitory actions of ANP were mimicked by a cyclic GMP analog 8-bromo-cyclic GMP. Taken together, ANP directly inhibits the growth factor-induced cardiomyocyte hypertrophy at least partly via induction of MKP-1. Our present study suggests that the formation of cardiac hypertrophy is regulated not only by positive but by negative factors in response to hemodynamic load.

Animals↗
PubMed2004

Na+/Ca2+ exchange current (I(Na/Ca)) and sarcoplasmic reticulum Ca2+ release in catecholamine-induced cardiac hypertrophy.

OBJECTIVE: Catecholamines that accompany acute physiological stress are also involved in mediating the development of hypertrophy and failure. However, the cellular mechanisms involved in catecholamine-induced cardiac hypertrophy, particularly Ca2+ handling, are largely unknown. We therefore investigated the effects of cardiac hypertrophy, produced by isoprenaline, on I(Na/Ca) and sarcoplasmic reticulum (SR) function in isolated myocytes. METHODS: I(Na/Ca) was studied in myocytes from Wistar rats, using descending (+80 to -110 mV) voltage ramps under steady state conditions. Myocytes were also loaded with fura-2 and either field stimulated or voltage clamped to assess [Ca2+]i and SR Ca2+ content. RESULTS: Ca2+-dependent, steady state I(Na/Ca) density was increased in hypertrophied myocytes (P<0.05). Ca2+ release from the SR was also increased, whereas resting [Ca2+]i and the rate of decline of [Ca2+]i to control levels were unchanged. SR Ca2+ content, estimated by using 10.0 mmol/l caffeine, was also significantly increased in hypertrophied myocytes, but only when myocytes were held and stimulated from their normal resting potential (-80 mV) but not from -40 mV. However, the rate of decline of caffeine-induced Ca2+ transients or I(Na/Ca) was not significantly different between control and hypertrophied myocytes. Ca2+-dependence of I(Na/Ca), examined by comparing the slope of the descending phase of the hysteresis plots of I(Na/Ca) vs. [Ca2+]i, was also similar in the two groups of cells. CONCLUSION: Data show that SR Ca2+ release and SR Ca2+ content were increased in hypertrophied myocytes, despite an increase in the steady state I(Na/Ca) density. The observation that increased SR function occurred only when myocytes were stimulated from -80 mV suggests that Na+ influx may play a role in altering Ca2+ homeostasis in hypertrophied cardiac muscle, possibly through increased reverse Na+/Ca2+ exchange, particularly at low stimulation frequencies.

Action Potentials↗
PubMed2006

Cross talk between corticosteroids and alpha-adrenergic signalling augments cardiomyocyte hypertrophy: a possible role for SGK1.

OBJECTIVE: Mineralocorticoids and glucocorticoids have been implicated in the pathogenesis of cardiac diseases; however, both in vivo and in vitro studies indicate that changes in the cellular milieu of either the cardiomyocyte and/or cells of the vasculature is required for corticosteroid signalling to be pathological. The aim of the current study was to directly address whether signalling pathways that are activated during myocyte hypertrophy alter corticosteroid signalling and thus enable these steroids to significantly impact on the hypertrophic response. METHODS: Neonatal rat ventricular cardiomyocytes were treated with phenylephrine or phorbol ester for 48 h to induce myocyte hypertrophy. Following treatment, the expression of glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase were determined by ribonuclease protection assay. In addition, the activity of 11beta-hydroxysteroid dehydrogenase and the ability of glucocorticoid and mineralocorticoid receptors to induce serum- and glucocorticoid-induced kinase 1 (SGK1) gene transcription were assessed. Corticosteroid effects on phenylephrine and phorbol ester-induced hypertrophy were determined by measuring atrial natriuretic peptide (ANP) mRNA expression, protein synthesis, or induction of rDNA transcription. RESULTS: Incubation of cardiomyocytes with phenylephrine and phorbol ester for 48 h led to a hypertrophic response with an associated 8- to 12-fold increase in ANP mRNA and 2-fold increase in rDNA transcription. Cardiomyocyte hypertrophy led to a significant 2-fold increase in glucocorticoid receptor and mineralocorticoid receptor expression that resulted in enhanced receptor signaling as judged via the ability of corticosterone and aldosterone to induce SGK1 gene transcription. 11beta-Hydroxysteroid dehydrogenase2 was not detected in normal or hypertrophied cardiomyocytes, and 11beta-hydroxysteroid dehydrogenase exclusively demonstrated reductase activity, converting the inactive 11-ketometabolite back to active glucocorticoid. 11beta-Hydroxysteroid dehydrogenase1 expression and reductase activity were increased with phorbol ester-induced hypertrophy but not phenylephrine-induced hypertrophy. In basal cardiomyocytes, either aldosterone or corticosterone induced only a minor increase in ANP mRNA and protein synthesis; however, in cardiomyocytes primed with phenylephrine, both corticosteroids significantly potentiated phenylephrine-mediated effects via activation of the glucocorticoid receptor. CONCLUSION: In the present study we demonstrate that significant cross talk exists in the cardiomyocyte between corticosteroid receptor-activated pathways and both protein kinase C and alpha-adrenergic signalling. Cellular changes associated with the hypertrophic response promote corticosteroid signalling and allow for corticosteroid-mediated potentiation of alpha-adrenergic receptor signalling. Such augmentation of cardiomyocyte hypertrophy may in part explain the role that corticosteroid hormones play in the pathophysiological progression of heart disease.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Epigallocathechin-3 gallate inhibits cardiac hypertrophy through blocking reactive oxidative species-dependent and -independent signal pathways.

