Transient outward current in catecholamine-induced cardiac hypertrophy in the rat

1996 ◽  
Vol 271 (6) ◽  
pp. H2360-H2367 ◽  
Author(s):  
J. Meszaros ◽  
K. O. Ryder ◽  
G. Hart
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Outward Current ◽  
Cell Voltage ◽  
Underlying Mechanism ◽  
Left Ventricular ◽  
Daily Injection ◽  
Heart Weight ◽  
Inactivation Kinetics ◽  
Transient Outward Current

We have demonstrated that a daily injection of isoproterenol (5 mg/kg ip) for 7 days induces a 30% increment in heart weight-to-body weight ratio and prolongs the action potential duration (APD) in male Wistar rats. The underlying mechanism of the prolonged APD was investigated in this model of hypertrophy by measuring the transient outward potassium current (Ito) in left ventricular myocytes of the rat with whole cell voltage-clamp techniques. Cell membrane capacitance was increased by 39%: 122 +/- 3 (n = 23) and 171 +/- 5 (SE) pF (n = 20) in control and hypertrophy, respectively (P < 0.001). Ito was evoked in sodium-free solutions containing 0.5 mM Ca2+ and 2 mM Co2+ by step depolarizations from a holding potential of -80 mV. The amplitude of the 4-aminopyridine-sensitive Ito (at 70 mV) was reduced by 28% in hypertrophy: 3.2 +/- 0.3 (n = 23) and 2.3 +/- 0.4 (SE) nA (n = 20) in control and hypertrophy, respectively (P < 0.05). When normalized for cell capacitance, the reduction was much larger: 26.4 +/- 2.5 and 13.1 +/- 1.8 pA/pF in control and hypertrophy, respectively (P < 0.001). The voltage dependence of Ito was similar in both cell types. No change was observed in the steady-state activation and inactivation kinetics in the two groups, nor was there a change in the time dependence of inactivation. The recovery from inactivation of Ito when fitted with a monoexponential function was not changed significantly in hypertrophy: time constants = 8.2 +/- 0.4 (n = 13) and 8.3 +/- 0.3 ms (n = 12) in control and hypertrophy, respectively. These results show that Ito density is decreased in catecholamine-induced cardiac hypertrophy, but current kinetics are not affected. The reduced Ito density may underlie the prolongation of APD in this model of hypertrophy.

scholarly journals PKC-β is not necessary for cardiac hypertrophy

2001 ◽  
Vol 280 (5) ◽  
pp. H2264-H2270 ◽  
Author(s):  
Brian B. Roman ◽  
David L. Geenen ◽  
Michael Leitges ◽  
Peter M. Buttrick
Keyword(s):  
Cardiac Hypertrophy ◽  
Gene Knockout ◽  
Weight Ratio ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Hypertrophic Response ◽  
Pathological Hypertrophy ◽  
Pkc Β ◽  
And Control

Studies in human and rodent models have shown that activation of protein kinase C-β (PKC-β) is associated with the development of pathological hypertrophy, suggesting that ablation of the PKC-β pathway might prevent or reverse cardiac hypertrophy. To explore this, we studied mice with targeted disruption of the PKC-β gene (knockout, KO). There were no detectable differences in expression or distribution of other PKC isoforms between the KO and control hearts as determined by Western blot analysis. Baseline hemodynamics were measured using a closed-chest preparation and there were no differences in heart rate and arterial or left ventricular pressure. Mice were subjected to two independent hypertrophic stimuli: phenylephrine (Phe) at 20 mg · kg−1 · day−1 sq infusion for 3 days, and aortic banding (AoB) for 7 days. KO animals demonstrated an increase in heart weight-to-body weight ratio (Phe, 4.3 ± 0.6 to 6.1 ± 0.4; AoB, 4.0 ± 0.1 to 5.8 ± 0.7) as well as ventricular upregulation of atrial natriuretic factor mRNA analogous to those seen in control animals. These results demonstrate that PKC-β expression is not necessary for the development of cardiac hypertrophy nor does its absence attenuate the hypertrophic response.

scholarly journals Protocatechuic acid attenuates isoproterenol-induced cardiac hypertrophy via downregulation of ROCK1–Sp1–PKCγ axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liyan Bai ◽  
Hae Jin Kee ◽  
Xiongyi Han ◽  
Tingwei Zhao ◽  
Seung-Jung Kee ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Acid Treatment ◽  
Protocatechuic Acid ◽  
Therapeutic Potential ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Transcriptional Level ◽  
Cell Area ◽  
Protective Effects

AbstractCardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists. Here, we investigated the protective effects and the regulatory mechanism of protocatechuic acid, a phenolic compound, using a mouse model of isoproterenol-induced cardiac hypertrophy. Our results demonstrated that protocatechuic acid treatment significantly downregulated the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), cardiomyocyte size, heart weight to body weight ratio, cross-sectional area, and thickness of left ventricular septum and posterior wall. This treatment also reduced the expression of isoproterenol-induced ROCK1, Sp1, and PKCγ both in vivo and in vitro. To investigate the mechanism, we performed knockdown and overexpression experiments. The knockdown of ROCK1, Sp1, or PKCγ decreased the isoproterenol-induced cell area and the expression of hypertrophic markers, while the overexpression of Sp1 or PKCγ increased the levels of hypertrophic markers. Protocatechuic acid treatment reversed these effects. Interestingly, the overexpression of Sp1 increased cell area and induced PKCγ expression. Furthermore, experiments using transcription inhibitor actinomycin D showed that ROCK1 and Sp1 suppression by protocatechuic acid was not regulated at the transcriptional level. Our results indicate that protocatechuic acid acts via the ROCK1/Sp1/PKCγ axis and therefore has promising therapeutic potential as a treatment for cardiac hypertrophy.

Myocardial metabolic and functional responses to acetylcholine are altered in thyroxine-induced cardiac hypertrophy

1995 ◽  
Vol 73 (6) ◽  
pp. 729-735 ◽  
Author(s):  
Harvey R. Weiss ◽  
James Tse
Keyword(s):  
Blood Flow ◽  
Cardiac Hypertrophy ◽  
Muscarinic Receptor ◽  
Coronary Blood Flow ◽  
Muscarinic Receptors ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Receptor Density ◽  
Functional Responses

We tested the hypothesis that acetylcholine would reduce myocardial O2 consumption and function, and that thyroxine (T4, 0.5 mg/kg for 16 days) induced cardiac hypertrophy would change this relationship. Anesthetized open-chest New Zealand white rabbits were divided into four groups: control–vehicle (CV, n = 8), control–acetylcholine (CA, n = 10), T4–vehicle (T4V, n = 9), and T4-acetylcholine (T4A, n = 10). Either vehicle or acetylcholine (10−3 M) was topically applied to the left ventricular surface. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption, and muscarinic receptor density and affinity were also determined. T4 increased the heart weight/body weight ratio from 2.6 ± 0.1 to 3.4 ± 0.1. T4-treated animals had higher heart rates, blood pressures, and left ventricular dP/dtmax than control rabbits. Topical acetylcholine depressed hemodynamic parameters with a greater decrement in pressures and cardiac output in the T4A group (CA, −25%, T4A, −40%). Myocardial O2 consumption and coronary blood flow were higher in the T4-treated hearts. Myocardial O2 consumption significantly declined in both groups during acetylcholine, but the reduction was greater in the T4-treated hearts (CV 7.9 ± 0.4 to CA 5.8 ± 0.6 and T4V 18.8 ± 3.0 to T4A 7.3 ± 1.0 mL O2∙min−1∙100 g−1). Muscarinic receptor density (Bmax) was elevated by 41% in the T4-treated hearts, but affinity (Kd) was not altered. Thus, the T4-treated hearts responded to acetylcholine to a greater extent than control hearts in terms of functional and O2 consumption decrements. This may, in part, be related to the elevated number of muscarinic receptors in the T4-treated rabbit hearts.Key words: thyroxine, cardiac hypertrophy, acetylcholine, muscarinic receptors, coronary blood flow, myocardial O2 consumption, rabbit.

Genistein prevents isoproterenol-induced cardiac hypertrophy in rats

2012 ◽  
Vol 90 (8) ◽  
pp. 1117-1125 ◽  
Author(s):  
Subir Kumar Maulik ◽  
Pankaj Prabhakar ◽  
Amit Kumar Dinda ◽  
Sandeep Seth
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Body Weight ◽  
Nitric Oxide Synthase ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Once Daily ◽  
Oxide Synthase

Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150–200 g, 10–12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)–1) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg–1, subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (L-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities.

