INTRODUCTION
Historically, evidence for the involvement of opioids in blood pressure responses has focused on the role of specific opioid receptors in the delay of hypovolemic shock. In the ischemic hemorrhage model, there are three successive phases of the autonomic response (compensatory, decompensatory, and recompensatory) to the rapid loss of blood. Initially, during the compensatory phase, mean arterial pressure (MAP) is maintained primarily by increasing the sympathetic drive to the heart and blood vessels (1 1-3 4
A role for endogenous opioids was first demonstrated by the evidence that i.v. injection of the opioid antagonist naloxone could inhibit the decompensatory phase and the subsequent fall in MAP caused by hemorrhage in rats (5 6 7
Further studies have shown that opioids have a major role in modulation of ischemic shock both in central and in peripheral pathways. Studies of the application of selective δ-opioid antagonists have shown that the decompensatory phase involves δ1 - and not δ2 -opioid peptides in the brain stem (8 1 -opioid receptors in the brain stem during the decompensatory phase of hemorrhage (9
In the isolated heart model, cardiac function was maintained if rats were pretreated with a nonselective δ-opioid agonist, [D-Ala(2), D-Leu(5)]-enkephalin (DADLE) (10, 11 2 -opioid receptor antagonist naltriben methanosulfonate (NTB), implicating the positive role of the δ2 -opioid receptor agonist in ischemic models (12 2 -specific deltorphin D (deltorphin Dvar ) was cardioprotective in the ischemic models of pigs (13 14
Additional evidence for the δ2 -opioid receptor in cardioprotection was the finding that deltorphin Dvar , a selective δ2 -opioid receptor agonist, administered after moderate (approximately 30%) hemorrhage facilitated MAP and HR recovery through disinhibition of sympathetic drive and increased baroreflex sensitivity (15 2 -opioid receptor agonists can act at central and/or peripheral targets to facilitate recovery of blood pressure and to provide cellular protection against ischemia. Therefore, during moderate hemorrhage, the δ-opioid receptor agonist's ability to prevent sympathoinhibition indicates that opioid peptides play an active role in the recompensatory phase in hemorrhage (3
During severe hemorrhage (approximately 50% total blood volume loss), there is a precipitous fall in MAP that ultimately leads to shock by abruptly inhibiting sympathetic activity (2, 4, 16-18 var facilitated recovery from severe (approximately 53% total blood volume loss) hemorrhagic shock during the recompensatory phase by improving hemodynamic stability and survival (19 var -induced MAP recovery was correlated with retardation of the anaerobic glycolytic pathways, inducing metabolic depression similar to that observed in hibernation (19 2 -opioid receptor activation has been shown to inhibit lipopolysaccharide and proinflammatory cytokine-induced release of nitric oxide (NO) in cell culture (20 21 , and NO-mediated vasodilation (21 21 22
The focus of the present study is to explore the use of pharmaceutical intervention after severe hemorrhage using a novel opioid peptide, deltorphin E. Deltorphin E may extend hemodynamic stability in severe hemorrhage and would have potential clinical benefit in multiple trauma arenas. The biomarkers for posthemorrhage, pharmaceutically induced hemodynamic improvement were (1) restoration of hemodynamic stability using MAP and HR, (2) increased posthemorrhagic survival time, (3) baroreflex sensitivity, (4) alteration of pulse pressure (i.e., difference between systolic and diastolic pressure, expressed in millimeters of mercury), and (5) reduction of lactic acid production. In addition, the possible specific receptor sites activated by deltorphin E were also assessed by using the response of opioid receptor inhibitors on hemodynamic biomarkers. A potential role of the potassium-sensitive adenosine triphosphate (KATP ) channels was studied by using the specific KATP channel blocker glibenclamide.
