Reduced subendocardial ryanodine receptors and consequent effects on cardiac function in conscious dogs with left ventricular hypertrophy

The goal of this study was to examine the transmural distribution of ryanod ine receptors in left ventricular (LV) hypertrophy (LVH) and its in vivo co nsequences. Dogs were chronically instrumented with an LV pressure gauge, u ltrasonic crystals for measurement of LV internal diameter and wall thickne ss, and a left circumflex coronary blood flow velocity transducer. Severe L VH was induced by chronic banding of the aorta (12+/-1 months), which resul ted in a 78% increase in LV/body weight. When ryanodine was infused directl y into the circumflex coronary artery, it did not affect LV global function or systemic hemodynamics; however, it reduced LV wall thickening and delay ed relaxation in the posterior wall in control dogs but was relatively inef fective in dogs with LVH. In LV sarcolemmal preparations, [H-3]ryanodine li gand binding revealed a subendocardial/subepicardial gradient in normal dog s. In LVH there was a 45% decrease in ryanodine receptor binding and a loss in the natural subendocardial/subepicardial gradient, which roughly correl ated inversely with the extent of LVH and directly with regional wall motio n. Both mRNA and Western analyses revealed similar findings, with a reducti on of the transmural mRNA levels and a loss in the natural gradient between subendocardial and subepicardial layers in LVH. Thus, ryanodine receptor m essage and binding in LVH is reduced preferentially in the subendocardium w ith consequent attenuation of the action of ryanodine in vivo. The selectiv ely altered ryanodine regulation subendocardially in LVH could reconcile so me of the controversy in this field and may play a role in mediating decomp ensation from stable LVH.