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Am J Physiol Heart Circ Physiol 274: H909-H914, 1998;
0363-6135/98 $5.00
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Vol. 274, Issue 3, H909-H914, March 1998

TAN-67, a delta 1-opioid receptor agonist, reduces infarct size via activation of Gi/o proteins and KATP channels

Jo El J. Schultz1, Anna K. Hsu1, Hiroshi Nagase2, and Garrett J. Gross1

1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 2 Toray Industries, Basic Research Laboratories, Kanagawa 248, Japan

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

We have previously shown that delta (delta )-opioid receptors, most notably delta 1, are involved in the cardioprotective effect of ischemic preconditioning (PC) in rats; however, the mechanism by which delta -opioid receptor-induced cardioprotection is mediated remains unknown. Therefore, we hypothesized that several of the known mediators of ischemic PC such as the ATP-sensitive potassium (KATP) channel and Gi/o proteins are involved in the cardioprotective effect produced by delta 1-opioid receptor activation. To address these possibilities, anesthetized, open-chest Wistar rats were randomly assigned to five groups. Control animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. To demonstrate that stimulating delta 1-opioid receptors produces cardioprotection, TAN-67, a new selective delta 1-agonist, was infused for 15 min before the long occlusion and reperfusion periods. In addition, one group received 7-benzylidenenaltrexone (BNTX), a selective delta 1-antagonist, before TAN-67. To study the involvement of KATP channels or Gi/o proteins in delta 1-opioid receptor-induced cardioprotection, glibenclamide (Glib), a KATP channel antagonist, or pertussis toxin (PTX), an inhibitor of Gi/o proteins, was administered before TAN-67. Infarct size (IS) as a percentage of the area at risk (IS/AAR) was determined by tetrazolium stain. TAN-67 significantly reduced IS/AAR as compared with control (56 ± 2 to 27 ± 5%, n = 5, P < 0.05). The cardioprotective effect of TAN-67 was completely abolished by BNTX, Glib, and PTX (51 ± 3, 53 ± 5, and 61 ± 4%, n = 6 for each group, respectively). These results are the first to suggest that stimulating the delta 1-opioid receptor elicits a cardioprotective effect that is mediated via Gi/o proteins and KATP channels in the intact rat heart.

glibenclamide; pertussis toxin; ischemic preconditioning

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

IN RECENT YEARS, a great deal of interest has focused on the phenomenon of ischemic preconditioning (PC) and the mechanisms by which its potent cardioprotective effect occurs. This fascinating observation has stimulated numerous studies to determine potential mediators and/or modulators of this myocardial protection. Liu et al. (30) showed that ischemic PC protected against myocardial infarction, and this effect was mediated by adenosine A1 receptors in the rabbit. Gross and Auchampach (14) were the first to demonstrate that preconditioning was mediated through the ATP-sensitive potassium (KATP) channel in the canine heart. In addition, Gi proteins (26, 54), protein kinase C (PKC) (65), muscarinic receptors (61, 62), and the Na+/H+ exchanger (1, 40, 44) have been implicated in the mechanism(s) of ischemic PC. The two prominent, potential cardioprotective mechanisms, the adenosine A1 receptor and the KATP channel, have also been investigated in the rat heart; however, Liu and Downey (31) found that neither mediator appeared to be responsible for ischemic PC in this species. Recently, the KATP channel has been shown to mediate ischemic PC in the intact rat model of myocardial infarction (42, 49, 51). Furthermore, stimulation of certain second messengers such as PKC (29, 53), heat stress proteins (8), and muscarinic receptor activation (42, 43) have been proposed to reduce myocardial necrosis in intact rats.