MATERIALS AND METHODS
Experiments were conducted using 12- to 16-week-old Charles River rats (weight, 341-411 g) from the colony of the University of Wyoming Zoology and Physiology Department. The animals were kept in steel mesh cages in a temperature-controlled environment with 12-h light/dark cycle. The rats were given ad libitum access to Purina rat chow and regular tap water. Selected animals (n = 30) were randomly assigned to one of five different posthemorrhage treatment groups: 1 mL/100 g saline control (n = 6), 2.85 mg/kg deltorphin E (n = 6), 4.2 mg/kg deltorphin E (n = 6), 5.5 mg/kg deltorphin E (n = 6), and 14 mg/kg deltorphin E (n = 6). The deltorphin E concentration doses selected were chosen to test against a dose range of concentrations found effective in hemorrhagic recovery using the δ-opioid receptor agonist deltorphin Dvar (15, 19
In addition, a different set of selected animals (n = 16) were randomly assigned to one of four different 30-min prehemorrhage pretreatment groups with specific inhibitors: NTB (n = 4), naltrexone (n = 4), glibenclamide (n = 4), and 7-benzylidenenaltrexone (BNTX; n = 4). These animals received a pretreatment injection 30 min before hemorrhage (23
Surgery
Before the rats underwent hemorrhagic stress, femoral catheters were inserted to monitor changes in MAP and HR. Two catheters were prepared by inserting a 4.5-cm length of PE-10 tubing 0.5 cm into a 10-cm length of PE-50 tubing, and then securing the junction with superglue. The rats were anaesthetized with a mixture injection of ketamine (dose, 100 mg/kg i.p.) and xylazine (dose, 10 mg/kg i.p.). The animals were shaved of hair posterior to the skull and along the junction of the abdomen and the animals' right hind limb. An incision was made through the dermis at the base of the skull and another along the right hind leg to access the femoral artery and vein. Both catheters were inserted in a trocar and brought under the skin from the right hind leg incision to the incision on the back of the neck. Catheters were then flushed with heparinized saline to make certain that there were no air pockets in either catheter. The femoral artery and vein were exposed, and a 5-cm length of PE-10 tubing was inserted into each vessel. Once inserted, each catheter was tied in place with braided silk thread, covered with a piece of hypoallergenic mesh to prevent kinking, and glued in place (15
The incision was closed with wound clips; then, the catheters were flushed with heparinized saline to prevent clotting, sutured behind the head to keep out of reach of the animal, and heat-sealed until testing. The animals were left in cages with access to food and water to recover for 24 h.
Hemorrhaging and injections
After 24 h of recovery, the rats underwent volume-controlled hemorrhage. The rats were left in their regular recovery cages during the entire course of testing, although both their food and water were removed before hemorrhage. The catheters were opened and the arterial line was connected to a pressure transducer that interfaced with a model MP 100 blood pressure monitoring system (BIOPAC Systems, Inc., Santa Barbara, Calif) to collect measurements on MAP and HR. The venous catheter was attached to a syringe containing the various saline and opioid treatments. Deltorphin E (Tyr-d-Ala-Phe-Ala-Ile-Gly-Asp-Phe-Ser-Ile-NH2 ) was presynthesized and supplied by Dr. Peter Oeltgen. The various deltorphin E concentrations supplied were dissolved in 1.0-mL lactated Ringer's solution (pH value, 7.4). Before venous catheter injection, the solutions were brought up to an injection dose (1 mL/100 g) with regular saline (pH value, 7.4). Before hemorrhage, MAP and HR were recorded to establish baseline levels. During hemorrhage, approximately 48% of the total blood volume was removed at a rate of 3 mL/100 g during a 9- to 11-min period. After the final milliliter of blood was removed, the various venous catheter treatment injections were administered; MAP and HR were recorded continuously for the duration of survival or up to 6 h.
