title: Depressed contractile function and adrenergic responsiveness of cardiac myocytes in an experimental model of Parkinson disease, the MPTP-treated mouse.
abstract: Radiotracer and biochemical studies have shown that patients with Parkinson disease lack functional sympathetic innervation to the heart. The same observation was made in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an experimental model of Parkinson disease. This study examined the mechanical properties, adrenergic receptor level and intracellular Ca2+ handling in cardiac myocytes isolated from C57/BL6 mice that received either MPTP (30 mg/kg, i.p., twice in 24 h) or vehicle. Mechanical properties were evaluated using an IonOptix MyoCam system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocities of shortening and relengthen (+/-dL/dt). Intracellular Ca2+ handling was evaluated with fura 2. Myocytes from MPTP-treated mice exhibited a depressed PS (85% of normal), normal TPS, prolonged TR90 (147% of normal), and reduced +/-dL/dt (both 79% of normal). These results were correlated with a 67% reduction of beta-adrenergic receptor expression in myocardial membranes from MPTP-treated mice when compared to normal. Myocytes from MPTP-treated mice also exhibited a reduced peak of intracellular Ca2+ sequestration and sarcoplasmic reticulum (SR) Ca2+ load (55 and 38% of normal, respectively). The resting intracellular Ca2+ and Ca2+-transient decay were comparable to the values seen in myocytes from untreated mice. Myocytes from MPTP-treated and untreated mice were equally responsive over a range of stimulation frequencies (0.1, 0.5, 1, 3 and 5 z). Response to norepinephrine (1 microM) and isoproterenol (1 microM) was reduced in myocytes from MPTP-treated mice. These results demonstrate substantial cardiac dysfunctions in this model of experimental Parkinson disease, probably due to reduced adrenergic responsiveness and SR Ca2+ load.
authors.affiliation: Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58203, USA. jren@uwyo.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: James E
authors.initials: JE
authors.lastname: Porter
authors.forename: Loren E
authors.initials: LE
authors.lastname: Wold
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Aberle
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Muralikrishnan
authors.forename: James R
authors.initials: JR
authors.lastname: Haselton
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation; D005110:Extracellular Space / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology*; D009638:Norepinephrine / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011869:Radioligand Assay; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D015259:Dopamine Agents; D013566:Sympathomimetics; D002110:Caffeine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007545:Isoproterenol; D002118:Calcium; D009638:Norepinephrine