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 Ca 2+ 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 (TR 90), and maximal velocities of shortening and relengthening (±d L/d t). Intracellular Ca 2+ handling was evaluated with fura 2. Myocytes from MPTP-treated mice exhibited a depressed PS (85% of normal), normal TPS, prolonged TR 90 (147% of normal), and reduced ±d L/d t (both 79% of normal). These results were correlated with a 67% reduction of β-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 Ca 2+ sequestration and sarcoplasmic reticulum (SR) Ca 2+ load (55 and 38% of normal, respectively). The resting intracellular Ca 2+ and Ca 2+-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 Hz). Response to norepinephrine (1 μM) and isoproterenol (1 μM) 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 Ca 2+ load.