Biomarker protocols
Survival time was determined by measuring the posthemorrhage time after injection until death or a predetermined 360-min survival interval. Death was defined as systolic blood pressure without pulsation. The animals were observed for several more minutes to ensure that autoresuscitation did not occur. Any animal surviving for 360 min was euthanized using urethane (dose, 1.0 g/kg; Sigma-Aldrich, St. Louis, Mo) in accordance with our protocol. This 360-min survival time was established in our protocol to minimize any discomfort to the animal and because d-alanine deltorphins reportedly exhibit plasma half-lives of 6 h (24
Plasma lactic acid levels were determined from arterial blood samples obtained before and after hemorrhage using a Vitros 950 chemistry analyzer (Ortho-Clinical Diagnostics, Rochester, NY). Samples at beginning of hemorrhage (BOH) were obtained from the first milliliter of arterial blood removed during hemorrhage. Samples at end of hemorrhage (EOH) were collected from arterial blood 10 min after the venous catheter injections were administered. Plasma lactic acid analysis was conducted by the Clinical Pathology Laboratory at the University of Kentucky.
Pulse pressure was determined by measuring the difference (in millimeters of mercury) between the systolic and the diastolic pressure levels during a single cardiac cycle. A total of six measurements for each treatment group were performed after venous catheter injection at a frequency of one every 5 min for the first 30 min.
Opioid receptor antagonists
The opioid receptor antagonists (naltrexone, NTB, BNTX) and the KATP channel blocker (glibenclamide) were administered 30 min before hemorrhage (23 ATP channel blocker.
Data analysis
Statistical analysis was performed using SPSS software, with P value less than 0.05 considered significant. The mean differences in survival, MAP, HR, and lactic acid values between groups were analyzed using one-way analysis of variance (ANOVA). Post hoc least square differences analyses were used to compare all possible pairs of means after the F test rejected the null hypothesis that there are no differences between the group means.
The steady-state changes in MAP and HR were fitted to a sigmoid logistic equation and were plotted; the derivatives of the equation were used to obtain the upper and the lower HR plateaus and to create curves that reflect instantaneous change and the median blood pressure (BP50 ), the MAP halfway between the upper and the lower HR plateaus (15, 25, 26 26
RESULTS
At the beginning (mean MAP ± SEM, 112 ± 1.9 mmHg) or end (mean MAP ± SEM, 33 ± 0.63 mmHg) of hemorrhage, there was no significant difference in MAP between any of the treatment groups using post hoc least square differences tests. However, the post-treatment MAP of the 5.5-mg/kg deltorphin E-treated group was significantly (P < 0.01) increased when compared with that of the saline control group during the entire interval examined (Fig. 1 ); the MAP of the 2.9-mg/kg and the 4.2-mg/kg deltorphin E-treated groups also significantly (P < 0.05) increased compared with that of the saline control group during the interval examined. The MAP of 14.0-mg/kg deltorphin E-treated group significantly (P < 0.01) decreased compared with that of the saline control group; this dose was found lethal. The maximum MAP recorded during the recovery interval after hemorrhage was significantly greater in 2.9-mg/kg (P < 0.05), 4.2-mg/kg (P < 0.05), 5.5-mg/kg (P < 0.01), and 14.0-mg/kg (P < 0.05)-treated deltorphin E group compared with that in the saline control group (50 ± 17 mmHg, 53 ± 11 mmHg, 58 ± 7 mmHg, and 51 ± 15 mmHg, respectively, vs. 35 ± 9 mmHg) (Fig. 1 ). However, HR trended downward in all groups, with no significant difference in HR between the control group and any deltorphin E-treated group.
Fig. 1: Post-severe hemorrhage deltorphin E treatment shows dose-dependent recovery of MAP during recompensatory phase. The 5.5-mg/kg deltorphin E treatment induced a rapid significant recovery of MAP during the first 100 min and maintained an overall significantly higher MAP throughout the entire recovery period. All deltorphin E-treated groups had a significantly different maximum MAP versus saline, but only the 5.5-mg/kg deltorphin E-treated group was able to maintain survival during the 6-h test period. The 14.0-mg/kg deltorphin E treatment was lethal, and the group showed a significant decrease in MAP. Each data point represents specific treatment group means with SEM (*P < 0.05 and **P < 0.01 compared with saline control group). EOH indicates end of hemorrhage.
One-way ANOVA post hoc least square differences analysis revealed a significant (P < 0.01) increase in survival time in the 2.9-mg/kg, 4.2-mg/kg, and 5.5-mg/kg deltorphin E-treated groups compared with the saline control group (107 ± 1 min, 232 ± 14 min, and 331 ± 18 min, respectively, vs. 50 ± 8 min) (Fig. 2 ). The survival time in the 14.0-mg/kg lethal deltorphin E dose was not significantly different from that in the saline control group, although the mean survival rate was decreased. The use of ANOVA post hoc least square differences comparisons to compare all possible pairs of means indicated that all of the deltorphin E treatment groups were significantly (P < 0.01) different from one another, indicating a dose-dependent increase in survival time (Fig. 2 ).
Fig. 2: Deltorphin E dose-dependent increase in survival time (expressed in minutes) after severe hemorrhage. All deltorphin E treatment groups showed a significant increase in survival time after severe hemorrhage (except for the group administered with 14.0-mg/kg deltorphin E dose, which was toxic) when compared with saline-treated groups. Each data series represents specific treatment group means with SEM. **P < 0.01 compared with saline control group.
Deltorphin E did not significantly alter the BP50 or HR gain using the 5.5-mg/kg deltorphin E dose. Nevertheless, in this study, we found that among the doses tested, the 5.5-mg/kg deltorphin E dose is the most effective in restoring hemodynamic parameters after hemorrhage when compared with the saline control group (Fig. 3 ).
Fig. 3: After severe hemorrhage, the average HR gain (bpm/mmHg and BP50 ) after treatment with saline or 5.5-mg/kg deltorphin E. Treatment with 5.5-mg/kg deltorphin E did not significantly alter the average HR gain of the baroreflex or significantly modify the BP50 compared with saline treatment.
Mean lactic acid levels at the end of hemorrhage in saline controls increased sixfold (from 1.55 ± 0.10 mmol/L to 8.88 ± 0.12 mmol/L), whereas the increase was only fourfold in the 5.5-mg/kg deltorphin E-treated animals (from 1.54 ± 0.26 mmol/L to 6.54 ± 1.54 mmol/L). Among the doses tested, only the 5.5-mg/kg deltorphin E-treated group was found to have significantly (P < 0.01) lower lactic acid levels versus the saline control group (Fig. 4 ).
Fig. 4: Deltorphin E dose-dependent decrease in lactic acid concentration (expressed in millimolar concentration). Lactic acid levels were measured from arterial blood samples. There was no significant difference in lactic acid levels at BOH between the control and any deltorphin E-treated groups. However, at the end of hemorrhage, only the 5.5-mg/kg deltorphin E-treated group had significantly lower lactic acid levels (mean ± SEM, 6.54 ± 1.25 mmol/L) compared with the saline-treated group (mean ± SEM, 8.88 ± 0.13 mmol/L). Each data point represents specific treatment group means with SEM. *P < 0.05. BOH indicates beginning of hemorrhage; EOH, end of hemorrhage.
Comparison of posthemorrhage lactic acid concentration and survival time using linear regression analysis resulted in a correlation coefficient of R = 0.9845, indicating that lactic acid concentration is a good predictor of survival time. For every 0.1-mmol/L decrease on lactic acid level in the deltorphin E-treated animals, there was a 12.5-min increase in survival time (Fig. 5 ).
Fig. 5: Lactic acid production (expressed in millimolar) versus survival time (expressed in minutes). The lactic acid values were determined at the end of hemorrhage for saline: 2.9 mg/kg, 4.2 mg/kg, and 5.5 mg/kg of deltorphin E. For the deltorphin E-treated groups, every 0.1 mmol/L decrease in lactic acid concentration correlated with a 12.5-min increase in survival time.
Posthemorrhage injections of deltorphin E significantly (P < 0.01) increased pulse pressure (systolic pressure minus diastolic pressure) for all the deltorphin E-treated groups versus the saline control group in a dose-dependent manner (mean ± SEM, 42 ± 0.37 mmHg, 44 ± 0.41 mmHg, 48 ± 0.56 mmHg, and 94 ± 0.89, versus 38 ± 0.44 mmHg) (Fig. 6 ). Although the 14.0-mg/kg dose of deltorphin E significantly (P < 0.01) increased pulse pressure than did any of the other deltorphin E-treated groups, this increase was not beneficial with respect to overall survival time. Therefore, there seems to be a limit to the benefit of increased pulse pressure .
