Morphine Attenuates Microvascular Hyperpermeability via a Protein Kinase A-Dependent Pathway

Puana, Rudolph; McAllister, Russell K.; Hunter, Felicia A.; Warden, Julie; Childs, Ed W.

doi:10.1213/ane.0b013e318160648b

Cited by 7 publications

(5 citation statements)

References 20 publications

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“…Each rat received an intravenous infusion of either saline (control) or GLP-1-(7-36) amide (30 pmol·kg ; Sigma-Aldrich, St. Louis, MO). At the doses selected, GLP-1 has been shown to potently recruit muscle microvasculature (8) and H89 to abolish morphine-mediated attenuation of microvascular hyperpermeability via the PKA-dependent pathway (37). H89 infusion was started 30 min before the commencement of saline or GLP-1 infusion and had no significant effect on muscle microvascular recruitment (Fig.…”

Section: Methodsmentioning

confidence: 99%

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

Dong

Chai

Wang

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment. Am J Physiol Endocrinol Metab 304: E222-E228, 2013. First published November 27, 2012 doi:10.1152/ajpendo.00473.2012.-Glucagon-like peptide-1 (GLP-1) causes vasodilation and increases muscle glucose uptake independent of insulin. Recently, we have shown that GLP-1 recruits muscle microvasculature and increases muscle glucose use via a nitric oxide (NO)-dependent mechanism. Protein kinase A (PKA) is a major signaling intermediate downstream of GLP-1 receptors. To examine whether PKA mediates GLP-1's microvascular action in muscle, GLP-1 was infused to overnight-fasted male rats for 120 min in the presence or absence of H89, a PKA inhibitor. Hindleg muscle microvascular recruitment and glucose use were determined. GLP-1 infusion acutely increased muscle microvascular blood volume within 30 min without altering microvascular blood flow velocity or blood pressure. This effect persisted throughout the 120-min infusion period, leading to a significant increase in muscle microvascular blood flow. These changes were paralleled with an approximately twofold increase in plasma NO levels and hindleg glucose extraction. Systemic infusion of H89 completely blocked GLP-1-mediated muscle microvascular recruitment and increases in NO production and muscle glucose extraction. In cultured endothelial cells, GLP-1 acutely increased PKA activity and stimulated endothelial NO synthase phosphorylation at Ser 1177 and NO production. PKA inhibition abolished these effects. In ex vivo studies, perfusion of the distal saphenous artery with GLP-1 induced significant vasorelaxation that was also abolished by pretreatment of the vessels with PKA inhibitor H89. We conclude that GLP-1 recruits muscle microvasculature by expanding microvascular volume and increases glucose extraction in muscle via a PKA/NOdependent pathway in the vascular endothelium. This may contribute to postprandial glycemic control and complication prevention in diabetes.glucagon-like peptide 1; protein kinase A; microvascular recruitment; nitric oxide GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is a major incretin hormone and acts on its 64-kDa G protein-coupled receptor to increase cAMP production and mediates glucose-induced insulin secretion. Recent evidence suggests that GLP-1 is capable of increasing muscle glucose uptake independent of insulin (2). This was most convincingly demonstrated by an observation of increased myocardial uptake of glucose in Langendorff-perfused rat heart preparation (41). In conscious dogs, both GLP-1 and its active metabolite are able to increase myocardial glucose uptake without altering plasma insulin concentrations (32, 33).The mechanisms underlying GLP-1-stimulated glucose uptake in muscle are poorly understood. Endothelial cells (ECs) express abundant GLP-1 receptors (35), and GLP-1 has been shown to increase coronary blood flow and myocardial glucose uptake independent of insulin (34, 41). We have reported recently that GLP-1...