Recently, our laboratory demonstrated that the opioid receptor system is involved in eliciting the cardioprotective effect of ischemic PC in the rat (45-48, 50). We showed that delta (delta )-opioid receptors, most notably the delta 1-opioid receptor, mediate the cardioprotective effect of ischemic PC (47, 48). A number of investigators have provided evidence that delta -opioid receptors exist on rat cardiac myocytes (23, 55, 56, 66). In addition, Wittert et al. (59) determined the distribution of expression of the mu (µ)-, kappa (kappa )-, and delta -opioid receptors in peripheral tissue of the rat and found that delta -receptor transcripts were predominantly detected in the heart, whereas a weak kappa - and no µ-receptor transcripts were measured. Therefore, we tested the hypothesis that stimulating delta 1-opioid receptors would reduce myocardial infarct size (IS) and that this opioid receptor-mediated cardioprotection involved a mechanism similar to that observed with ischemic PC in the rat heart.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

This study was performed in accordance with the guidelines of the Animal Care Committee of the Medical College of Wisconsin, which is accredited by the American Association of Laboratory Animal Care.

General surgical preparation. Male Wistar rats weighing 350-450 g were used. The rats were anesthetized by intraperitoneal administration with the long-acting thiobutabarbital Inactin (100 mg/kg iv). A tracheotomy was performed, and the rat was intubated with a cannula connected to a rodent ventilator (model 683, Harvard Apparatus, South Natick, MA). The rat was ventilated with room air at 65-70 breaths/min. Atelectasis was prevented by maintaining a positive end-expiratory pressure of 5-10 mmH2O. Arterial pH, PCO2, and PO2 were monitored at baseline, at 15 min of occlusion, and at 15, 60, and 120 min of reperfusion by a blood gas system (AVL 995, Automatic Blood Gas System, Roswell, GA) and maintained within a normal physiological range (pH 7.35-7.45; PCO2 25-40 mmHg; PO2 80-110 mmHg) by adjusting the respiratory rate and/or tidal volume. Body temperature was monitored (Yellow Springs Instruments Tele-Thermometer, Yellow Springs, OH) and maintained at 37 ± 1°C (SE) using a heating pad. Blood glucose for the glibenclamide (Glib) plus TAN-67 protocol was measured at the same time points as the blood gas measurements as well as at 30 min post-Glib administration and 15 min post-TAN-67 infusion using a blood glucose monitor (model 780, Tracer II, Boehringer Mannheim Diagnostics) and glucose reagent strips (Tracer bG Strips, Boehringer Mannheim).

The right carotid artery was cannulated to measure blood pressure and heart rate (HR) via a Gould PE50 or Gould PE23 pressure transducer that was connected to a Grass (model 7) polygraph. The right jugular vein was cannulated to infuse saline or drugs. A left thoracotomy was performed ~10 mm from the sternum to expose the heart at the fifth intercostal space. The pericardium was removed, and the left atrial appendage was moved to reveal the location of the left coronary artery. The vein descending along the septum of the heart was used as the marker for the left coronary artery. A ligature (6-0 prolene), along with a snare occluder, was placed around the vein and left coronary artery close to the place of origin. After surgical preparation, the rat was allowed to stabilize for 15 min before the various interventions.

Drugs. Inactin and pertussis toxin (PTX) were purchased from Research Biochemicals International (Natick, MA). 2-Methyl-4aalpha -(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha -octahydro-quinolino[2,3,3-g]isoquinoline [(-)-TAN-67] and 7-benzylidenenaltrexone (BNTX) were from Toray Industries (Kanagawa, Japan). 2,3,5-Triphenyltetrazolium chloride (TTC), adenosine (Ado), acetylcholine (ACh), and Glib were purchased from Sigma Chemical (St. Louis, MO). Inactin, Ado, ACh, and TAN-67 were dissolved in 0.9% saline. Each 50-µg vial of PTX was reconstituted with 500 µl sterile distilled water. BNTX was dissolved in distilled water and brought up to volume with saline. Glib was dissolved in a 1:1:1:2 cocktail mixture of polyethylene glycol, 95% ethanol, 0.1 N sodium hydroxide, and 0.9% saline, respectively. We have previously shown that saline or Glib vehicle has no effect on IS in nonpreconditioned rat hearts (45). TTC was dissolved in a 100 mM phosphate buffer.