Fig. 6: Deltorphin E dose-dependent increase in pulse pressure (difference between systolic and diastolic pressure, expressed in millimeters of mercury). Posthemorrhage injections of deltorphin E significantly increased pulse pressure for all the treated groups versus the saline groups in a dose-dependent manner. A total of six measurements for each treatment group were obtained after administration of the deltorphin E injection at a frequency of one measurement every 5 min for the first 30 min. Despite the significant increase in pulse pressure versus the other deltorphin E-treated groups, the 14.0-mg/kg deltorphin E dose was considered lethal because it actually decreased animal survival time. Each data series represents treatment group means with SEM (**P < 0.01).
The general δ-opioid receptor antagonist naltrexone and the specific δ2 -opioid receptor antagonist NTB blocked the posthemorrhage hemodynamic recovery benefits of 5.5-mg/kg deltorphin E dose. On the other hand, BNTX, the δ1 -opioid receptor antagonist, did not block the 5.5-mg/kg deltorphin E dose improvement in survival and MAP recovery. Likewise, glibenclamide did not alter the survival advantage of post-treatment with 5.5-mg/kg deltorphin E because there were no statistically significant differences found between survival time distributions and maximum MAP distributions between the group pretreated with glibenclamide and the groups treated only with deltorphin E (Table 1 ).
Table 1: Hemodynamic biomarker response to 30-min antagonist pretreatment before 5.5-mg/kg Deltorphin E posthemorrhage injection
DISCUSSION
Our study shows for the first time that i.v. administration of the opioid deltorphin E, an effective pharmaceutical agent, can improve hemodynamic stability biomarkers, delay hypovolemic shock, and significantly improve survival time when administered even after the onset of hemorrhagic shock and without fluid resuscitation. The nonselective δ-opioid receptor antagonist, naltrexone, partially blocked the hemodynamic recovery effects of deltorphin E, indicating that deltorphin E was acting on a δ-opioid receptor. Further investigation with specific δ-opioid receptor antagonists NTB (δ2 ) and BNTX (δ1 ) revealed that only the δ2 -opioid receptor antagonist NTB blocked the effect of deltorphin E on shock and survival after severe hemorrhage. Therefore, the site of action for deltorphin E is a δ2 -opioid receptor, which, after i.v. administration, promotes significant recovery of hemodynamic biomarkers after severe hemorrhage.
Several studies have indicated the role of both peripheral and brain δ-opioid receptors in responses to hemorrhage. In rabbits, the central opioid activation of δ1 -opioid receptors initiates the detrimental decompensatory phase of acute hemorrhage (8 27 var , a selective δ2 -opioid receptor agonist, greatly increased hemodynamic stability after moderate hemorrhage (15 var before severe (53% total blood volume loss) hemorrhage markedly improved survival and MAP and decreased the end-of-hemorrhage lactic acid production compared with controls (19 2 -opioid receptors with the novel deltorphin E peptide facilitates increased hemodynamic stability when infused immediately after severe hemorrhage by restoration of MAP, HR, survival time, and pulse pressure and decrease in end-of-hemorrhage lactic acid production without alteration of the baroreflex response or additional fluid resuscitation.
At least four mechanisms have been noted previously to facilitate recovery with alternative pathways, operative alone, or in combination during the recompensatory phase. These mechanisms include modification of the baroreflex sensitivity (15 28 ATP channels (29 19 pulse pressure .
Activation of δ2 -opioid receptors by the selective agonist deltorphin Dvar provides recovery from hemorrhagic shock by involving changes in baroreflex function (15 4 15 versus saline controls (mean ± SEM, 35 ± 9 mmHg) without increasing HR, suggesting that baroreflex sensitivity is not altered. Thus, the hemodynamic recovery observed in deltorphin E treatment is operating via alternate pathways.