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Section: Methodsmentioning

confidence: 99%

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

Dong

Chai

Wang

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…In some trauma centers, anesthesiologists begin opioid titration once hemodynamic stability is achieved and surgical hemostasis obtained. 12 Fentanyl and morphine have been shown to potentially dilate the microcirculation, thereby facilitating blood flow in vasoconstricted vascular beds 13,14 which supports the higher opioid doses used at some trauma centers. This requires further study given the complex changes in vascular tone after injury, during resuscitation and vasopressor use.…”

Section: Discussionmentioning

confidence: 92%

Association of Opioid Administration During General Anesthesia and Survival for Severely Injured Trauma Patients: A Preplanned Secondary Analysis of the PROPPR Study

Levy

Livingston

Saroukhani

et al. 2023

Anesthesia &Amp; Analgesia

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BACKGROUND: There is a lack of reported clinical outcomes after opioid use in acute trauma patients undergoing anesthesia. Data from the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) study were analyzed to examine opioid dose and mortality. We hypothesized that higher dose opioids during anesthesia were associated with lower mortality in severely injured patients. METHODS: PROPPR examined blood component ratios in 680 bleeding trauma patients at 12 level 1 trauma centers in North America. Subjects undergoing anesthesia for an emergency procedure were identified, and opioid dose was calculated (morphine milligram equivalents [MMEs])/h. After separation of those who received no opioid (group 1), remaining subjects were divided into 4 groups of equal size with low to high opioid dose ranges. A generalized linear mixed model was used to assess impact of opioid dose on mortality (primary outcome, at 6 hours, 24 hours, and 30 days) and secondary morbidity outcomes, controlling for injury type, severity, and shock index as fixed effect factors and site as a random effect factor. RESULTS: Of 680 subjects, 579 had an emergent procedure requiring anesthesia, and 526 had complete anesthesia data. Patients who received any opioid had lower mortality at 6 hours (odds ratios [ORs], 0.02–0.04; [confidence intervals {CIs}, 0.003–0.1]), 24 hours (ORs, 0.01–0.03; [CIs, 0.003–0.09]), and 30 days (ORs, 0.04–0.08; [CIs, 0.01–0.18]) compared to those who received none (all P < .001) after adjusting for fixed effect factors. The lower mortality at 30 days in any opioid dose group persisted after analysis of those patients who survived >24 hours (P < .001). Adjusted analyses demonstrated an association with higher ventilator-associated pneumonia (VAP) incidence in the lowest opioid dose group compared to no opioid (P = .02), and lung complications were lower in the third opioid dose group compared to no opioid in those surviving 24 hours (P = .03). There were no other consistent associations of opioid dose with other morbidity outcomes. CONCLUSIONS: These results suggest that opioid administration during general anesthesia for severely injured patients is associated with improved survival, although the no-opioid group was more severely injured and hemodynamically unstable. Since this was a preplanned post hoc analysis and opioid dose not randomized, prospective studies are required. These findings from a large, multi-institutional study may be relevant to clinical practice.

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“…Morphine (0.3 mg/kg) [ 16 ] was administered intravenously 10 minutes before ischemia. The PKA inhibitor H-89 (10 μg/kg) [ 17 ] and the mPTP opener atractyloside (5 mg/kg) [ 18 ] were given 15 minutes before the onset of ischemia. At the end of the experiments hearts were excised and infarct sizes were determined using a previously described method [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore

et al. 2016

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BackgroundMorphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway.MethodsMale Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 μg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP-opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition.ResultsMorphine reduced infarct size from 64±5% to 39±9% (P<0.05 vs. Con). H-89 completely blocked preconditioning by morphine (64±9%; P<0.05 vs. M-PC), but H-89 itself had not effect on infarct size (61±10%; P>0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65±9%; P<0.05 vs. M-PC) but had no influence on infarct size itself (64±5%; P>0.05 vs. Con). In isolated hearts STAT3 inhibitor Stattic completely abolished morphine-induced preconditioning. Administration of Stattic and mPTP inhibitor cyclosporine A reduced infarct size to 31±6% (Stat+CsA, P<0.05 vs. Con). Cyclosporine A alone reduced infarct size to 26±7% (CsA P<0.05 vs. Con). In cardiomyocytes, PKA activity was increased by morphine.ConclusionOur data suggest that morphine-induced cardioprotection is mediated by STAT3-activation and inhibition of mPTP, with STA3 located upstream of mPTP. There is some evidence that protein kinase A is involved within the signalling pathway.

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Morphine Attenuates Microvascular Hyperpermeability via a Protein Kinase A-Dependent Pathway

Cited by 7 publications

References 20 publications

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

Protein kinase A mediates glucagon-like peptide 1-induced nitric oxide production and muscle microvascular recruitment

Association of Opioid Administration During General Anesthesia and Survival for Severely Injured Trauma Patients: A Preplanned Secondary Analysis of the PROPPR Study

Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore

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