Study groups and experimental protocols. Animals were randomly assigned to one of the five experimental studies. The control group was subjected to 30 min of occlusion and 2 h of reperfusion (group I, n = 6). Experiments were performed to test whether a delta 1-opioid receptor agonist could mimic the protective effect of ischemic PC and which signal transduction pathway might be involved (Fig. 1). TAN-67 (10 mg/kg iv), a nonpeptidic delta 1-opioid receptor agonist, was infused for 15 min before the 30-min occlusion period (group II, n = 5). In group III (n = 6), BNTX (3 mg/kg iv), a specific delta 1-opioid receptor antagonist, was given 10 min before the 15-min TAN-67 infusion (10 mg/kg iv) to test whether TAN-67 is stimulating the delta 1-opioid receptor. This dose of BNTX has been previously shown to have no effect on IS in nonpreconditioned rats in our laboratory (48). In group IV (n = 6), Glib (0.3 mg/kg iv), the KATP channel antagonist, was given 30 min before the 15-min infusion of TAN-67 to demonstrate an involvement of myocardial KATP channels in delta 1-opioid receptor-induced cardioprotection. Previously, we showed that Glib when administered 30 min before, but not 5 min before, the preconditioning stimuli completely abolished the cardioprotective effect (51). Therefore, in this study, we administered Glib 30 min before TAN-67 infusion to allow time for antagonism of the KATP channels. This dose of Glib was shown previously in our laboratory to have no effect on IS in nonpreconditioned rats (45, 51). Group V (n = 6) tested an interaction between Gi/o proteins and the delta 1-opioid receptor. Animals were pretreated with PTX (10 µg/kg ip), an inhibitor of Gi/o proteins via ADP-ribosylation of the alpha -subunit, for 48 h before the 15-min TAN-67 infusion (10 mg/kg iv). The dose of PTX was based on the protocol of Endoh et al. (11) in which PTX (0.125-1.0 µg/100 g Wistar rat body wt) dose dependently attenuated the inhibitory effects of atrial muscarinic receptor activity. During observation, the animals did not appear to be physically sick at this dose of PTX used in the present study. To demonstrate that PTX inhibited the G proteins, the changes in HR induced by ACh and Ado (responses previously shown to be mediated by Gi proteins) were measured (13). In a separate experiment using four rats, ACh (0.15 mg/kg iv) and Ado (1 mg/kg iv) produced marked decreases in HR from 515 ± 35 to 310 ± 10 and 475 ± 35 to 285 ± 15 beats/min, respectively. These responses to ACh and Ado were completely abolished in six PTX-treated rats (PTX control, HR of 450 ± 10 beats/min vs. PTX + ACh, HR of 432 ± 9 beats/min and PTX + Ado, HR of 426 ± 13 beats/min). This dose of PTX had no effect on IS in nonpreconditioned rats (53.3 ± 9.3% vs. control IS/AAR of 55.6 ± 2.1%).


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  		Fig. 1.   Protocol bar indicating experiments used to study mechanism of delta 1-opioid receptor-induced cardioprotection in rat. Groups consisted of the following: I) control (Con); II) TAN-67 (TAN), delta 1-opioid receptor agonist, produced by 15 min of TAN infusion (10 mg/kg iv) before a 30-min occlusion period; III) 7-benzylidenenaltrexone (BNTX; 3 mg/kg iv), a delta 1-opioid receptor antagonist, given 10 min before 15-min TAN infusion (BNTX + TAN); IV) glibenclamide (Glib; 0.3 mg/kg iv), a KATP channel antagonist, given 45 min before 15-min TAN infusion (Glib + TAN); and V) pertussis toxin (PTX; 10 µg/kg ip), an inhibitor of Gi/o proteins, administered 48 h before 15-min TAN infusion (PTX + TAN).