Cardiac hypertrophy is a major cause of morbidity and mortality worldwide. Recent in vitro and in vivo studies have suggested that reactive oxygen species (ROS) may play an important role in cardiac hypertrophy. It was therefore thought to be of particular value to examine the effects of antioxidants on cardiac hypertrophy. Epigallocatechin-3-gallate (EGCG) is a major bioactive polyphenol present in green tea and a potent antioxidant. The current study was designed to test the hypothesis that EGCG inhibits cardiac hypertrophy in vitro and in vivo. In this study, we investigated the effects of EGCG on angiotensin II- (Ang II) and pressure-overload-induced cardiac hypertrophy. Our results showed that EGCG attenuated Ang II- and pressure-overload-mediated cardiac hypertrophy. Both reactive oxygen species generation and NADPH oxidase expressions induced by Ang II and pressure overload were suppressed by EGCG. The increased hypertension by pressure overload was almost completely blocked after EGCG treatment. Further studies showed that EGCG inhibited Ang II-induced NF-kappaB and AP-1 activation. Inhibition of the activity of NF-kappaB was through blocking ROS-dependent p38 and JNK signaling pathways, whereas inhibition of AP-1 activation was via blocking EGFR transactivation and its downstream events ERKs/PI3K/Akt/mTOR/p70(S6K). The combination of these actions resulted in repressing the reactivation of ANP and BNP, and ultimately preventing the progress of cardiac hypertrophy. These findings indicated that EGCG prevents the development of cardiac hypertrophy through ROS-dependent and -independent mechanisms involving inhibition of different intracellular signaling transductional pathways.

Angiotensin II↗
PubMed1997

Changes in collagen phenotypes during progression and regression of cardiac hypertrophy.

OBJECTIVE: Excessive deposition of collagen has been implied to be responsible for abnormal stiffness and altered cardiac function during hypertrophy and heart failure. In the present paper we studied the changes in collagen and their phenotypes during development of cardiac hypertrophy in spontaneously hypertensive rats (SHR) compared to age- and sex-matched Wistar Kyoto (WKY). We also studied the changes in collagen after regression of hypertrophy, with antihypertensive therapy with ACE inhibitors, captopril (C) and lisinopril (L). METHOD: Collagen was extracted from the heart tissue by cyanogen bromide (CNBr) digestion. Collagen phenotypes were separated and quantified by SDS-polyacrylamide gel electrophoresis. The transcript levels(mRNA) of collagen phenotypes were determined by Northern analysis. RESULTS: Our studies showed that the ventricular collagen and their phenotypes did not alter in SHR during the first 6 months of progression of hypertrophy when compared to WKY. After 40 weeks, however, in SHR there was an unexpected rise in collagen content and the distribution of collagen phenotype differs compared to WKY, especially during the chronic phase of hypertrophy (65 weeks of age). In WKY during the aging process there was a gradual increase in type III collagen, whereas in SHR it plateaus after 40 weeks of age. Treatment with antihypertensive drugs captopril and lisinopril showed a similar degree of reduction in blood pressure (P < 0.001), regressed hypertrophy (P < 0.001), and reduced collagen, whereas decrease in type I to III ratio was found with captopril only, but not with lisinopril. This decrease in type I to III ratio due to captopril treatment is primarily due to an increase in type III collagen (both protein and transcript level) in SHR. CONCLUSION: Our data showed, for the first time, that during the chronic phase of hypertrophy in SHR there is a gradual reduction in type I to III ratio, primarily due to a lack of increase in type III collagen during chronic phase of hypertrophy. This suggests that quality of collagen is an important factor in determining the degree of cardiac stiffness. Our data also showed that not all ACE inhibitors have similar actions on collagen phenotype production. This suggests that perhaps the mechanism of action of ACE inhibitors on collagen are independent of its effect on angiotensin II formation.

