- but not -opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats
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1 Am J Physiol Heart Circ Physiol 280: H384 H391, but not -opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats GUAN-YING WANG, SONG WU, JIAN-MING PEI, XIAO-CHUN YU, AND TAK-MING WONG Department of Physiology and Institute of Cardiovascular Sciences and Medicine, Faculty of Medicine, University of Hong Kong, Hong Kong Received 4 April 2000; accepted in final form 27 July 2000 Wang, Guan-Ying, Song Wu, Jian-Ming Pei, Xiao- Chun Yu, and Tak-Ming Wong. - but not -opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol Heart Circ Physiol 280: H384 H391, Two series of experiments were performed in the isolated perfused rat heart to determine the role of - and -opioid receptors (OR) in cardioprotection of ischemic preconditioning (IP). In the first series of experiments, it was found that IP with two cycles of 5-min regional ischemia followed by 5-min reperfusion each reduced infarct size induced by 30-min ischemia, and the ameliorating effect of IP on infarct was attenuated with blockade of either mol/l nor-binaltorphimine (nor-bni), a selective -OR antagonist, or mol/l naltrindole (NTD), a selective -OR antagonist. The second series showed that U50,488H, a selective -OR agonist, or D-Ala 2 -D-leu 5 -enkephalin (DADLE), a selective -OR agonist, dose dependently reduced the infarct size induced by ischemia, which mimicked the effects of IP. The effect of 10 5 mol/l U50,488H on infarct was significantly attenuated by blockade of protein kinase C (PKC) with specific PKC inhibitors, mol/l chelerythrine or mol/l calphostin C, as well as by blockade of ATP-sensitive K (K ATP ) channels with blockers of the channel, 10 5 mol/l glibenclamide or 10 4 mol/l 5-hydroxydecanoate. IP also reduced arrhythmia induced by ischemia. Nor-BNI, but not NTD, attenuated, while U50,488H, but not DADLE, mimicked the antiarrhythmic action of IP. In conclusion, the present study has provided first evidence that -OR mediates the ameliorating effects of IP on infarct and arrhythmia induced by ischemia, whereas -OR mediates the effects only on infarct. Both PKC and K ATP channels mediate the effect of activation of -OR on infarct. opioid receptor; protein kinase C; ATP-sensitive potassium channel ISCHEMIC PRECONDITIONING (IP) is a phenomenon in which brief exposures of the myocardium to ischemia protect the heart against subsequent severe ischemia (28). Cardioprotection is manifested in a reduction in infarct size, which is used as the prevailing measure (9). Antiarrhythmic action of IP has also been reported in rats (44, 53), dogs (53), and humans (30). Both adenosine and -opioid receptors (OR) have been shown to mediate the protective effect of IP (21, 40). A previous study in our laboratory (57) showed that the binding affinity of the -OR, the predominant OR in the heart (46, 51), is decreased during reperfusion after ischemia in rats subjected to IP, which correlates with an increase in ventricular fibrillation threshold. The observation suggests a role of the receptor in cardioprotection of IP. In support of the suggestion, another recent study in our laboratory (56) showed that -OR mediates protection of metabolic inhibition preconditioning against severe metabolic inhibition insult in the single ventricular myocyte. In view of the fact that preconditioning with other insults (such as hypoxia, metabolic inhibition, and high calcium) also provides protection to the heart against subsequent severe ischemic insults (2, 34, 61), a cross-tolerance phenomenon, it is therefore highly likely that the -OR mediates cardioprotection of IP. Both protein kinase C (PKC) (17, 24) and ATPsensitive K (K ATP ) channels, which are phosphorylated by PKC (18, 20), have been shown to mediate the cardioprotection of IP. It has also been shown that PKC mediates cardioprotection of metabolic inhibition preconditioning and pretreatment with U50,488H, a -OR agonist (56). In addition, -OR stimulation activates PKC in the heart (4). It is possible that -OR may mediate cardioprotection of IP via PKC and K ATP channels. The purpose of this study was, first, to determine the role of -OR in the cardioprotection of IP and, secondly, to delineate the underlying signaling mechanism. First, we determined the effects of IP and stimulation of -OR with its selective agonist in the absence and presence of its antagonist on infarct induced by ischemia in the isolated perfused rat heart. The effect of stimulation of -OR, which has previously been shown to mediate cardioprotection of IP (19, 39, 42), was also studied for comparison. Second, we studied the effects of pretreatment with a -OR agonist on infarct on blockade of PKC or K ATP channels with respective blockers. Finally, we determined the roles of - and -ORs in the antiarrhythmic action of IP. We found that -OR mediated the ameliorating effects of IP on both infarct and arrhythmia, whereas -OR mediated the effects only on infarct. Both PKC and K ATP chan- Address for reprint requests and other correspondence: T.-M. Wong, Dept. of Physiology, Faculty of Medicine, Univ. of Hong Kong, Li Shu Fan Bldg., Sassoon Rd., Hong Kong The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. H /00 $5.00 Copyright 2001 the American Physiological Society