Abstract 153: Inhibition of the 5-a-reductase Reduces Cardiac Hypertrophy and Improves Cardiac Function

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Carolin Zwadlo ◽  
Natali Froese ◽  
Johann Bauersachs ◽  
Joerg Heineke
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Capillary Density ◽  
Left Ventricular ◽  
Heart Weight ◽  
Rat Cardiomyocytes ◽  
Male And Female ◽  
Female Mice

Objectives: Left ventricular hypertrophy (LVH) is an independent risk factor for increased cardiovascular mortality and a precursor of heart failure. Gender-specific differences point to a pivotal role of androgens in the development of pathological LVH. Dihydrotestosterone (DHT) is metabolized from testosterone via the enzyme 5-α-reductase. The 5-α-reductase is upregulated in the hypertrophied myocardium, leading to our assumption that DHT rather than testosterone is the crucial component in the development of LVH and might therefore constitute a potential therapeutic target. Methods: One week after transverse aortic constriction (TAC) or sham surgery male wild-type mice were treated for 2 weeks via an oralgastric tube with the 5-α-reductase inhibitor finasteride (daily dose 25mg/kg BW) or were left untreated (controls). Male and female transgenic Gαq (TG, a model of dilative cardiomyopathy) or non-transgenic mice were treated with finasteride for 6 weeks. Results: Cardiac hypertrophy after TAC was dramatically reduced by finasteride in male mice (heart weight/ body weight ratio, HW/BW in mg/g: control 6.65±0.35 versus finasteride treated 5.23±0.3; p<0.01). The reduced hypertrophy in these mice was accompanied by a reduction in cardiomyocyte diameter, ANP expression and fibrosis, but increased capillary density and Serca2a expression. Accordingly, finasteride also markedly reduced hypertrophy in isolated primary rat cardiomyocytes in vitro . Amelioration of hypertrophy by finasteride was associated with blunted activation of the prohypertrophic kinase mTOR in vitro and in vivo . Left ventricular dilation in male Gαq TG mice was markedly reduced by treatment with finasteride, which also led to an improvement in left ventricular function (determined as fractional area change in % by echocardiography: finasteride 44.72±1.71 vs. control 32.8±3.84, p<0.05) and a similar trend was observed in female mice. Interestingly, finasteride reduced pulmonary congestion in male and female mice alike. Conclusion: Finasteride treatment reduces hypertrophy and eccentric cardiac remodelling in mice, indicating a possible involvement of DHT in these processes as well as a potential benefit of 5-α-reductase inhibition in cardiac disease.

Abstract MP166: PRKAR1A Deficiency Abrogates Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yuening Liu ◽  
Peng Xia ◽  
Jingrui Chen ◽  
Patricia W Bandettini ◽  
Lawrence S Kirschner ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Postnatal Development ◽  
Contractile Function ◽  
Mitochondrial Fission ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Complications ◽  
The Impact

Protein kinase A (PKA) is pivotal for cardiac function of human heart, and its dysregulation is involved with various cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by PRKAR1A gene) controls PKA kinase activity by sequestering the PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) and may die prematurely from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart growth during postnatal development. Here, we show that left ventricular mass is reduced in young CNC patients with PRKAR1A mutations or deletions. To investigate the impact of PRKAR1A deficiency on heart growth, we generated cardiac-specific PRKAR1A heterozygous knockout mice. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight to body weight ratio and cardiomyocyte size without altering contractile function. Cardiomyocyte hypertrophy in response to activation of the α1-adrenergic receptor, was completely abolished by silencing of PRKAR1A . Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, resulting in impaired mitochondrial fission and diminished cardiomyocyte hypertrophy. In conclusion, PRKAR1A deficiency abrogates cardiac hypertrophy during postnatal development, likely through inhibiting Drp1-mediated mitochondrial fission. Our study provides novel mechanistic insights regarding the cardiac mortality associated with CNC.

Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction

1998 ◽  
Vol 274 (1) ◽  
pp. H259-H265 ◽  
Author(s):  
George J. Rozanski ◽  
Zhi Xu ◽  
Kun Zhang ◽  
Kaushik P. Patel
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Hypertrophy ◽  
Pyruvate Dehydrogenase ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Heart Weight ◽  
Transient Outward Current ◽  
Coronary Artery Ligation ◽  
Channel Function ◽  
Failing Heart