Aging↗
PubMed1984

Electrocardiographic detection of left ventricular hypertrophy using echocardiographic determination of left ventricular mass as the reference standard. Comparison of standard criteria, computer diagnosis and physician interpretation.

Electrocardiographic findings of left ventricular hypertrophy were compared with echocardiographic left ventricular mass in 148 patients to assess performance of standard electrocardiographic criteria, the IBM Bonner program and physician interpretation. On echocardiography, 43% of the patients had left ventricular hypertrophy (left ventricular mass greater than 215 g). Sokolow-Lyon voltage-(S in V1 + R in V5 or V6) and Romhilt-Estes point score correlated modestly with left ventricular mass (r = 0.40, p less than 0.001 and r = 0.55, p less than 0.001, respectively). Sensitivity of Sokolow-Lyon voltage greater than 3.5 mV for left ventricular hypertrophy was only 22%, but specificity was 93%. Point score for probable left ventricular hypertrophy (greater than or equal to 4 points) had 48% sensitivity and 85% specificity, whereas definite hypertrophy (greater than or equal to 5 points) had 34% sensitivity and 98% specificity. Computer analysis resulted in 45% sensitivity and 83% specificity. Overall diagnostic accuracy of the IBM Bonner program (67%) was better than that of Sokolow-Lyon voltage (62%), but worse than the Romhilt-Estes point score (69% for greater than or equal to 4 points or 70% for greater than or equal to 5 points). Three cardiologists interpreted electrocardiograms independently and in a blinded fashion. Physician sensitivity was 56%, specificity 92% and accuracy 76%. Correlation with left ventricular hypertrophy was good (r = 0.70, p less than 0.001). It is concluded that: 1) computer diagnosis of left ventricular hypertrophy by the IBM Bonner program is no more accurate than diagnosis by Sokolow-Lyon or Romhilt-Estes criteria, and 2) physician recognition of left ventricular hypertrophy is more accurate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo.

Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms. The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in vitro, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy. Furthermore, rapamycin, a selective blocker of mTOR, blocked hypertrophy in all models tested, without causing atrophy in control muscles. In contrast, the calcineurin pathway was not activated during hypertrophy in vivo, and inhibitors of calcineurin, cyclosporin A and FK506 did not blunt hypertrophy. Finally, genetic activation of the Akt/mTOR pathway was sufficient to cause hypertrophy and prevent atrophy in vivo, whereas genetic blockade of this pathway blocked hypertrophy in vivo. We conclude that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of the Akt/mTOR pathway can oppose muscle atrophy induced by disuse.

Animals↗
PubMed2001

Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Galphaq/Galpha11 in cardiomyocytes.

Myocardial hypertrophy is an adaptational response of the heart to increased work load, but it is also associated with a high risk of cardiac mortality due to its established role in the development of cardiac failure, one of the leading causes of death in developed countries. Multiple growth factors and various downstream signaling pathways involving, for example, ras, gp-130 (ref. 4), JNK/p38 (refs. 5,6) and calcineurin/NFAT/CaM-kinase have been implicated in the hypertrophic response. However, there is evidence that the initial phase in the development of myocardial hypertrophy involves the formation of cardiac para- and/or autocrine factors like endothelin-1, norepinephrine or angiotensin II (refs. 7,8), the receptors of which are coupled to G-proteins of the Gq/11-, G12/13- and Gi/o-families. Cardiomyocyte-specific transgenic overexpression of alpha1-adrenergic or angiotensin (AT1)-receptors as well as of the Gq alpha-subunit, Galphaq, results in myocardial hypertrophy. These data demonstrate that chronic activation of the Gq/G11-family is sufficient to induce myocardial hypertrophy. In order to test whether Gq/G11 mediate the physiological hypertrophy response to pressure overload, we generated a mouse line lacking both Galphaq and Galpha11 in cardiomyocytes. These mice showed no detectable ventricular hypertrophy in response to pressure-overload induced by aortic constriction. The complete lack of a hypertrophic response proves that the Gq/G11-mediated pathway is essential for cardiac hypertrophy induced by pressure overload and makes this signaling process an interesting target for interventions to prevent myocardial hypertrophy.