2 - AND -OPIOID RECEPTORS IN ISCHEMIC PRECONDITIONING H385 Fig. 1. Experimental protocol for the study of the role of - and -opioid receptors in cardioprotection of ischemic preconditioning (IP). Timing of interventions is indicated by timing line at bottom. BNI, nor-binaltorphimine; U50, U50,488H; NTD, naltrindole; DADLE, D-Ala 2 -D-Leu 5 -enkephalin. nels were involved in cardioprotection (reduced infarct size) of pretreatment with a -OR agonist. MATERIALS AND METHODS Langendorff-perfused isolated rat heart preparation. The Langendorff-perfused isolated rat heart preparation was used (57). In brief, male Sprague-Dawley rats weighing g were killed by decapitation with a guillotine. The heart was removed immediately and perfused retrogradely with a Krebs-Ringer solution containing (in mm) 115 NaCl, 5 KCl, 1.2 MgSO 4, 1.2 KH 2 PO 4, 1.25 CaCl 2, 25 NaHCO 3, and 11 glucose. The solution was aerated with 95% O 2-5% CO 2,pH 7.4, under a constant pressure of 100 cmh 2 O. The temperature of the perfusion solution was maintained at 36 C. Total coronary arterial flow was measured by timed collection of the coronary venous effluent in a graduated cylinder. A 2-0 silk thread was passed around the left main coronary artery close to its origin with a taper needle, and the ends were passed through a small vinyl tube to form a snare. The coronary artery was occluded by pulling the snare. Myocardial ischemia was confirmed by regional cyanosis and a substantial fall in coronary flow (CF). Reperfusion was achieved by releasing the snare. In the first 15 min of perfusion, the heart was allowed to stabilize, and any heart exhibiting arrhythmia during this period was discarded. Experimental protocol. After an initial stabilization period of 15 min, the heart was subjected to 30-min regional ischemia and 120-min reperfusion. IP was produced by two cycles of 5-min regional ischemia followed by 5-min reperfusion (Fig. 1). Figure 1 also shows the experimental protocol for the study on the effect of OR blockade on cardioprotection of IP. In this series of experiment, mol/l norbinaltorphimine (nor-bni), a selective -OR antagonist (32), or mol/l naltrindole (NTD), a selective -OR antagonist (33), was perfused for a period of 10 min before the first ischemic episode to 10 min after the second ischemic episode. To determine whether pretreatment with OR agonist mimicked the effect of IP, a selective -OR agonist, U50,488H (52), or a selective -OR agonist, D-Ala 2 -D-Leu 5 -enkephalin (DADLE) (13), was infused for two cycles of 5 min, as shown in Fig. 1. Figure 2 shows the experimental protocol for the study on the roles of PKC and K ATP channels. Phorbol 12- myristate 13-acetate (PMA; 10 7 mol/l), an activator of PKC (23), was perfused for 10 min before 30-min ischemia. The inhibitors of PKC, mol/l chelerythrine (Che) (18) and mol/l calphostin C (Calph) (48), and the K ATP channel blockers, 10 5 mol/l glibenclamide (Glib) (12) and 10 4 mol/l 5-hydroxydecanoate (5-HD) (3), were infused for the period of 10 min before the first ischemic episode to 10 min after the second ischemic episode. Measurement of ischemic (risk) zone and infarct size. At the end of the experiment, the silk snare was securely tightened, and 0.25% Evans blue was then infused into the heart to determine the myocardial risk zone. The heart was weighed, frozen, and cut into 2-mm slices. After removal of the right ventricle and connective tissue, we incubated the slices in 1% 2,3,5-triphenyltetrazolium chloride (TTC) in ph 7.4 buffer for 15 min at 37 C. The slices were immersed in 10% formalin overnight. The areas of infarct (TTC negative) and risk zone (TTC stained) were determined by a computerized planimetry technique (SigmaScan program 4). Volumes of left ventricle, infarct size, and risk zone were calculated by multi- Fig. 2. Experimental protocol for the study of the underlying mechanism of cardioprotection of pretreatment with a -opioid receptor agonist. Timing of interventions is indicated by timing line at bottom. PMA, phorbol 12- myristate 13-acetate; Che, chelerythine; Calph, calphostin C; 5-HD, 5-hydroxydecanoate; Glib, glibenclamide.
3 H386 - AND -OPIOID RECEPTORS IN ISCHEMIC PRECONDITIONING plying each area with slice thickness and summing products. Infarct size was expressed as a percentage of the risk zone. Evaluation of arrhythmias. Fine platinum electrodes were placed on the right atrium and the apex of the left ventricle, allowing an epicardial electrogram to be recorded. A typical electrocardiographic trace consists of a P wave and QRS complex, which occurred at regular intervals. Both premature ventricular contraction (PVC) and ventricular tachycardia (VT) were the main arrhythmias observed within 30-min ischemia. VT was defined as a successive run of at least six PVCs of uniform QRS complex. In this study, the incidence of PVC and duration of VT were determined. Drugs and chemicals. U50,488H, DADLE, Che, PMA, Glib, TTC, and Evans blue were purchased from Sigma Chemical; nor-bni from Tocris Cookson; and Calph, 5-HD, and NTD from Research Biochemicals International. All chemicals were dissolved in distilled water except Glib, Calph, and PMA, which were dissolved in DMSO to a final concentration 0.1%, at which no effect was observed. The concentrations of NTD (37), nor-bni (43), Che (58), Calph (48), Glib (7), and 5-HD (8) used in this study were based on previous studies. At the concentrations used, the OR antagonists, PKC inhibitors, and K ATP channel blockers, which themselves had no effect, blocked the effects of the respective OR agonists, PKC, and K ATP channels. Exclusions. Rat hearts were excluded for the following reasons: five hearts were excluded during the stabilization period because of a CF 15 ml/min, and nine hearts were excluded as a consequence of irreversible ventricular fibrillation (more than 2 min; 3 control, 1 IP, 2 DADLE, 2 DADLE NTD, and 1 NTD heart). Three hearts were excluded due to an excessively large risk volume mm 3 (2 nor-bni IP and 1 control heart) at the end of experiment. Statistical analysis. Data were expressed as means SE. One-way ANOVA was used to detect differences between groups. Paired t-test was used for within-group analyses to Table 1. Hemodynamic parameters Treatment n test drug effects on hemodynamic parameters before ischemia. When multiple comparisons with t-tests were performed, Bonferroni s correction was adopted. P 0.05 was considered statistically significant. RESULTS Hemodynamic data. Heart rate and CF data were summarized in Table 1. Heart rate and CF were comparable in all groups under baseline conditions. Pretreatment with 10 5 mol/l U50,488H or mol/l DADLE induced a transient reduction in heart rate, which was measured at 2 min after the treatment. The heart rate in both groups recovered before ischemia (data not shown). Che ( mol/l) caused an increase in CF, whereas Glib (10 5 mol/l) led to a reduction in CF (Table 1). Coronary artery occlusion resulted in a marked reduction in CF in all of the experimental groups. On reperfusion, CF was restored to normal immediately (data not shown). There were no significant differences in heart rate and CF among groups at the end of reperfusion. Effects of IP or pretreatment of - or -OR agonist on infarct caused by ischemia in isolated perfused rat hearts. There was no significant difference in the risk area among all groups. Ischemia induced myocardial infarct. In agreement with a previous finding (22), exposure to two cycles of 5-min ischemia each reduced the infarct size caused by ischemia (Table 2). In the presence of either mol/l nor-bni or NTD, which themselves had no effect at all, the ameliorating effect of IP on infarct was significantly attenuated (Table 2). Baseline Treatment Ischemia Reperfusion HR CF HR CF HR CF HR CF Control IP BNI IP NTD IP U * U50 BNI BNI DADLE * DADLE NTD NTD PMA U50 Che * U50 Calpn Che Calph U50 5-HD U50 Glib * HD Glib * Values are means SE; n is the number of hearts. Baseline, at 10 min of perfusion; treatment, 1 min after treatment; ischemia, 5 min after regional ischemia; reperfusion, 120 min after reperfusion; ischemic preconditioning (IP): 5-min regional ischemia followed by 5-min reperfusion for two cycles. Concentrations were the following (in mol/l): U50, 488H (U50), 10 5 ; D-Ala 2 -D-Leu 5 -enkephalin (DADLE), ; nor-binaltorphimide (BNI), ; naltindole (NTD), ; phorbol 12-myristate 13-acetate (PMA: 10 7 ; chelerythrine (Che), ; calphostin C (Calph), ; 5-hydrodecanoate (5-HD), 10 4 ; and glibenclamide (Glib), HR, heart rate in beats/min; CF, coronary flow in ml/min. *P 0.05 vs. baseline.