Determination of IS. After each experiment, the left coronary artery was reoccluded, and Patent blue dye was injected into the venous catheter to stain the normally perfused region of the heart. The rat was euthanized with 15% KCl through the arterial catheter. The heart was excised, and the left ventricle was removed and sliced into five cross-sectional pieces. This procedure allowed for visualization of the normal, nonischemic region and the area at risk (AAR). The AAR was separated from the normal area using a dissecting scope (Cambridge Instruments). Both tissue regions (nonischemic and AAR) were incubated at 37°C for 15 min in a 1% 2,3,5-triphenyltetrazolium stain in 100 mM phosphate buffer (pH 7.4). TTC was used as an indicator to separate out viable and nonviable tissue (21). The tissue was stored overnight in a 10% formaldehyde solution. The following day, the infarcted tissue was separated from the AAR by using the dissecting scope. The different regions (nonischemic, AAR, and infarct) were determined by gravimetry, and IS was calculated as a percentage of the AAR (IS/AAR).

Exclusion criteria. A total of 32 animals were enrolled in the study. One animal in the control group was excluded because of intractable ventricular fibrillation. Two animals in the Glib + TAN group were excluded because of hypotension. A total of 29 animals completed the study.

Statistical analysis of the data. All values are expressed as means ± SE. One-way analysis of variance was used to determine differences among groups for IS and AAR. Differences between groups in hemodynamics at various time points were compared by using a two-way analysis of variance for time and treatment with repeated measures and Fisher's least significant difference test if significant F ratios were obtained. Statistical differences were considered significant if the P value was <0.05.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Hemodynamics. The mean ± SE data for HR, mean arterial blood pressure (MBP), and rate-pressure product (RPP; HR × systolic blood pressure) measured before drug administration (baseline), at 30 min of occlusion, and at 2 h of reperfusion are summarized in Table 1. With the exception of the TAN group at baseline, there were no significant differences in HR between groups at any time point measured. MBP was significantly lower at baseline, 30 min of occlusion, and 2 h of reperfusion for the PTX + TAN group. In addition, TAN and the BNTX + TAN groups had a significantly lower MBP at 2 h of reperfusion. The RPP was not significantly different among groups for any time point reported.

                              
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  		Table 1.   Hemodynamic data

Blood glucose (mg/dl) levels were measured in the animals treated with Glib before TAN-67 infusion (baseline = 169 ± 21; 15-min occlusion = 133 ± 23; 15-min reperfusion = 95 ± 4; 1-h reperfusion = 76 ± 5; 2-h reperfusion = 77 ± 7, P < 0.05 vs. baseline for all but 15-min occlusion). Blood glucose significantly decreased ~1-1.5 h after Glib administration similar to that seen previously in this laboratory (51).

IS and AAR. Table 2 depicts the weights in grams of the left ventricle (LV), AAR, and IS. In addition, IS data expressed as a percentage of the area at risk (IS/AAR), a measure of cardioprotection, are shown in Table 2 and Fig. 2. The LV weight in the BNTX + TAN group was significantly smaller compared with control; however, there were no significant differences among groups in AAR weights. TAN-67-treated groups had a significantly lower IS compared with control. Figure 2 shows IS/AAR for the individual rat hearts and the mean ± SE for each group. The average IS/AAR for the control group was 55.6 ± 2.1%. A 15-min infusion period of TAN-67 (10 mg/kg iv), the nonpeptidic delta 1-opioid receptor agonist, significantly reduced IS as compared with the control group (27.1 ± 4.8%, P < 0.05). The cardioprotection induced by TAN-67 was completely abolished by BNTX (3 mg/kg iv), a selective delta 1-opioid receptor antagonist, indicating that TAN produces its cardioprotective effect via delta 1-opioid receptors. Furthermore, delta 1-opioid receptor-induced cardioprotection appears to be mediated via the KATP channel, since Glib (0.3 mg/kg iv) administered 30 min before the TAN-67 infusion completely blocked the cardioprotection (53.0 ± 5.4%; Glib + TAN). A role for Gi/o proteins was also shown to be involved in the cardioprotective effect of TAN-67, since a 48-h pretreatment with PTX (10 µg/kg ip), an inhibitor of Gi/o proteins, abolished the cardioprotective effect induced by TAN-67 (60.8 ± 3.6%; PTX + TAN).

