Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics.

BACKGROUND: Halogenated anesthetics activate cardiac ryanodine receptor 2-mediated sarcoplasmic reticulum Ca release, leading to sarcoplasmic reticulum Ca depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. METHODS: Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. RESULTS: Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 µM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca activation of ryanodine receptor 2 but had no effect on Mg inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. CONCLUSIONS: At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide-binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca release was due to competition between adenosine and ATP, rather than between halothane and ATP.

Influence of the timing of internal fixation of femur fractures during shock resuscitation on remote organ damage.

BACKGROUND: Reamed intramedullary nailing is the gold standard for management of femur fractures. Nailing within 24 h is proven to reduce complications from ongoing bleeding, soft-tissue damage and pain. However, when combined with haemorrhagic shock, femur fracture and intramedullary nailing are associated with immune-mediated damage to remote organs. We studied whether delaying fracture fixation until resuscitation was succeeding would lead to a significant reduction in remote organ damage. METHODS: Twenty male rabbits underwent closed femur fracture, haemorrhagic shock, resuscitation and either immediate nailing (group: ImmFix, n = 9), delayed nailing (group: DelFix, n = 8) or just splinting (group: NoFix, n = 3). Haemorrhagic shock was maintained for 60 min. Resuscitation was with shed blood and Hartmann's solution. Animals were euthanized 8 h after fixation; the lungs and small bowel were scored histologically by two pathologists. RESULTS: Groups did not differ in weight, haemorrhage volume or magnitude of shock. At 8 h, there was no difference in end-organ damage between ImmFix and DelFix groups (11.3 ± 1.6 and 13.2 ± 1.6 versus 8.1 ± 1.3 and 12.9 ± 1.1, P = 0.26 between groups). However, the NoFix group had significantly greater end-organ damage when compared with the fixation at any time groups (17.3 ± 2.7 and 17.0 ± 3.3 versus 9.8 ± 1.1 and 13.1 ± 1, P = 0.01 between groups). CONCLUSION: In this laboratory model, we have demonstrated that timely femur fracture fixation outweighs the potential harmful effects of surgery performed during haemorrhagic shock with simultaneous resuscitation. We have failed to demonstrate a difference between immediate and delayed fixation during resuscitation.

Postexercise hypotension in conscious SHR is attenuated by blockade of substance P receptors in NTS.

In hypertensive subjects, a single bout of dynamic exercise results in an immediate lowering of blood pressure back toward normal. This postexercise hypotension (PEH) also occurs in the spontaneously hypertensive rat (SHR). In both humans and SHRs, PEH features a decrease in sympathetic nerve discharge, suggesting the involvement of central nervous system pathways. Given that substance P is released in the nucleus tractus solitarius (NTS) by activation of baroreceptor and skeletal muscle afferent fibers during muscle contraction, we hypothesized that substance P acting at neurokinin-1 (NK-1) receptors in the NTS might contribute to PEH. We tested the hypothesis by determining, in conscious SHRs, whether NTS microinjections of the NK-1 receptor antagonist SR-140333 before exercise attenuated PEH. The antagonist, in a dose (60 pmol) that blocked substance P- and spared D,L-homocysteic acid-induced depressor responses, significantly attenuated the PEH by 37%, whereas it had no effect on blood pressure during exercise. Vehicle microinjection had no effect. The antagonist also had no effect on heart rate responses during both exercise and the PEH period. The data suggest that a substance P (NK-1) receptor mechanism in the NTS contributes to PEH.