Mechanisms of isoflurane-induced myocardial preconditioning in rabbits

BACKGROUND: Isoflurane has cardioprotective effects that mimic the ischemic preconditioning phenomenon. Because adenosine triphosphate-sensitive potassium channels and adenosine receptors are implicated in ischemic preconditioning, the authors wanted to determine whether the preconditioning effect of isoflurane is mediated through these pathways. METHODS: Myocardial infarct size was measured in seven groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed only in the pretreatments given, and controls received no pretreatment. An ischemia-preconditioned group was pretreated with 5 min of coronary occlusion and 15 min of reperfusion. An isoflurane-preconditioned group was pretreated with 15 min end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus-glyburide group was administered 0.33 mg/kg glyburide intravenously before isoflurane pretreatment. An isoflurane plus 8-(p-sulfophenyl)-theophylline (SPT) group received 7.5 mg/kg SPT intravenously before isoflurane. Additional groups were administered identical doses of glyburide or SPT, but they were not pretreated with isoflurane. Infarct size and area at risk were defined by staining. Data were analyzed by analysis of variance or covariance. RESULTS: Infarct size, expressed as a percentage of the area at risk (IS:AR) was 30.2+/-11% (SD) in controls. Ischemic preconditioning and isoflurane preexposure reduced myocardial infarct size significantly, to 8.3+/-5% and 13.4+/-8.2% (P<0.05), respectively. Both glyburide and SPT pretreatment eliminated the preconditioning-like effect of isoflurane (IS:AR = 30.0+/-9.1% and 29.2+/-12.6%, respectively; P = not significant). Neither glyburide nor SPF alone increased infarct size (IS:AR = 33.9+/-7.6% and 31.8+/-12.7%, respectively; P = not significant). CONCLUSIONS: Glyburide and SPT abolished the preconditioning-like effects of isoflurane but did not increase infarct size when administered in the absence of isoflurane. Isoflurane-induced preconditioning and ischemia-induced preconditioning share similar mechanisms, which include activation of adenosine triphosphate-sensitive potassium channels and adenosine receptors.     

Isoflurane-induced dilation of porcine coronary microvessels is endothelium dependent and inhibited by glibenclamide

BACKGROUND: Isoflurane has been reported to cause dose-dependent constriction in isolated coronary microvessels. However, these results are inconsistent with data from in situ and in vivo heart preparations which show that isoflurane dilates the coronary vasculature. To clarify the direct effects of isoflurane on coronary tone, we measured the response of isolated porcine resistance arterioles (ID, 75 +/- 4.0 microm; range, 41-108 microm) to isoflurane in the presence and absence of adenosine triphosphate-sensitive and Ca2+-activated potassium channel blockers and also after endothelial removal. METHODS: Subepicardial arterioles were isolated, cannulated, and pressurized to 45 mmHg without flow in a 37 degrees C vessel chamber filled with MOPS buffer (pH = 7.4). After all vessels developed spontaneous (intrinsic) tone, dose-dependent (0.17-0.84 mm; approximately 0.5-2.5 minimum alveolar concentration) isoflurane-mediated effects on vessel ID were studied in the presence and absence of extraluminal glibenclamide (1 microm; an adenosine triphosphate-sensitive channel blocker) or iberiotoxin (100 nm; a Ca2+-activated potassium channel blocker) or before and after endothelial denudation using the nonionic detergent CHAPS (0.4%). Vessel ID was measured using an inverted microscope and videomicrometer, and vasomotor responses were analyzed by normalizing changes in arteriole ID to the dilation observed after exposure to 10-4 m sodium nitroprusside, which causes maximal dilation. RESULTS: Isoflurane caused dose-dependent dilation of all coronary arterioles. This vasodilation was 6.0 +/- 0.7 microm at an isoflurane concentration of 0.16 mm (approximately 0.5 minimum alveolar concentration) and 25.3 +/- 2.1 microm at 0.75 mm (approximately 2.5 minimum alveolar concentration). These values represent 18.1 +/- 1.7% and 74.1 +/- 3.3%, respectively, of that observed with 10-4 sodium nitroprusside (34 +/- 3 microm). Glibenclamide, but not iberiotoxin, exposure affected arteriolar dilation in response to isoflurane. Glibenclamide caused a downward displacement of the isoflurane dose-response curve, reducing isoflurane-mediated dilation by an average of 36%. Denuded arterioles showed a marked (approximately 70%) reduction in their ability to dilate in response to isoflurane. CONCLUSIONS: The authors conclude that isoflurane dilates coronary resistance arterioles in a dose-dependent manner, and that this dilation is partially mediated by adenosine triphosphate-sensitive channels and is highly dependent on the presence of a functioning endothelium.     

Prolonged reduction in polymorphonuclear adhesion following oral colchicine.

Polymorphonuclear leucocyte (PMN) function was studied in 7 healthy subjects before and after 5 mg of colchicine taken in divided doses over 24 hours. Mean adherence to nylon fibre colums fell from a pretreatment level of 51% to 33.6% by day 1, remained low (31.8%) at day 5, and returned to pretreatment levels only by about day 9. Random motility (agarose plate method) fell from 932 micrometers to 688 micrometers by day 1, but had returned to normal by day 5. Directed migration and the phagocytic index (opsonised Candida albicans method) were not affected by colchicine treatment. In this marked and prolonged reduction in PMN adhesion implies an influence on maturing PMN precursors in bone marrow. Adherence to nylon fibres may reflect in-vivo properties of PMN which are important in the pathogenesis of acute gouty arthritis.