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ABSTRACT: N-type (Ca(v)2.2) voltage-dependent calcium channels (VDCC) play an important role in presynaptic neurotransmitter release in the autonomic nervous system and may be clinically relevant in the treatment of cardiovascular diseases. The physiological impact of N-type VDCC ablation on cardiac function, stimulus-release coupling and cardiac autonomic regulation was studied using mice deficient in the α(1B) subunit of the N-type channel (N-type-/-).The positive inotropic effect (increase in +dP/dt) secondary to high frequency field stimulation (HFFS), mediated by the sympathetic nervous system, was decreased by 33 ± 12.6% in N-type-/- versus 89 ± 11.4% in Wild-Type (WT)(P<0.01), whereas the negative inotropic response (decrease in +dP/dt) following HFFS in the presence of propranolol, mediated by the parasympathetic nervous system, was similar to that in Wild-type (WT) animals 34 ± 5.0% and 35 ± 5.4%, respectively. There were no changes in the postsynaptic β-adrenergic responsiveness, β-adrenoreceptor density or adenylyl cyclase activity. N-type-/- hearts demonstrated an increased contractile response to α(1)-adrenoreceptor (α(1)-ADR) stimulation with 10(-5)M phenylephrine in the presence of the β-blocker propranolol, which might be attributed to an increased expression of PLCβ1. Protein abundance of other signal transducers for α(1) ADR transduction protein was not changed in the N-type-/- hearts. These results suggest that selective impairment of sympathetic inflow does not modulate postsynaptic β-adrenergic responsiveness, but causes increased functional response to α(1)-adrenergic stimulation.
Autonomic neuroscience: basic & clinical 10/2010; 160(1-2):9-15. · 1.82 Impact Factor
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ABSTRACT: Mice over-expressing the alpha(1)_subunit (pore) of the L-type Ca2+ channel (alpha(1C)TG) by 4 months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load. With advancing age (8-11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG),while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2-4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanodine receptor protein levels and phosphorylation become reduced. In FTG, the SR Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca2+ loading or release, as occurs in some other cardiomyopathic models.
PLoS ONE 02/2009; 4(1):e4133. · 4.09 Impact Factor
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ABSTRACT: Mice over-expressing the α1−subunit (pore) of the L-type Ca2+ channel (α1CTG) by 4months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load. With advancing age (8–11 mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG), while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2–4 Hz) signs of diastolic contractile failure appear in NFTG cells. The evolution of frank congestive failure in FTG is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanodine receptor protein levels and phosphorylation become reduced. In FTG, the SR Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca2+ loading or release, as occurs in some other cardiomyopathic models.
PLoS ONE 01/2009; 4(1). · 4.09 Impact Factor
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Roger Hullin,
Jan Matthes,
Sibylle von Vietinghoff,
Ilona Bodi,
Marta Rubio, Karen D'Souza,
Ismail Friedrich Khan,
Dennis Rottländer,
Uta C Hoppe,
Paul Mohacsi,
Eva Schmitteckert,
Ralf Gilsbach,
Moritz Bünemann,
Lutz Hein,
Arnold Schwartz,
Stefan Herzig
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ABSTRACT: Increased activity of single ventricular L-type Ca(2+)-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary beta-subunits as a possible explanation.
By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1) or beta(3) isoforms, beta(2a) and beta(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(2)-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V)1.2 also reveal increased single-channel activity and sarcolemmal beta(2) expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing ("Adaptive Phase"), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered beta(2) expression. Additional evidence for the cause-effect relationship between beta(2)-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V)1.2 and inducible beta(2) cardiac overexpression. Here in non-failing hearts induction of beta(2)-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure.
Our study presents evidence of the pathobiochemical relevance of beta(2)-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.
PLoS ONE 02/2007; 2(3):e292. · 4.09 Impact Factor
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Roger Hullin,
Jan Matthes,
Sibylle von Vietinghoff,
Ilona Bodi,
Marta Rubio, Karen D'Souza,
Ismail Friedrich Khan,
Dennis Rottländer,
Uta C. Hoppe,
Paul Mohacsi,
Eva Schmitteckert,
Ralf Gilsbach
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ABSTRACT: Background. Increased activity of single ventricular L-type Ca2+-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary b-subunits as a possible explanation. Methods and Results. By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC b-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac b-subunits: Unlike b1 or b3 isoforms, b2a and b2b induce a high- activity channel behavior typical of failing myocytes. In accordance, b2-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac CaV1.2 also reveal increased single-channel activity and sarcolemmal b2 expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing (''Adaptive Phase''), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered b2 expression. Additional evidence for the cause-effect relationship between b2-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive CaV1.2 and inducible b2 cardiac overexpression. Here in non-failing hearts induction of b2-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. Conclusions. Our study presents evidence of the pathobiochemical relevance of b2-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.
PLoS ONE 01/2007; 2(3). · 4.09 Impact Factor
