T-type Ca2+ channels are abnormal in genetically determined cardiomyopathic hamster hearts.

Sen, Luyi; Smith, Thomas W.

doi:10.1161/01.res.75.1.149

Cited by 137 publications

(79 citation statements)

References 31 publications

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“…With the utilization of intracellular calcium indicators, intracellular calcium transients can be recorded in multicellular preparations and in isolated myocytes. The spontaneously hypertensive rat model and Syrian hamster model have been extensively investigated with regard to [Ca 2+ ] i handling (Bing et al 1988;Brooks et al 1994Brooks et al ,1997Brooksby et al 1992Brooksby et al , 1993Finkel et al 1987;Pfeffer and Frohlich 1973;Sen and Smith 1994;Sen et al 1990). Rodent models, like all animal models, however, have limitations Gwathmey andDavidoff 1993,1994).…”

Section: Discussionmentioning

confidence: 99%

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Kim

Davidoff

Mäki

et al. 2000

Journal of Comparative Physiology B: Biochemical, Systemic, and

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Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm).Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current-and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates. Keywords

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Section: Discussionmentioning

confidence: 99%

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Kim

Davidoff

Mäki

et al. 2000

Journal of Comparative Physiology B: Biochemical, Systemic, and

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“…T-type currents have been found to be increased twofold in cardiomyopathic Syrian hamsters relative to other hamster strains (46,362). Studies using 8-mo-old animals found that the voltage dependence of activation and inactivation was shifted to more negative potentials in ventricular myocytes from cardiomyopathic animals (362). In contrast, studies using 1-day-old hamsters found that only inactivation was shifted (46).…”

Section: Properties Of T-type Currents In Peripheral Tissuesmentioning

confidence: 96%

“…T-type currents are also reexpressed in dedifferentiated rat ventricular myocytes (114). T-type currents have been found to be increased twofold in cardiomyopathic Syrian hamsters relative to other hamster strains (46,362). Studies using 8-mo-old animals found that the voltage dependence of activation and inactivation was shifted to more negative potentials in ventricular myocytes from cardiomyopathic animals (362).…”

Section: Properties Of T-type Currents In Peripheral Tissuesmentioning

confidence: 98%

“…These studies showed that cardiac T-type currents resembled those recorded from neurons, but differed from L-type channels in terms of their kinetics (transient), pharmacology (dihydropyridine insensitive), conductance of divalent cations (Ca 2ϩ ϭ Ba 2ϩ ), lack of regulation by ␤-adrenergic agonists, and smaller single-channel conductance of Ba 2ϩ . Subsequent work has established their presence in myocytes isolated from dog Purkinje (367), rabbit sinoatrial node (152), cat atrium and latent pacemaker cells (462), hamster ventricle (362), and rat atrium (446). In general, the currents were small, displaying a peak current density below Ϫ3 pA/pF.…”

Section: Heartmentioning

confidence: 99%

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Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,521

1,446

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T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

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“…Moreover, recent reports suggest that the reexpression of the T-type calcium channel in the failing heart may contribute to cardiac hypertrophy, 32 to remodeling after myocardial infarction 33,34 and to the development of cardiomyopathy. 35 In this study, LVMI, an important surrogate marker, 36 was significantly decreased after 18 months in the efonidipine group with the sustained reduction of ALD. Taken together with our findings, T-type calcium channel blockers such as efonidipine may be useful for the management of hypertension in patients with CHF.…”

mentioning

confidence: 47%

Long-term effect of efonidipine therapy on plasma aldosterone and left ventricular mass index in patients with essential hypertension

et al. 2009

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A certain percentage of aldosterone (ALD) breakthrough generally occurs in patients with hypertension and chronic heart failure and is an important issue during long-term treatment with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB). It has been reported that efonidipine decreases the plasma levels of ALD. However, the long-term effects of efonidipine on the plasma levels of ALD and the left ventricular mass index (LVMI) remain unknown in patients with hypertension. Sixty stable outpatients with essential hypertension who had received amlodipine and ACE-I or ARB for more than 1 year were randomized into two groups (amlodipine group (n¼30): continuous amlodipine treatment at a stable dose; efonidipine group (n¼30): amlodipine (5 mg day À1 ) was changed to efonidipine at a dose of 40 mg day À1 ). There was no difference in their baseline characteristics including the LVMI and plasma levels of ALD. In the amlodipine group, there were no significant changes in blood pressure, LVMI or plasma levels of ALD for 18 months. In the efonidipine group, blood pressure did not change after replacement of amlodipine with efonidipine, although there was a significant decrease in the plasma levels of ALD after 6 months. The decrease in ALD was sustained for 18 months and LVMI was significantly decreased after 18 months (121 ± 25 vs. 114 ± 21 g m À2 , Po0.05). There was a significant correlation between the changes in LVMI and % changes of ALD in the efonidipine group. These findings indicate that the effect of efonidipine on the suppression of plasma ALD was sustained for at least 18 months and that long-term efonidipine therapy decreases LVMI in patients with essential hypertension. INTRODUCTIONRecent clinical trials have shown that inhibiting the biological actions of aldosterone (ALD) using an ALD blocker alone or in combination with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) is reported to be a useful add-on therapy in hypertensive patients, reducing the incidence of cardiovascular events among patients with chronic heart failure (CHF). 1,2 Therefore, to prevent cardiovascular disease, targeting ALD synthesis and release may be clinically important. One of the major incentives for implementing the RALES and EPHESUS trial was the investigation of the ALD breakthrough phenomenon 3,4 in which ACE-I does not reliably induce significant decreases in plasma ALD levels. Therefore, in a certain percentage of patients with hypertension or CHF, ALD breakthrough generally occurs. This phenomenon is an important issue during a long-term treatment with ACE-I and ARB. 1,[5][6][7][8][9][10][11] Although the mechanisms of ALD breakthrough remain obscure, there was no apparent reduction of the left ventricular mass index (LVMI) in patients with ALD breakthrough(+) during the administration of ACE-I. 8 Aldosterone production in the adrenal gland is mediated mainly by the T-type calcium channel in vitro. 12 Recently, it has been reported that efonidipine, a...

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T-type Ca2+ channels are abnormal in genetically determined cardiomyopathic hamster hearts.

Cited by 137 publications

References 31 publications

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Intracellular calcium and the relationship to contractility in an avian model of heart failure

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Long-term effect of efonidipine therapy on plasma aldosterone and left ventricular mass index in patients with essential hypertension

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