title: Attenuation of cardiac contractility in Na,K-ATPase alpha1 isoform-deficient hearts under reduced calcium conditions.
abstract: We have previously reported that genetic reduction of the Na,K-ATPase alpha1 isoform (alpha1(+/-)) results in a hypocontractile cardiac phenotype. This observation was surprising and unexpected. In order to determine if calcium overload contributes to the depressed phenotype, cardiac performance was examined by perfusing the hearts with buffer containing 2 or 1.5 mM calcium. At 2 mM calcium, +dP/dt for the alpha1(+/-) hearts (1374 +/- 180) was significantly less than that of wild-type (2656 +/- 75, P < 0.05). At 1.5 mM calcium, a larger decrease in +dP/dt occurred (vs. 2 mM calcium) for the alpha1(+/-) hearts (517 +/- 92) compared to wild-type (2238 +/- 157). At 2 mM calcium, -dP/dt was 50% lower in alpha1(+/-) hearts (-1903 +/- 141) than wild-type (-982 +/- 143). At 1.5 mM calcium relaxation was further reduced in alpha1(+/-) compared to wild-type (-443 +/- 56 vs. - 1691 +/- 109). We also tested whether the compensatory upregulation of the Na,K-ATPase alpha2 isoform in the alpha1(+/-) hearts contributes to the hypocontractile phenotype. At 8 x 10(-6) M ouabain, that would completely inhibit the alpha2 isoform, a 30% increase in contractility was obtained in alpha1(+/-) hearts compared to no ouabain treatment, while a 63% faster time-to-peak (TTP) and 67% faster half-time-to-relaxation (RT(1/2)) were observed in alpha1(+/-) hearts treated with ouabain. These results suggest that upregulation of the alpha2 isoform may play a role in slower TTP and RT(1/2) in the alpha1(+/-) hearts. Furthermore, lowering extracellular calcium in the perfusate did not alleviate the depressed contractile phenotype in the alpha1(+/-) hearts and resulted in further depressed cardiac contractility suggesting that these hearts are not calcium overloaded.
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Moseley
authors.forename: Marc H
authors.initials: MH
authors.lastname: Cougnon
authors.forename: Ingrid L
authors.initials: IL
authors.lastname: Grupp
authors.forename: Jo
authors.initials: J
authors.lastname: El Schultz
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D010042:Ouabain / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014335:Tropomyosin / Q000378:metabolism; D019210:Troponin I / Q000378:metabolism; D015854:Up-Regulation; D017725:Ventricular Pressure / Q000187:drug effects / Q000502:physiology
chemical_list: D014335:Tropomyosin; D019210:Troponin I; D010042:Ouabain; C401838:Atp1a2 protein, mouse; D018995:Myosin Heavy Chains; C497344:Atp1a1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium