title: β(2)-Adrenergic and M(2)-muscarinic receptors decrease basal t-tubular L-type Ca2+ channel activity and suppress ventricular contractility in heart failure.
abstract: L-type Ca(2+) channels (LTCC) play a crucial role in cardiac excitation-contraction coupling. We previously found that in failing ventricular myocytes of mice chronically treated with isoproterenol, basal t-tubular (TT) LTCC activity was halved by activation of protein phosphatase (PP)2A whereas basal surface sarcolemmal (SS) LTCC activity was doubled by inhibition of PP1. Interestingly, chronic treatment of these mice with pertussis toxin almost completely normalized TT and SS LTCC densities and cardiac contractility. In the present study, we therefore sought to identify the Gi/o protein-coupled receptors in cardiac myocytes (i.e. β2-adrenergic, M2-muscarinic and A1-adenosine receptors) that are responsible for these abnormalities in heart failure by chronically administrating mice a selective antagonist of each receptor (ICI118,551, atropine and 8-cyclopentyl-1,3-dipropilxanthine (DPCPX), respectively) with isoproterenol. Compared with mice treated with isoproterenol alone, mice treated with isoproterenol plus ICI118,551 or atropine, but not DPCPX showed significantly lower lung weight/tibial length, higher fractional shortening, lower left ventricular end-diastolic pressure and higher dP/dtmax and dP/dtmin. In addition, ventricular myocytes of mice treated with isoproterenol plus ICI118,551 or atropine, but not DPCPX exhibited significantly higher TT and lower SS LTCC current densities than those of mice treated with isoproterenol alone due to normalization of the PP activities. These results indicate that β2-adrenergic, M2-muscarinic, but not A1-adenosine receptors contribute to reduced ventricular contractility at least partially by decreasing basal TT LTCC activity in heart failure. Therefore, antagonists of β2-adrenergic and/or M2-muscarinic receptors can be good adjuncts to β1-adrenergic receptor antagonists in the treatment of heart failure.
authors.affiliation: Department of Molecular Pharmacology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kashihara
authors.affiliation: Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Iwate Medical University, Morioka, Iwate, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Department of Pathology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimojo
authors.affiliation: Department of Molecular Pharmacology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakada
authors.affiliation: Department of Molecular Pharmacology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan; Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Simmon
authors.initials: S
authors.lastname: Gomi
authors.affiliation: Department of Cardiovascular Medicine, Shinshu University School of Health Science, Matsumoto, Nagano, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hongo
authors.affiliation: Department of Molecular Pharmacology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. Electronic address: myamada@shinshu-u.ac.jp.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009200:Myocardial Contraction / Q000502:physiology*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011412:Propanolamines / Q000494:pharmacology; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D011412:Propanolamines; D043585:Receptor, Muscarinic M2; D018343:Receptors, Adrenergic, beta-2; D014970:Xanthines; D019319:Okadaic Acid; C026777:ICI 118551; D001285:Atropine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D010749:Phosphoprotein Phosphatases
keywords: A(1)-adenosine receptor; Heart failure; L-type Ca(2+) channels; M(2)-muscarinic receptor; Protein phosphatase; β(2)-adrenergic receptor