A second possible mechanism for the increased survival observed in deltorphin E treatment after severe hemorrhage is the role of NO in response to ischemic stress (19 2 -specific peptides inhibited NO release in a dose-dependent response (20 2 -specific receptor agonist and may inhibit NO production in the in vivo hemorrhagic model in our present study by one or several known pathways described in the next sections.
In experimental models of hemorrhagic shock, evidence exists that (1) the prolonged increased concentrations of NO causes ischemic opening of vascular smooth muscle channels that contribute to vasodilation, and that (2) δ-opioid receptor stimulation acts to control contractile tone, promoting vasoconstriction (22 30 31 ATP channels by increasing protein G kinase phosphorylation (32, 33
Therefore, numerous previous studies indicate multiple pathways of NO pathology in hemorrhagic stress. The potential roles of deltorphin E in the pathology of NO pathways include (1) inhibitor of hypoxia, thus leading to NO production; (2) antioxidant; (3) inhibitor of inducible NO synthase and the proinflammatory pathway; (4) modulator of KATP channels; and (5) combinations of these roles. Further studies may identify useful strategies to increase survival after severe hemorrhage when resuscitation is delayed.
With respect to the role of the third mechanism, previous studies have shown in neuronal tissue that the antinociceptive effect of δ-opioid receptor activation is linked to K+ channels via G proteins (29 , 34-36 + channels (29 + channels blocker glibenclamide could antagonize the analgesic effect produced by the δ1 -opioid receptor agonist [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE), but not the δ2 -opioid receptor agonist deltorphin II (29 2 -opioid receptor agonist, was not blocked by glibenclamide, indicating that the hemodynamic recovery is mediated by a mechanism not necessarily linked to glibenclamide-sensitive K+ channels.
A fourth mechanism correlated with recovery after severe hemorrhagic shock is lactic acid concentration. In metabolic terms, it is well known that lactic acid is a product of the breakdown of glucose to lactate for energy in low oxygen levels. When oxygen levels are adequate, lactate converts to pyruvate. When the liver fails to metabolize lactate sufficiently or when too much pyruvate converts to lactate, an increase of lactic acid concentration occurs. It has been reported that the severity of hemorrhagic shock is associated with increased plasma lactate levels and has been suggested as a useful indicator of intestinal injury after hemorrhagic shock (37 pulse pressure , reaffirming the association of lactic acid concentration with the severity of hemorrhagic shock response.
In previous studies, 24-h pretreatment with the δ2 -opioid receptor agonist deltorphin Dvar interfered with the buildup of lactic acid in conscious rats stressed by severe hemorrhage (19 2 -opioid receptor agonist deltorphin E was still able to retard lactic acid accumulation in a dose-dependent manner. The greater the inhibition of lactic acid, the greater was the survival rate after severe hemorrhage. The δ2 -opioid receptor agonists potentially induce a hibernationlike state of metabolic depression, retarding the anaerobic glycolytic pathway that increases the levels of circulating lactate (19
The fifth possible pathway for deltorphin E is alteration of pulse pressure . The present study was the first to show that an opioid peptide induced modification of pulse pressure after severe hemorrhagic shock. The role of pulse pressure in ischemic stress response has not been fully characterized, but enhancement of pulse pressure can act as a treatment of hypoperfusion in shock (38 pulse pressure , which increases stroke volume and cardiac output, leading to greater tissue perfusion. After injections of deltorphin E, during stress, there was a dose-dependent significant increase in pulse pressure , which could promote greater tissue perfusion.
In summary, the novel deltorphin E peptide was found to be a δ2 -opioid receptor agonist, which could be used as an i.v. pharmaceutical agent to facilitate the recovery of hemodynamic biomarkers without accompanying fluid resuscitation, even after the onset of severe hemorrhagic shock. The results of this study indicated significant increase in survival, decreased lactic acid production, and recovery of MAP after severe hemorrhage. Deltorphin E, therefore, could be used as a potential intervention in stress-induced ischemia not only in hemorrhage but, perhaps, also in a wide range of ischemic scenarios.
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