Animals↗
PubMed1999

Interaction between the renin-angiotensin system and insulin-like growth factor I in aorto-caval fistula-induced cardiac hypertrophy in rats.

The effects of angiotensin converting enzyme inhibition and angiotensin II receptor blockade on the development of cardiac hypertrophy and myocardial insulin-like growth factor I (IGF-I) in volume overload were studied in male Wistar rats with aorto-caval fistulas (ACF). Rats were treated with ramipril (RAM, 3 mg kg(-1) day(-1)) for 4-20 days or losartan (LOS, 10 mg kg(-1) day(-1)) for 2-7 days. Myocardial IGF-I and IGF-I receptor (IGF-I-R) mRNA were determined by solution hybridization. ACF caused hypertrophy of left (LV) and right ventricles (RV). Hypertrophy appeared on day 2 and reached maximal values of +60% in LV and +75% in RV at day 12. Systolic blood pressure was initially reduced 15% but recovered by day 12. RAM abolished the recovery of blood pressure. Furthermore, RAM attenuated RV hypertrophy by 17% on day 7 and on day 20, RV weights were close to values found in controls. Beginning on day 9, RAM reduced LV weight back to control levels in parallel to blood pressure. In contrast, LOS affected neither RV nor LV hypertrophy. RV IGF-I mRNA increased 60-100% on day 7 alone in RV in ACF. RAM potentiated the increase in RV IGF-I to +400% and induced an increase in RV IGF-I-R mRNA on day 7 (+90%) in ACF. LOS did not affect RV IGF-I. Development of cardiac hypertrophy in ACF seemed independent of angiotensin II. RV hypertrophy was associated with activation of IGF-I independent of the renin-angiotensin system. IGF-I was further potentiated when development of hypertrophy was attenuated, possibly indicative of a greater urge for compensational growth in a relatively thinner and more volume-distended chamber.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Endothelin ETA receptor antagonism does not attenuate angiotensin II-induced cardiac hypertrophy in vivo in rats.

1. Angiotensin (Ang) II causes cardiac hypertrophy in vitro and in vivo. It also stimulates the release of endothelin (ET)-1. Endothelin-1 induces hypertrophy of cardiomyocytes in vitro. 2. In the present study, we examined whether the cardiac hypertrophic action of AngII in vivo was mediated by ET-1 via ETA receptors. We also determined whether arginine vasopressin (AVP), another ET-1 stimulator, could cause cardiac hypertrophy in vivo through an ET-1-dependent pathway. 3. In Sprague-Dawley rats (n = 8 per group), we determined whether the orally administered ETA receptor antagonist BMS 193884 could attenuate the cardiac hypertrophic effect of: (i) i.v. AngII infusion at either 100 or 200 ng/kg per min, i.v., for 1 week; (ii) AngII infusion at 100 ng/kg per min, i.v., for 2 weeks; and (iii) AVP infusion at either 2 or 10 ng/kg per min, i.v., for 1 week. Mean arterial pressure and heart rate were also measured. 4. Infusion with AngII for both 1 and 2 weeks increased left ventricular weight. Only AngII infusion at 200 ng/kg per min for 1 week increased blood pressure. Endothelin ETA receptor blockade did not attenuate the left ventricular hypertrophy, even though it reduced the hypertensive effect of AngII. Arginine vasopressin increased blood pressure, but did not cause cardiac hypertrophy. 5. We showed that AngII can cause cardiac hypertrophy through a direct, blood pressure-independent effect on the heart. Endothelin-1 did not mediate the cardiac hypertrophic effect of AngII through ETA receptors. This may indicate the involvement of ETB receptors in this model of cardiac hypertrophy. Arginine vasopressin did not cause cardiac hypertrophy in vivo.

Aldosterone↗
PubMed1997

Mechanism of beta-adrenergic receptor desensitization in cardiac hypertrophy is increased beta-adrenergic receptor kinase.

