Biomedical subjects

R M Krivosic-Horber

Publications and source records attributed to R M Krivosic-Horber.

12 recordsLinked to original sources

PubMed1998

Effects of veratridine on mechanical responses of human malignant hyperthermic muscle fibers.

BACKGROUND: To determine if alteration in the function of the sodium channel may in turn modify halothane-induced changes in mechanical responses of muscle bundles from patients susceptible to malignant hyperthermia (MH). METHODS: Mechanical responses of muscle bundles from 12 MH-susceptible and 20 MH non-susceptible patients were measured prior to and during administration of halothane alone and in the presence of 10 microM veratridine, an inhibitor of sodium channel inactivation. Peak tension (PT), time to peak tension (TPT), positive peak of isometric tension derivative (+dP/dtmax) were used to characterize the inotropic state. Analysis of relaxation process was performed using half relaxation time (RT 1/2) and the negative peak of isometric tension derivative (-dP/dtmax). The ratio (R) = (+dP/dtmax)/(-dP/dtmax) was used to measure the coupling between contraction and relaxation under isometric condition. RESULTS: Veratridine significantly enhanced the 0.5, 1, 2 and 3 vol% halothane-induced contracture and induced a negative inotropic effect in MH-susceptible muscle bundles. R increased by nearly 90% indicating that the combined effects were more pronounced in the relaxation phase. In MH non-susceptible muscle, veratridine did not significantly enhance the effects of halothane. CONCLUSIONS: These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of an inhibitor of sodium channel inactivation.

Calcium↗

PubMed1997

[Effect of chlorocresol vs caffeine on muscle contracture in malignant hyperthermia susceptible patients].

The phenotype of susceptibility to malignant hyperthermia (MHS); can only be detected reliably by the in vitro caffeine-halothane contracture test (CHCT). Enhanced sensitivity of the calcium-induced calcium release mechanism is responsible for the exaggerated contracture response of skeletal muscle fibers from MHS patients to halothane and caffeine. Chlorocresol was demonstrated to be a potent activator of Ca++ release from skeletal muscle sarcoplasmic reticulum. This effect is probably mediated through action on a ryanodine sensitive Ca++ release channel known to be more sensitive in MH. We studied the effect of chlorocresol on the mechanical contracture response of skeletal muscle from patients presenting for the in vitro CHCT. Chlorocresol induces contracture response in a concentration 1/200 of that of caffeine in muscle strips from MH patients. By adding chlorocresol to the protocol of the CHCT, there is clearer discrimination between the responses of MH patients and normal subjects can be achieved.

Adolescent↗

PubMed1997

Malignant hyperthermia susceptibility: anaesthetic implications and risk stratification.

Malignant hyperthermia (MH) is a rare autosomal dominant trait that predisposes individuals to great danger when exposed to certain anaesthetic triggering agents, such as potent volatile anaesthetics and succinylcholine. Sudden hypermetabolic reaction occurs in skeletal muscle, leading to hyperthermia and massive rhabdomyolysis. Precautions must be taken before the anaesthesia of MH-susceptible patients. No triggering agents should be administered, central body temperature and ETCO2 should be carefully monitored, and dantrolene must be immediately available. In addition, the anaesthesia machine should be carefully washed to remove traces of halogenated agents, and the use of fresh disposable anaesthetic circuits is recommended. Early diagnosis of the syndrome by alert, informed anaesthesiologists, and the immediate administration of dantrolene and other supportive measures, has reduced mortality. Patients with MH susceptibility should be instructed to alert the anaesthesiologist about their condition whenever anaesthesia is needed. Although people diagnosed with MH susceptibility should not change their lifestyle in general, military service is limited.

Adolescent↗

PubMed1994

Viability criterion of muscle bundles used in the in vitro contracture test in patients with neuromuscular diseases.

We have compared the viability criteria of muscle bundles used in the in vitro contracture test for susceptibility to malignant hyperthermia (MH) in a group of 28 patients with various neuromuscular diseases (NMD) and 93 MH-related family patients. In the patients with NMD, this standard test gave one positive, six equivocal and 21 negative results. Compared with MH-related family patients, muscle bundles used had significantly smaller resting membrane potentials and smaller predrug twitch tension amplitudes. Some results from the group with NMD were obtained with muscles which were damaged, more rapidly deteriorating, non-standard or both, and should not be taken to indicate that the patients have the genetic trait for MH. The in vitro contracture test is not always relevant for myopathic muscle (especially dystrophic muscle) and this could explain the lack of specificity for MH.

Caffeine↗

PubMed1994

Halothane and isoflurane decrease calcium sensitivity and maximal force in human skinned cardiac fibers.

