Reduced ryanodine receptor to dihydropyridine receptor ratio may underlie slowed contraction in a rabbit model of left ventricular cardiac hypertrophy.
Cardiac hypertrophy is associated with contractile dysfunction, a feature of which is a slowing of the time to reach peak contraction. We have examined the main mechanisms involved in the initiation of contraction and investigated if their functions are changed during cardiac hypertrophy. Cardiac hypertrophy was induced by constriction of the ascending aorta in the rabbit. After 6 weeks left ventricular myocytes were isolated or left ventricular and septal mixed membrane preparations were produced for electrophysiological and radioligand binding studies, respectively. Aortic constriction resulted in a 24% and 23% increase in heart weight to body weight ratio and cell capacitance, respectively. Action potential duration and time-to-reach 50% and 90% peak contraction (TTP(50)and TTP(90), respectively) were significantly prolonged in myocytes from hypertrophied hearts. The prolongation of TTP(50)and TTP(90)could not be explained by altered peak calcium current density or SR calcium content which were unchanged in hypertrophy. Radioligand binding studies performed on tissue preparations from the same hearts, revealed a 34% reduction in ryanodine receptor (RYR) density with no change in dihydropyridine receptor (DHPR) density. This resulted in a reduction in the ratio of RYR to DHPR from 4.4:1 to 3.3:1 in hypertrophy. Ryanodine receptor Ca(2+)-sensitivity was unchanged between sham operated and hypertrophied groups. A reduction in the ratio of RYRs to DHPRs may result in a degree of "functional uncoupling" causing defective release of Ca(2+)from the SR. These findings may underlie the slowed TTP of myocyte contraction in hypertrophy.
Milnes
J T
JT
Dept. Cardiac Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London, SW3 6LY, UK.
MacLeod
K T
KT
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D017275:Isradipine / Q000378:metabolism; D009200:Myocardial Contraction; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002118:Calcium; D017275:Isradipine