Doctor of Philosophy
Dr. Njanoor Narayanan; Dr. Stephen M. Sims
L-type Ca2+ channels (dihydropyridine receptors, DHPRs) in the sarcolemma are essential to cardiac excitation-contraction (E-C) coupling. Thus, Ca2+ influx through DHPRs upon cardiomyocyte excitation triggers Ca2+ release from the sarcoplasmic reticulum (SR) through ryanodine receptors (RyRs) to initiate myofilament activation and muscle contraction. Muscle relaxation occurs upon sequestration of Ca2+ back into the SR lumen by sarco/endoplasmic reticulum calcium-ATPase (SERCA) in the SR. As a treatment option for hypertension, long-term use of DHPR blockers is associated with increased risk of heart failure; underlying mechanisms are unknown. This research used male Wistar rats treated with verapamil (subcutaneously, 625 µg/h/kg for 4 weeks) to determine the impact of chronic DHPR blockade in vivo, on E-C coupling events and heart function at all levels ranging from molecules to whole organism. The results presented in chapter 2 demonstrate that chronic DHPR blockade caused functional remodeling of RyRs and spatio-temporal dyssynchrony of E-C coupling events, resulting in systolic dysfunction and enhanced susceptibility to arrhythmia. Findings in chapter 3 reveal that chronic DHPR blockade was accompanied by depressed SERCA function, abnormal cardiomyocyte Ca2+ handling, and diastolic dysfunction. Results in chapter 4 reveal adaptational changes in protein phosphorylation-dependent regulation of SR/cardiomyocyte Ca2+ cycling due to chronic DHPR blockade. These include over-expression of Ca2+/calmodulin-dependent protein kinases II (CaMKII), hyper-phosphorylation of SR Ca2+ cycling proteins by CaMKII and cAMP-dependent protein kinase (PKA), paradoxically diminished SR Ca2+ content and contractile reserve, and blunted inotropic response to beta-adrenergic stimulation. The above adaptations to chronic DHPR blockade occurred in the absence of cardiac hypertrophy or fibrosis. Thus, molecular remodeling may invoke cardiac pathology and heart failure without microscopic structural changes in cardiomyocytes. The findings from this thesis reveal, for the first time, integrated mechanisms underlying the increased risk of heart failure associated with chronic DHPR blockade. In addition to urging caution in the conventional clinical use of DHPR blockers, the novel mechanistic events and molecular remodeling revealed here imply that manipulation of the stoichiometry of molecular players in E-C coupling demand critical attention and careful scrutiny in the design and deployment of therapeutic approaches for heart diseases.
Zhou, Ji, "Cardiac Adaptation To Chronic Blockade Of Voltage-Gated, L-Type Calcium Channels In The Sarcolemma" (2010). Electronic Thesis and Dissertation Repository. 54.