                              
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  		Table 2.   Infarct size data


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  		Fig. 2.   Infarct sizes in rat hearts subjected to control (Con); TAN-67 (TAN), delta 1-opioid receptor agonist, produced by 15 min of TAN infusion (10 mg/kg iv) before a 30-min occlusion period; BNTX (3 mg/kg iv), a delta 1-opioid receptor antagonist, given 10 min before 15-min TAN infusion (BNTX + TAN); Glib (0.3 mg/kg iv), a KATP channel antagonist, given 45 min before 15-min TAN infusion (Glib + TAN); and PTX (10 µg/kg ip), an inhibitor of Gi/o proteins, administered 48 h before 15-min TAN infusion (PTX + TAN). Open circles indicate infarct sizes from individual hearts, and solid circles in each group indicate group mean infarct size. Values are means ± SE. * P < 0.05 vs. control.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

The present results indicate that the nonpeptidic delta 1-opioid receptor agonist TAN-67 reduced IS and elicited a cardioprotective effect via delta 1-opioid receptor stimulation (27.1 ± 4.8%, P < 0.05 vs. control; Fig. 2). These findings support our current hypothesis and previous findings (48) that delta 1-opioid receptors are involved in the cardioprotective effect of ischemic PC. Previously, TAN-67 has been shown to be selective for the delta 1-opioid receptor (6, 18, 22, 37), having a high affinity for delta 1-opioid receptors with a 2,070-fold lower affinity at the µ-opioid receptor and 1,600-fold lower affinity at the kappa -opioid receptor (37). In addition, the cardioprotective effect afforded by TAN-67 infusion was completely abolished by BNTX, a selective delta 1-opioid receptor antagonist (41, 52), which demonstrates that TAN-67 is most likely stimulating the delta 1-opioid receptor to elicit cardioprotection. The involvement of a delta 1-opioid receptor mechanism in cardioprotection of the rat heart supports and extends the results of Mayfield and D'Alecy (33, 34). This group demonstrated that the synthetic delta -opioid receptor agonist [D-Pen2,5]enkephalin increased the survival time of mice subjected to hypoxia, and this protection was abolished by BNTX (34). Similarly, Chien and colleagues (4) also demonstrated that delta -opioid receptor stimulation with the synthetic delta -agonist [D-Ala2,D-Leu5]enkephalin increased tissue preservation time up to 48 h for several canine organ systems (heart, lung, liver, kidney) before transplantation.

To further clarify the cellular mechanisms by which activation of the delta 1-opioid receptor produces cardioprotection in the rat, we studied the role of Gi/o proteins and the KATP channel in mediating this effect. The delta -opioid receptor has been well documented to be linked to K+ channels via G proteins in neuronal tissue (15, 38, 57, 58). Wild et al. (57) demonstrated that the antinociceptive effect produced by delta -opioid receptor activation was mediated via K+ channels, and the subtypes of this receptor were linked to different K+ channels. Their results demonstrated that the analgesia produced by the delta 1-opioid receptor agonist DPDPE could be antagonized by Glib, indicating that the delta 1-receptor subtype was linked to neuronal KATP channels (57). However, the antinociceptive effect of deltorphin II, a delta 2-opioid receptor agonist, was not blocked by Glib but was antagonized by tetraethylammonium bromide, a voltage-gated K+ channel blocker, which demonstrates that the delta 2-receptor subtype was linked to K+ channels other than the KATP channel (57). Our present results show that the cardioprotection induced by TAN-67, a delta 1-agonist, was blocked by Glib, which indicates that the myocardial protection is mediated by an interaction between the delta 1-opioid receptor and the myocardial KATP channel (Figs. 2 and 3). These data agree with our previous results which showed that morphine-induced cardioprotection was mediated through a KATP channel-linked mechanism (45). Recently, Ytrehus et al. (64) indicated that in the isolated buffer-perfused rat heart, there is an association between opioid receptors, lipoxygenase, PKC, and KATP channels in mediating ischemic PC against myocardial infarction.


