Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium.
L-Arginine, the sole substrate for the nitric oxide (NO) synthase (NOS) enzyme in producing NO, is also a substrate for arginase. We examined normal feline hearts and hearts with compensated left ventricular (LV) hypertrophy (LVH) produced by ascending aorta banding. Using Western blot analysis, we examined the abundance of arginase isozymes in crude homogenates and isolated cardiac myocytes obtained from the LVs of normal and LVH hearts. We examined the functional significance of myocyte arginase via measurement of shortening and intracellular calcium in isolated myocytes in the presence and absence of boronoethyl chloride (BEC), a specific pharmacological inhibitor of arginase. Both arginase I and II were detected in crude myocardial homogenates, but only arginase I was present in isolated cardiac myocytes. Arginase I was downregulated in LVH compared with normal. Inhibition of arginase with BEC reduced fractional shortening, maximal rate of shortening (+dL/dt) and relengthening (-dL/dt), and the peak of the free cytosolic calcium transient in normal myocytes but did not affect these parameters in LVH myocytes. These negative inotropic actions of arginase inhibition were associated with increases in cGMP generation. These studies indicate that only arginase I is present in cardiac myocytes where it tends to limit NO and cGMP production with the effect of supporting basal contractility. In experimental LVH induced by pressure overload, our studies demonstrate reduced arginase I expression and reduced functional significance, allowing greater arginine substrate availability for NO/cGMP signaling.
Jung
Albert S
AS
Department of Physiology, Temple Universtity, Philadelphia, PA, USA.
Kubo
Hajime
H
Wilson
Rachel
R
Houser
Steven R
SR
Margulies
Kenneth B
KB
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D002415:Cats; D002478:Cells, Cultured; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D066298:In Vitro Techniques; D032342:Muscle Cells / Q000201:enzymology* / Q000473:pathology; D009200:Myocardial Contraction; D009569:Nitric Oxide / Q000378:metabolism*
D009569:Nitric Oxide; D001119:Arginase