BAY K 8644 and nifedipine alter halothane but not caffeine contractures of malignant hyperthermic muscle fibers

Abstract

The purpose of these experiments was to determine if the Ca2+ agonist BAY K 8644 and the Ca2+ antagonist nifedipine alter the mechanical responses of malignant hyperthermia-susceptible (MHS) skeletal muscle to halothane and caffeine. Muscle fiber bundles were dissected from MHS porcine skeletal muscle and exposed to BAY K 8644 (10 microM), nifedipine (1 microM), low-Ca2+ media [Ca2+ replaced by 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid], or diltiazem (30 microM) administered alone and with halothane (3%) or caffeine (0.5-0.8 mM). When administered alone, both halothane and BAY K 8644 evoked a significant change in resting tension (i.e., contracture) of 193.7 +/- 61.0 and 51.9 +/- 21.5 mN/cm2, respectively. When administered in combination, BAY K 8644 had no effect on the magnitude of the halothane contracture (195.2 +/- 58.6 mN/cm2) but reduced its onset time from 306.7 +/- 36.3 to 105.9 +/- 8.9 s. Nifedipine, low Ca2+, and diltiazem significantly reduced the halothane contracture (103.1 +/- 30.3, 123.1 +/- 20.6, and 112.6 +/- 16.2 mN/cm2, respectively) but had no effect on its onset time. In addition, low Ca2+ reduced the magnitude of the BAY K 8644 contracture (8.2 +/- 2.1 mN/cm2). BAY K 8644 also increased contractures induced by low caffeine concentrations (0.5-2.0 mM) but did not alter contractures induced by 4.0 and 8.0 mM caffeine, whereas nifedipine, low Ca2+, and diltiazem had no effect on these contractures. These results suggest that extracellular Ca2+ influx may have some influence on halothane but not on caffeine contractures of MHS skeletal muscle.

A malignant hyperthermia–inducing mutation in RYR1 (R163C): consequent alterations in the functional properties of DHPR channels

“…This observation suggests that one of the retrograde effects of R163C mutation on the L-type channel activity of the DHPR is to facilitate entry of the channel into the long–open gating state (i.e., mode 2; Nowycky et al, 1985), which might explain the enhanced potentiation by ±Bay K 8644. Interestingly, Bay K 8644 enhances pharmacologically (halothane or isofluorane) induced contractures in both swine and human MHS muscle (Williams et al, 1991; Adnet et al, 1992), consistent with the idea that altered L-type current may contribute to the pathogenesis of this disease.…”

“…Williams et al (1991) showed that Bay K 8644 lowers the threshold for halothane-induced contractures in MHS swine muscle fibers. Because the DHPR is the molecular target for Bay K 8644, we tested directly how this agonist affected L-type currents in R163C Het and Hom myotubes.…”

Novel Interventions for Heat/Exercise Induced Sudden Death and Fatigue

“…Oxidative and nitrosative modifications of RyR1 and other muscle proteins result in a feed-forward cycle that drives both the myopathy and the EHR [17]. Several groups have suggested that Ca 2+ influx may contribute to sustained Ca 2+ increases associated with the MH response [43][44][45][46], but the possibilities that Ca 2+ influx via stretch-, store-, or voltage-operated Ca 2+ channels contributes to the EHR in the YS mice remains to be investigated.…”