4 - AND -OPIOID RECEPTORS IN ISCHEMIC PRECONDITIONING H387 Table 2. Effects of IP on myocardial infarct upon blockade of - or -opioid receptor Treatment n Rat Weigh, g LV, cm 3 RA, cm 3 IA, cm 3 I/R Control IP # # BNI IP * * NTD IP * * BNI NTD Values are means SE. IP: 5-min regional ischemia followed by 5-min reperfusion for two cycles. Concentrations were the following (in mol/l): BNI, and NTD, ; LV, left ventricle area; RA, risk zone area; IA, infarct size area; I/R, % infarction of risk zone. *P 0.01 vs. IP. #P 0.01 vs. control. Fig. 3. Effects of pretreatment with opioid receptor agonists U50 and DADLE on infarct in the absence or presence of respective antagonists. In the U50 BNI and DADLE NTD groups, the concentrations of U50 and DADLE were 10 5 and mol/l, respectively. Both BNI and NTD were mol/l. Infarct size was measured as a percentage of risk zone. Control, n 6; U50 (10 5 mol/l), n 7; U50 ( mol/l), n 8; U50 (10 6 mol/l), n 6; U50 BNI, n 9; DADLE (10 8 mol/l), n 6; DADLE (10 7 mol/l), n 7; DADLE ( mol/l), n 6; and DADLE NTD, n 6 (where n is the number of hearts in each group). Values are expressed as means SE. *P 0.01 vs. control; #P 0.01 vs. corresponding group. Similar to the effect of IP, pretreatment with either U50,488H, a selective -OR agonist, or DADLE, a selective -OR agonist, concentration dependently reduced the infarct size induced by ischemia (Fig. 3). The effect of the agonists at the highest concentrations of the concentration ranges used in this study was abolished by their respective antagonists (Fig. 3). Effects of IP or pretreatment of - or -OR agonist on arrhythmia induced by ischemia in isolated perfused rat hearts. Ischemia induced mainly PVC and VT. IP significantly reduced the number of PVCs and duration of VT (Fig. 4). Interestingly, the ameliorating effect of IP was attenuated in the presence of mol/l nor-bni but not mol/l NTD (Fig. 4). It is important to note that, at the concentrations used, both OR antagonists, which had no effects on arrhythmia (Fig. 4), attenuated the effects of IP on infarct (Table 2). Pretreatment with U50,488H at mol/l also concentration dependently attenuated the arrhythmogenic effects of ischemia (Fig. 5). On the other hand, pretreatment with DADLE at a similar concentration range ( mol/l) had no effect on arrhythmia at all (Fig. 5). Effects of pretreatment with U50,488H on infarct and arrhythmia on blockade of PKC in isolated perfused rat hearts. As shown in Fig. 6, the ameliorating effect of pretreatment with U50,488H on infarct was mimicked by 10 7 mol/l PMA, an activator of PKC, and completely blocked by selective PKC inhibitors, mol/l Che or mol/l Calph. On the other hand, blockade of PKC with either of the two selective inhibitors did not alter the effect of pretreatment with U50,488H on arrhythmia (Fig. 7). Effects of pretreatment with U50,488H on infarct with blockade of K ATP channel in isolated perfused rat hearts. As shown in Fig. 6, the ameliorating effect of U50,488H on infarct induced by ischemia was abolished on blockade of K ATP channel with two inhibitors, Glib and 5-HD, which themselves had no effect at all (Fig. 6). The effects on arrhythmia were not studied because the inhibitors of the K ATP channel themselves induced arrhythmia. DISCUSSION The most interesting observations in this study are 1) the -OR antagonist, nor-bni, attenuated the ameliorating effects of IP on infarct and arrhythmia induced by ischemia in the isolated perfused rat heart and 2) pretreatment with a -OR agonist, U50,488H, reduced the effects of ischemia on infarct and arrhythmia, which mimicked the effect of IP. These observations provided evidence indicating that -OR mediates cardioprotection and the antiarrhythmic action of IP. This extends the previous findings that the affinity of the -OR binding site is decreased during reperfusion after ischemia in rats subjected to IP (57) and that -OR mediates cardioprotection of metabolic inhibition preconditioning (56). The findings are not in agreement with the results of previous studies, which showed that nor-bni does not antagonize the ameliorating effects of hypoxic preconditioning on survival time in mice (25), and of IP on infarct in the anesthetized Wistar rat (42) and in an isolated perfused rat heart (1), respectively, suggesting that -OR is not involved in protection of preconditioning with either hypoxia or ischemia. However, nor-bni has been shown not to be sufficiently active in vivo previously in two studies (6, 29). The concentration of nor-bni used in the isolated rat heart study was M (1), much lower than the con-