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  		Fig. 3.   Schematic of rat myocardial membrane depicting mechanism(s) of action for cardioprotection produced by activation of opioid receptors. delta 1-Opioid receptors elicit their cardioprotective effect by stimulating opening of KATP channels most likely via a direct interaction with Gi/o proteins. However, second messengers such as protein kinase C (PKC), protein kinase A (PKA), and tyrosine kinase may have a role in the cardioprotective effect induced by delta 1-opioid receptor stimulation.

Gi/o protein-coupled muscarinic and adenosine receptors have been shown to induce the cardioprotective effect of ischemic PC (26, 30, 42, 61, 62). This cardioprotection produced by these G protein-coupled receptors has been suggested to be mediated by the interaction of the alpha -subunit from the Gi protein and the myocardial KATP channel (17, 20, 24, 25). In addition, opioid receptors belong to this family of G protein-coupled receptors (2, 12, 19, 36, 63). Opioid receptors (µ, delta , and kappa ) have been demonstrated to be linked to K+ channels via Gi proteins (3, 5, 7, 15, 38). Our present results clearly indicate that PTX abolished the cardioprotection induced by the delta 1-opioid receptor agonist TAN-67 (Fig. 2), which suggests a role of Gi/o proteins in delta 1-opioid receptor-mediated myocardial protection. A number of physiological responses of delta -opioid receptor stimulation, including inhibition of adenylate cyclase activity, cell proliferation, regulation of myocardial intracellular pH, and inhibition of cardiac beta -adrenergic effects, have also been shown to be PTX sensitive (9, 27, 35, 39, 60).

In summary, TAN-67, a delta 1-opioid receptor agonist, produced a reduction in IS in the rat. The results of this study are the first to demonstrate that the mechanism of delta 1-opioid receptor-mediated cardioprotection involves an interaction with the myocardial KATP channel and Gi/o proteins in the rat heart (Fig. 3). Although not the focus of the present study, second messengers such as PKC, protein kinase A, and tyrosine kinase may have a role in the cardioprotective effect induced by delta 1-opioid receptor stimulation. Both PKC and tyrosine kinase have been implicated in ischemic PC (16, 29, 32, 53, 64, 65) and along with protein kinase A to interact with delta -opioid receptors in cardiac and neuronal tissue (3, 5, 10, 27, 28, 64). However, North et al. (38) concluded that adenosine 3',5'-cyclic monophosphate-dependent protein kinase and PKC are not directly involved in the coupling between the delta -opioid receptor and K+ channel in the guinea pig submucous plexus. Childers (5) also stated that the effects of delta -agonists in opening potassium channels are not mediated via second messengers but instead through direct interaction between G proteins and ion channels. Therefore, further studies need to be performed to determine the involvement of various kinases in delta 1-opioid receptor-mediated cardioprotection. The present results have provided evidence for a physiological role of delta 1-opioid receptors in the cardiovascular system and have enhanced our understanding of the mechanism(s) by which this receptor elicits a cardioprotective effect. These findings have important clinical ramifications, since synthetic opioid derivatives will not only alleviate pain postoperatively but may also provide a cardioprotective effect to patients receiving cardiac surgical interventions if these agents are administered preoperatively.

    ACKNOWLEDGEMENTS

We thank Jeannine Moore for excellent technical assistance.

    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grant HL-08311 and an advanced predoctoral fellowship from the Pharmaceutical Research and Manufacturers of America Foundation.

Address for reprint requests: G. J. Gross, Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226.

Received 7 September 1997; accepted in final form 1 December 1997.

    REFERENCES
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Abstract
Introduction
Methods
Results
Discussion
References

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AJP Heart Circ Physiol 274(3):H909-H914
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