The aim of the present study was to define the cellular mechanisms underlying changes in K+ channel function in the failing heart after myocardial infarction. Rats with left coronary artery ligation were prepared and allowed to recover for 16 wk before study. Animals with chronic infarction exhibited marked cardiac hypertrophy and signs of heart failure, as indicated by a nearly twofold increase in heart weight- and lung weight-to-body weight ratios, respectively, compared with time-matched controls. Cardiac hypertrophy was also evident by a 49% increase in whole cell capacitance of isolated left ventricular myocytes ( P < 0.05). Voltage-clamp experiments revealed that the maximum density of the Ca2+-independent, transient outward current ( I to), measured at +60 mV, was 42% less in myocytes from infarcted hearts than in myocytes from control hearts ( P < 0.05), whereas the inward rectifier current ( I K1) density was not different between groups. The reduced I to density in the infarcted group was reversed, however, in 4–5 h by treatment with exogenous dichloroacetate or pyruvate, both activators of pyruvate dehydrogenase. Moreover, control myocytes incubated for 6 h in the presence of an inhibitor of pyruvate dehydrogenase, 3-bromopyruvate, exhibited a concentration-dependent decrease in I to density compared with untreated cells. The present data demonstrate that I to density is reversibly decreased in surviving myocytes from infarcted hearts and suggest that mechanisms related to glucose metabolism via pyruvate dehydrogenase may be involved. These postinfarction changes in myocyte I to channel function may relate to impaired contractility and arrhythmogenesis, which are characteristic of the intact, failing heart.

Relationship between cGMP and myocardial O2 consumption is altered in T4-induced cardiac hypertrophy

1995 ◽  
Vol 268 (2) ◽  
pp. H686-H691 ◽  
Author(s):  
H. R. Weiss ◽  
E. Rodriguez ◽  
J. Tse
Keyword(s):  
Cardiac Hypertrophy ◽  
Guanylate Cyclase ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Cyclase Activity ◽  
Heart Weight ◽  
O2 Consumption ◽  
Guanylate Cyclase Activity ◽  
O2 Extraction ◽  
Myocardial O2 Consumption

We tested the hypothesis that increases in guanosine 3',5'-cyclic monophosphate (cGMP) would reduce myocardial O2 consumption and that thyroxine (T4)-induced (0.5 mg/kg for 16 days) cardiac hypertrophy would change this relationship. Anesthetized open-chest New Zealand White rabbits were divided into four groups: control vehicle (CV, n = 7), control nitroprusside (CN, n = 6), T4 vehicle (T4V, n = 8), and T4 nitroprusside (T4N, n = 8). Vehicle or sodium nitroprusside (10(-4) M) was topically applied to the left ventricular subepicardium for 15 min. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption. Guanylate cyclase activity and cGMP were determined by radioimmunoassay. T4 increased the heart weight-to-body weight ratio from 2.7 +/- 0.1 to 3.4 +/- 0.2. Topical application of nitroprusside had no significant hemodynamic effects. Nitroprusside significantly increased myocardial cGMP in control hearts (CV = 4.1 +/- 0.3 to CN = 12.4 +/- 5.0 pmol/g) and T4 hearts (T4V = 3.9 +/- 0.3 to T4N = 5.2 +/- 0.4). The increase in the level of myocardial cGMP was significantly greater in CN (+202%) than in T4N (+33%). There were no significant differences in basal or total guanylate cyclase activity between control and T4 rabbits. Myocardial O2 consumption significantly declined in both groups during nitroprusside (10.8 +/- 1.4 for CV to 7.3 +/- 1.0 for CN (-32%) and 13.6 +/- 1.2 for T4V to 9.9 +/- 1.4 ml O2.min-1.100 g-1 for T4N (-27%).(ABSTRACT TRUNCATED AT 250 WORDS)

Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin

2019 ◽  
Vol 116 (1) ◽  
pp. 101-113 ◽  
Author(s):  
Hairuo Lin ◽  
Yang Li ◽  
Hailin Zhu ◽  
Qiancheng Wang ◽  
Zhenhuan Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Body Weight ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
Body Weight Ratio

Abstract Aims Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms. Methods and results Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy. Conclusion Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling.

Characterization of mice with a combined suppression ofI to and I K,slow

2001 ◽  
Vol 281 (3) ◽  
pp. H1201-H1209 ◽  
Author(s):  
Michael Brunner ◽  
Weinong Guo ◽  
Gary F. Mitchell ◽  
Peter D. Buckett ◽  
Jeanne M. Nerbonne ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Outward Current ◽  
Cell Voltage ◽  
Left Ventricular ◽  
Transient Outward Current ◽  
Specific Expression ◽  
Left Ventricular Apex ◽  
Significant Prolongation ◽  
Electrocardiogram Monitoring

Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K+ current ( I K,slow), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current ( I to) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of I to and the 4-aminopyridine-sensitive component of I K,sloware eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring ( n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I to in addition to I K,slow in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.

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