5 H388 - AND -OPIOID RECEPTORS IN ISCHEMIC PRECONDITIONING Fig. 4. Effect of IP on number of premature ventricular contractions (PVCs) and duration of ventricular tachycardia (VT) induced by 30-min ischemia in the presence or absence of mol/l BNI, a -OR antagonist, or NTD, a -OR antagonist. Control, n 11; IP, n 12; IP BNI, n 12; IP NTD, n 8; BNI, n 6; and NTD, n 6. Values are means SE. *P 0.01 vs. control; #P 0.05 vs. IP. centration ( M) required to block the cardioprotection of IP in the same preparation, as demonstrated in this study. In addition, the findings in this study are not in agreement with the finding that 30 nmol/l bremazocine and 1 mol/l DADLE increased the infarct size in the isolated rat heart subjected to ischemia, and the effects were antagonized by nor-bni (1). These observations suggest that -OR stimulation exacerbated the ischemia-induced infarct rather than producing protection. It should be noted that bremazocine is a nonselective -OR agonist with a preference for the 2 -OR subtype (47, 60), whereas DADLE is a -OR agonist. The concentration of bremazocine (30 nmol/l) used in the previous study was much lower than the concentration range (1 10 mol/l) used in this study. Further study is needed to clarify the discrepancies in the two studies. In this study, we also obtained evidence that -OR is involved in the ameliorating effect of IP on infarct. This is in agreement with the previous finding that -OR mediates cardioprotection of IP (41, 42). Interestingly, unlike -OR, -OR is not involved in the antiarrhythmic effect of IP. The fact that effects of stimulation of - and -ORs are similar on infarct but different on arrhythmia also supports the suggestion that different mechanisms may be involved for these two parameters (31, 50). The observation that -OR mediates the ameliorating effects of IP on infarct and arrhythmia, whereas -OR mediates the effect only on infarct, indicates that -OR agonists may provide more protection against injury and arrhythmia than that on injury alone with a -OR agonist. So -OR agonists may be more useful for the treatment of cardiac disorders. On the other hand, the -OR agonist produces cardioprotection at a concentration range of mol/l, which is much lower than that of the -OR agonist, mol/l. The observation indicates that a much higher concentration of -OR agonist may be needed to produce cardioprotection. The high concentration needed for -OR agonist to produce cardioprotection means more undesirable effects. In our previous studies, we found that administration of -OR agonists, dynorphin 1-13 (16) and U50,488H at mol/l, induces arrhythmias in the isolated perfused rat heart (5, 54, 55). The arrhythmogenic action of -OR stimulation may not be beneficial. On the other hand, we have also shown that U50,488H at as low as mol/l attenuates arrhythmias induced by low flow and augmented by -adrenoceptor stimulation in the isolated perfused rat heart, an effect antagonized by nor-bni (59), suggesting that -OR stimulation may also produce antiarrhythmic action during ischemia. So in the in vivo situation, -OR stimulation may have both arrythmogenic and antiarrhythmic actions. In this study, we also observed that the ameliorating effect of pretreatment with U50,488H on infarct was attenuated by blockade of PKC with two selective inhibitors, Che and Calph, and that activation of PKC with a selective PKC activator, PMA, mimicked the effect of pretreatment with U50,488H. A previous study (26) showed that morphine produces early cardioprotection similar to that of IP and that the protection of morphine is blocked by naloxone in the isolated rabbit heart. The protective effect of morphine is also blocked by blockade of PKC with a selective inhibitor, suggesting that PKC mediates the effect of OR stimulation (26). Similarly, Wu et al. (56) also showed that the -OR agonist U50,488H Fig. 5. Effects of pretreatment with U50,488H or DADLE on number of PVCs and duration of VT in the absence or presence of respective antagonists. In the U50 BNI group, U50 concentration was 10 5 mol/l and BNI concentration was mol/l. Control, n 11; U50 (10 5 mol/l), n 11; U50 ( mol/l), n 12; U50 (10 6 mol/l), n 11; U50 (10 7 mol/l), n 10; U50 BNI, n 13; DADLE ( mol/l), n 10; and DADLE (10 5 mol/l), n 9. Values are means SE. *P 0.05 vs. control; #P 0.05 vs. U50 (10 5 mol/l).
