Circulation Research, Vol 61, 761-771, Copyright © 1987 by American Heart Association

ARTICLES

Inotropic response to hypothermia and the temperature-dependence of ryanodine action in isolated rabbit and rat ventricular muscle: implications for excitation-contraction coupling

MJ Shattock and DM Bers
Division of Biomedical Sciences, University of California, Riverside 92521.

We have used the sarcoplasmic reticulum (SR) inhibitor ryanodine to assess the contribution of the SR to the increase in twitch tension seen on cooling the mammalian myocardium. To select a suitable concentration of ryanodine, i.e., one that will exert a maximal effect at all temperatures studied, concentration-response curves for ryanodine action were constructed at 37 degrees, 29 degrees, and 23 degrees C in ventricular muscle from rabbit and rat. Using a concentration of ryanodine (1 microM) that exerted a maximal effect at all temperatures studied, the ability of ryanodine to inhibit SR function at 37 degrees, 29 degrees, and 23 degrees C was then confirmed by using rapid cooling contractures (RCCs) to provide an indirect assessment of the SR calcium content. To estimate the rest decay of the SR calcium content in the absence and presence of ryanodine (1 microM), RCCs were initiated after a range of rest intervals (0.3-300 seconds) in rabbit muscles maintained at 37 degrees, 29 degrees, or 23 degrees C. In the absence of ryanodine, low temperatures elevated RCCs at all rest intervals studied. In the presence of ryanodine, RCCs were only seen at rest intervals shorter than 2.0 seconds, even at 23 degrees C, the lowest temperature studied. Thus, even at 23 degrees C, ryanodine appears to be effective at inhibiting SR calcium release in muscles stimulated at 0.5 Hz (i.e., after 2 seconds rest). Therefore, using this concentration of ryanodine (1 microM) and a stimulation rate of 0.5 Hz, we have investigated the contribution of the SR to the positive inotropic response to hypothermia. Under these conditions, the positive inotropic response to cooling in rabbit ventricle was almost unaffected by the inhibition of the SR with ryanodine. In rat ventricle, a tissue in which SR calcium release may dominate excitation-contraction (EC) coupling, the inotropic response to hypothermia was still observed, although developed tension was strongly depressed at all temperatures. These results suggest that a change in SR function is not the principal mediator of the large (400-500%) increase in force associated with cooling mammalian ventricular muscle from 37 degrees to 25 degrees C. The ryanodine-sensitive fraction of tension development was greatest at 37 degrees C, suggesting that the relative contribution of the SR to tension development in rabbit ventricle is reduced at temperatures below 37 degrees C.(ABSTRACT TRUNCATED AT 400 WORDS)

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