Pressure overload cardiac hypertrophy in the mouse was achieved following 7 days of transverse aortic constriction. This was associated with marked beta-adrenergic receptor (beta-AR) desensitization in vivo, as determined by a blunted inotropic response to dobutamine. Extracts from hypertrophied hearts had approximately 3-fold increase in cytosolic and membrane G protein-coupled receptor kinase (GRK) activity. Incubation with specific monoclonal antibodies to inhibit different GRK subtypes showed that the increase in activity could be attributed predominately to the beta-adrenergic receptor kinase (betaARK). Although overexpression of a betaARK inhibitor in hearts of transgenic mice did not alter the development of cardiac hypertrophy, the beta-AR desensitization associated with pressure overload hypertrophy was prevented. To determine whether the induction of betaARK occurred because of a generalized response to cellular hypertrophy, betaARK activity was measured in transgenic mice homozygous for oncogenic ras overexpression in the heart. Despite marked cardiac hypertrophy, no difference in betaARK activity was found in these mice overexpressing oncogenic ras compared with controls. Taken together, these data suggest that betaARK is a central molecule involved in alterations of beta-AR signaling in pressure overload hypertrophy. The mechanism for the increase in betaARK activity appears not to be related to the induction of cellular hypertrophy but to possibly be related to neurohumoral activation.

Animals↗
PubMed1991

Effect of pressure overload on cardiac Ca2+ antagonist binding sites of guinea pig. Comparison with the adaptational response of the hypertrophied rat heart.

STUDY OBJECTIVE: The aim was to determine if the adaptational process of the cardiac calcium channel to pressure overload observed in rat heart also occurs in species characterised by a higher sensitivity to external calcium than in the rat. This adaptation occurs via a maintained density of dihydropyridine receptors and calcium current in hypertrophied rat heart. DESIGN: The guinea pig was chosen and the dissociation constant (Kd), association and dissociation rate constants (k+1,k-1), and maximal number (Bmax) of the dihydropyridine receptors were measured through binding of [3H]PN 200-110 to crude sarcolemma fractions from control and hypertrophied guinea pig left ventricle. EXPERIMENTAL MATERIAL: Hypertrophy of the left ventricle was obtained by stenosis of the abdominal aorta in guinea pigs. MEASUREMENTS AND MAIN RESULTS: Hypertrophy reached at least 50% in 15% of the surviving animals. No significant differences in the binding of [3H]PN 200-110 to the dihydropyridine receptor were observed between control and hypertrophied left ventricle microsomal preparations: Kd = 1.59(SEM 0.22) and 1.17(0.36) nM; Bmax = 225(18) and 213(4) fmol.mg-1 of protein; k-1 = 2.30(0.26) and 2.00(0.13) min-1 x 10(-2); k+1 = 3.8(0.7) and 3.5(0.3) nM-1.min-1 x 10(-2) respectively. CONCLUSIONS: In guinea pig as in rat, the total number of dihydropyridine receptors per left ventricle increased proportionately to the hypertrophy. This is consistent with an unchanged density of the cardiac Ca2+ channels in the hypertrophied guinea pig heart as previously shown in hypertrophied rat heart.

Adaptation, Physiological↗
PubMed1993

Relationship of abnormal intracellular calcium mobilisation to myocyte hypertrophy in human ventricular myocardium.

OBJECTIVE: Calcium transients in muscles from patients with end stage heart failure consist of two components (L1 and L2) at physiological extracellular calcium concentrations ([Ca2+]o); the second component (L2) can appear in normal human myocardium at high [Ca2+]o. In muscles from end stage heart failure patients L2 is associated with significant hypertrophy. To expand these observations a group of muscles from control patients with mild hypertrophy but without overt heart disease was studied (n = 8), in which a second calcium transient component was present during high [Ca2+]o. METHODS: Using the ratio of the two components of the calcium transient (L2/L1) seen in trabeculae from heart failure patients as a marker of intracellular calcium mobilisation, the hypothesis was tested that the extent of abnormality in transsarcolemmal calcium flux, and/or sarcoplasmic reticular calcium release and reuptake, correlates with the degree of hypertrophy present. RESULTS: In contrast to non-hypertrophied myocardium, hypertrophied myocardium from patients without heart failure often showed an increase in the L2/L1 ratio at higher [Ca2+]o. Hypertrophied myocardium from patients with failure showed a progressive increase in the L2/L1 ratio, reflecting further impairment of calcium mobilisation. There was a positive correlation between the degree of hypertrophy and calcium mobilisation alterations that was enhanced by raised [Ca2+]o. Altered [Ca2+]i mobilisation may develop early in the course of hypertrophy, before the onset of clinical signs of cardiac dysfunction.

Aequorin↗