6 - AND -OPIOID RECEPTORS IN ISCHEMIC PRECONDITIONING H389 Fig. 6. Effects of pretreatment with U50,488H on infarct with blockade of protein kinase C (PKC) and ATP-sensitive K channels. Infarct size was measured as a percentage of risk zone. Concentrations were the following (in mol/l): U50, 10 5 ; BNI, ; PMA, 10 7 ; Che, ; Calph, ; 5-HD, 10 4 ; and Glib, Control, n 6; U50, n 7; U50 BNI, n 6; PMA, n 6; U50 Che, n 8; U50 Calph, n 7; U50 5-HD, n 6; U50 Glib, n 6; Che, n 5; Calph, n 6; Glib, n 6; and 5-HD, n 6. Values are expressed as means SE. *P 0.01 vs. control; #P 0.01 vs. U50 group. produces similar cardioprotection as metabolic inhibition preconditioning and that nor-bni blocks the effects of metabolic inhibition preconditioning and U50,488H, suggesting that -OR mediates the delayed cardioprotection of metabolic inhibition preconditioning via PKC in the rat ventricular myocyte. The observations are in agreement with the finding of this study. It is important to note that PKC also mediates cardioprotection of IP (17, 24) and that stimulation of the adenosine A 1 receptor (21) and bradykinin receptor (11), which activate PKC, mimics cardioprotection of IP, as does OR. The observations from the present and previous studies suggest that PKC may be the central mechanism mediating cardioprotection of IP. On the other hand, PKC inhibitors have also been reported to fail to block the cardioprotection of IP in anesthetized dogs and pigs (45, 49). Interestingly, blockade of PKC with the same inhibitors did not affect the ameliorating effects of pretreatment with U50,488H on arrhythmia, indicating that the messenger does not mediate the action of pretreatment with a -OR agonist on arrhythmia. These observations indicate that different mechanisms are involved in mediating the action of pretreatment with a -OR agonist on infarct and arrhythmia. Previous studies have demonstrated that both - and -ORs activate K channels, which are linked to G protein (15). K ATP channel blockers have been shown to abolish both early and delayed cardioprotection of -OR stimulation (10, 39) and morphine pretreatment (38). In the present study, we also observed that blockade of the K ATP channels also attenuated the ameliorating effect of pretreatment with U50,488H on infarct, indicating that the K ATP channel mediates the effect of pretreatment with U50,488H. So the signaling pathway activated on -OR stimulation during IP includes PKC and K ATP channels. Whether -OR stimulation directly activates the K ATP channel via a pertussis toxin-sensitive G protein or activation of PKC needs further study. Glib is a nonselective inhibitor of K ATP channels (14), whereas 5-HD is considered a selective mitochondrial K ATP channel inhibitor by some (36) but not others (27, 35). The result from this study does not provide sufficient evidence on the role of sarcolemmal and mitochondrial K ATP channel. In this study, we found that Che increased CF, whereas another PKC inhibitor, Calph, had no effect. Glib reduced CF, whereas another blocker of K ATP channels had no effect. All of these agents, which themselves had no effect on infarct, attenuated the ameliorating effect of U50,488H on infarct induced by ischemia. It is unlikely that the effect of these drugs on CF has any correlation with their effect on infarct. In conclusion, this study has provided evidence for the first time that -OR mediates the ameliorating effects of IP on infarct and arrhythmia, whereas -OR mediates the effect only on infarct. Pretreatment with a -OR agonist, U50,488H, may provide more beneficial effects than pretreatment with a -OR agonist, DADLE. However, a higher concentration is required for the -OR agonist to produce cardioprotection. Both PKC and K ATP channels are involved in the cardioprotection (reduced infarct size), whereas PKC is not involved in the antiarrhythmic action of -OR stimulation. Fig. 7. Effects of pretreatment with U50,488H on arrhythmias with blockade of PKC. Concentrations were the following (in mol/l): U50, 10 5 ; Che, ; Calph, ; control, n 11; U50, n 11; U50 Che, n 8; U50 Calph, n 7; Che, n 5; and Calph, n 6. Values are expressed as means SE. *P 0.01 vs. control.
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