BACKGROUND: Reports of the direct effects of volatile anesthetics on cardiac myofibrils, studied in various mammalian species but not in humans, have conflicted. To determine whether volatile anesthetics directly affect cardiac contractile proteins in humans, we examined the effects of various equianesthetic doses of halothane (0.46, 0.83, and 1.23 mM, equivalent to 0.75, 1.50, and 2.25%, respectively) and isoflurane (0.63, 1.22, and 1.93 mM, equivalent to 1.15, 2.30, and 3.50%, respectively) on the Ca2+ sensitivity and maximal force in human skinned cardiac fibers. METHODS: Left ventricular muscle strips were obtained from seven patients undergoing cardiac surgery. Sarcolemma was disrupted with EGTA (ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid), and sarcoplasmic reticulum was destroyed with EGTA plus BRIJ 58 detergent. Ca2+ sensitivity was studied by observing the isometric tension developed by skinned fiber bundles challenged with solutions of increasing Ca2+ concentrations expressed in pCa (where pCa = -log10[Ca2+]). Maximal force was measured with a pCa 4.8 solution. RESULTS: Both anesthetics shifted the pCa-tension curves toward higher Ca2+ concentrations and decreased pCa for half-maximal activation in a dose-dependent and reversible fashion (from 5.71 for control to 5.56 and 5.55 for 1 MAC halothane and isoflurane, respectively) without changing the slope of this relationship (Hill coefficient). No differences between agents were observed at equianesthetic concentrations. The two agents also decreased the maximal activated tension in a dose-dependent fashion (-27 and -28% vs. control for 2 MAC halothane and isoflurane, respectively). CONCLUSIONS: The current study indicates that halothane and isoflurane decrease Ca2+ sensitivity and maximal force in human skinned cardiac fibers at 20 degrees C. If these effects extend to higher temperatures, they may contribute to the negative inotropic effect of these agents.

Aged↗

PubMed1992

Effect of Bay K 8644 on the magnitude of isoflurane and halothane contracture of skeletal muscle from patients susceptible to malignant hyperthermia.

Isoflurane has a lesser ability than halothane to induce contracture in malignant hyperthermia (MH) muscle in vitro. This does not necessarily imply that isoflurane is not as potent an MH trigger as halothane in vivo. A hypothesis was tested that in vitro treatment with Bay K 8644, an activator of both the dihydropyridine receptors as well as the sodium channels of the T-tubules, potentiates isoflurane-induced MH-susceptible skeletal muscle contracture. In addition to the usual halothane-caffeine test, other muscle bundles were exposed to 10 microM Bay K 8644-halothane and equipotent anesthetic concentrations (expressed in multiple minimum alveolar concentration [MAC]) of isoflurane either alone or combined with Bay K 8644. In 14 MH-susceptible muscle bundles, the mean maximum contracture induced by 2 MAC isoflurane was 0.20 +/- 0.22 g (mean +/- SD), and this value was significantly less than that obtained with 2 MAC halothane (0.68 +/- 0.40 g). Bay K 8644 did not induce muscle contracture on its own but consistently enhanced both the 0.5 MAC isoflurane and halothane to the same maximal isometric tension (1.09 +/- 0.35 g and 1.11 +/- 0.37 g, respectively). Such an effect was not observed in the MH-nonsusceptible group. Under the conditions of this in vitro study, 0.5 MAC isoflurane appears to be as potent as halothane in inducing muscle contracture in skeletal muscle bundles from individuals susceptible to MH.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1992

Is resting membrane potential a possible indicator of viability of muscle bundles used in the in vitro caffeine contracture test?

In 22 patients susceptible to and 34 patients not susceptible to malignant hyperthermia, we examined which muscle conditions may influence the degree of sensitivity of skeletal muscle to the in vitro caffeine contracture test: predrug resting membrane potential, predrug twitch tension, and maximum contracture induced by 32 mM caffeine in two caffeine tests performed respectively at 30 and 75 min after biopsy. No differences in the measured variables were observed between the first and the second caffeine tests in the 34 patients susceptible to malignant hyperthermia. The first caffeine test was found to be positive in all of the 22 patients susceptible to malignant hyperthermia. However, in eight patients, the second caffeine test was negative and the muscle fibers were found to be significantly depolarized. Resting membrane potential was -73.4 +/- 7.9 mV before the first caffeine test and -65.8 +/- 8.8 mV before the second test. We suggest that when time-induced partial depolarization of malignant hyperthermia-susceptible fibers occurs, fibers may become less sensitive to caffeine.

Caffeine↗

PubMed1991

Effects of calcium-free solution, calcium antagonists, and the calcium agonist BAY K 8644 on mechanical responses of skeletal muscle from patients susceptible to malignant hyperthermia.

The purpose of this investigation was to determine if alteration in the function of the dihydropyridine receptor may in turn modify halothane-induced contractures in muscle bundles from patients susceptible to malignant hyperthermia (MH). The effects of Ca(2+)-free Krebs Ringer (KR) solution, 5 microM verapamil, 5 microM nifedipine, and 10 microM of the Ca2+ agonist BAY K 8644 on halothane-induced contracture were therefore investigated. The halothane-induced contracture was prevented in the absence of extracellular Ca2+ and significantly reduced in the presence of verapamil or nifedipine. BAY K 8644 significantly enhanced the 0.5-, 1.0-, and 1.5-vol % halothane-induced contracture in MH-susceptible muscle bundles. When BAY K 8644 was dissolved in Ca(2+)-free KR solution, no contracture was observed in MH-susceptible muscle bundles. These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of Ca2+ agonists or antagonists to the dihydropyridine receptor. The role of Ca2+ entry phenomena remains unclear, but the results suggest that extracellular Ca2+ is required to reprime or to bind to some sites of the dihydropyridine receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Diltiazem and nifedipine reduce the in vitro contracture response to halothane in malignant hyperthermia-susceptible muscle.

The effects of diltiazem (1 microM) and nifedipine (1 microM) were examined separately on the in vitro halothane tests for malignant hyperthermia (MH) susceptibility. Eighteen patients with MH susceptibility were diagnosed as MH-susceptible (MHS) according to the protocol of the European MH Group. In addition, halothane tests were carried out in the presence of either diltiazem (ten patients) or nifedipine (eight patients). These two calcium channel blockers significantly reduced the halothane contracture. Furthermore, in five of the ten MHS patients tested in the presence of diltiazem as well as in five of the eight MHS patients tested in the presence of nifedipine the halothane contracture test could be classified as negative. It is concluded that the presence of clinical concentrations of either diltiazem or nifedipine in the muscle bath affects the in vitro discrimination for MH susceptibility to halothane.

Depression, Chemical↗

PubMed1990

Clinical concentrations of verapamil affect the in vitro diagnosis of susceptibility to malignant hyperpyrexia.

We examined the effects of verapamil on the in vitro caffeine and halothane tests for malignant hyperpyrexia (MH) susceptibility. Ten consecutive MH-susceptible patients were investigated according to the protocol of the European MH group. Additional tests were carried out in the presence of verapamil 10(-6) mol litre-1. In four of the 10 patients, the halothane contracture response following pretreatment with verapamil was classified as positive to halothane. In contrast, in nine of the 10 patients, contracture tests of muscle in the presence of verapamil were classified as negative to caffeine. It is advised that verapamil should be discontinued before performing a contracture test.

Caffeine↗

PubMed1990

Use of the calcium agonist BAY K 8644 for in vitro diagnosis of susceptibility to malignant hyperthermia.

We have studied the effects of the calcium agonist BAY K 8644 on the in vitro halothane test in 10 malignant hyperthermia-susceptible (MHS), 12 MH "equivocal" to halothane (MHEh), 30 MH non-susceptible (MHN) and 10 control patients. BAY K 8644 potentiated the halothane-induced contracture in muscle strips from both MHS and MHEh patients. The drug produced a more obvious difference in contracture responses between the MHEh group compared with the MHN and control groups.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1989

The association between the neuroleptic malignant syndrome and malignant hyperthermia.

The neuroleptic malignant syndrome (NMS) is an uncommon but dangerous complication of treatment with neuroleptic drugs. A primary defect in skeletal muscle has been suggested in view of similarities in the clinical presentations of NMS and anaesthetic-induced malignant hyperthermia (MH). The in vitro halothane-caffeine contracture tests are the most reliable method of identifying individuals susceptible to MH. The aim of this study was to define if a relationship exists between NMS and MH susceptibility. Hence, the in vitro halothane and caffeine contracture tests were performed on muscle tissue obtained from eight NMS, ten MH-susceptible and ten control patients. The results, which are expressed in accordance with the criteria of the European MH Group, defined the eight NMS subjects as MH non-susceptible. The response to halothane and caffeine exposure of skeletal muscle from NMS and control subjects was the same and significantly different from that of muscle from patients susceptible to MH. Furthermore, muscle from subjects in NMS and control group responded similarly to increasing concentrations of chlorpromazine. These results do not point towards an association between NMS and MH.

Adult↗