Scientific societies fostering inclusivity through speaker diversity in annual meeting programming: a call to action.

Scientific societies aiming to foster inclusion of scientists from underrepresented (UR) backgrounds among their membership often delegate primary responsibility for this goal to a diversity-focused committee. The National Science Foundation has funded the creation of the Alliance to Catalyze Change for Equity in STEM Success (ACCESS), a meta-organization bringing together representatives from several such STEM society committees to serve as a hub for a growing community of practice. Our goal is to coordinate efforts to advance inclusive practices by sharing experiences and making synergistic discoveries about what works. ACCESS has analyzed the approaches by which member societies have sought to ensure inclusivity through selection of annual meeting speakers. Here we discuss how inclusive speaker selection fosters better scientific environments for all and identify challenges and promising practices for societies striving to maximize inclusivity of speakers in their scientific programming.

Scientific Societies Fostering Inclusive Scientific Environments through Travel Awards: Current Practices and Recommendations.

Diversity-focused committees continue to play essential roles in the efforts of professional scientific societies to foster inclusion and facilitate the professional development of underrepresented minority (URM) young scientists in their respective scientific disciplines. Until recently, the efforts of these committees have remained independent and disconnected from one another. Funding from the National Science Foundation has allowed several of these committees to come together and form the Alliance to Catalyze Change for Equity in STEM Success, herein referred to as ACCESS. The overall goal of this meta-organization is to create a community in which diversity-focused committees can interact, synergize, share their collective experiences, and have a unified voice on behalf of URM trainees in science, technology, engineering, and mathematics disciplines. In this Essay, we compare and contrast the broad approaches that scientific societies in ACCESS use to implement and assess their travel award programs for URM trainees. We also report a set of recommendations, including both short- and long-term outcomes assessment in populations of interest and specialized programmatic activities coupled to travel award programs.

Effects of Community-Based Exercise in Adults With Severe Burns: A Randomized Controlled Trial.

OBJECTIVE: To investigate the efficacy of community-based exercise programs in the rehabilitation of adult patients with burns compared with standard of care (SOC). DESIGN: Randomized controlled trial, with 2:1 randomization. SETTING: Assessments were performed in a hospital setting. The intervention was performed in a community setting. PARTICIPANTS: Adult patients (N=45) with ≥30% total body surface area burns were randomized to participate in a community-based exercise program (n=31) or SOC (n=14). Patient sampling was consecutive and referred. INTERVENTIONS: The community-based exercise program consisted of 12 weeks of exercise with a community-based trainer after hospital discharge. The SOC group did not receive exercise training. MAIN OUTCOME MEASURES: Change in lean body mass index, peak torque, and peak oxygen consumption from discharge to 12 weeks postdischarge, presented as mean ± SE. RESULTS: The community-based exercise program group showed a significant increase in peak oxygen consumption compared with SOC (community-based exercise program: Δ=7.723±1.522mL/kg/min, P=.0006; SOC: Δ=2.200±1.150mL/kg/min, P=.0765; community-based exercise program vs SOC, P=.0236). The community-based exercise program group exhibited a significant within group increase in lean body mass index (Δ=1.107±0.431kg/m2, P=.0003; SOC: Δ=1.323±0.873kg/m2, P=.2808). Both groups showed significant within-group increases in peak torque (community-based exercise program: Δ=35.645±7.566Nm, P=.0003; SOC: Δ=34.717±11.029Nm, P=.0082). No significant differences were noted between the 2 groups for lean body mass index or peak torque. CONCLUSIONS: Patients who participate in a community-based exercise program show significant improvements in cardiopulmonary fitness compared with SOC, supporting the use of a community-based exercise program as an alternative therapy to SOC in adults with severe burns.

Challenges in IBD Research: Novel Technologies.

Novel technologies is part of five focus areas of the Challenges in IBD research document, which also includes preclinical human IBD mechanisms, environmental triggers, precision medicine and pragmatic clinical research. The Challenges in IBD research document provides a comprehensive overview of current gaps in inflammatory bowel diseases (IBD) research and delivers actionable approaches to address them. It is the result of a multidisciplinary input from scientists, clinicians, patients, and funders, and represents a valuable resource for patient centric research prioritization. In particular, the novel technologies section is focused on prioritizing unmet clinical needs in IBD that will benefit from novel technologies applied to: 1) non-invasive detection and monitoring of active inflammation and assessment of treatment response; 2) mucosal targeted drug delivery systems; and 3) prevention of post-operative septic complications and treatment of fistulizing complications. Proposed approaches include development of multiparametric imaging modalities and biosensors, to enable non invasive or minimally invasive detection of pro-inflammatory signals to monitor disease activity and treatment responses. Additionally, technologies for local drug delivery to control unremitting disease and increase treatment efficacy while decreasing systemic exposure are also proposed. Finally, research on biopolymers and other sealant technologies to promote post-surgical healing; and devices to control anastomotic leakage and prevent post-surgical complications and recurrences are also needed.

Buprenorphine-Sustained Release Alters Hemodynamic Parameters in a Rat Burn Model.

BACKGROUND: It has been previously shown that anesthesia and analgesia can affect outcomes in the rat burn model and that buprenorphine alleviated pain without drastically altering the outcomes of interest. Recently, the use of a sustained release (SR) formulation of buprenorphine has been promoted over conventional buprenorphine. In this study, we assessed whether buprenorphine-SR altered hemodynamic parameters in our rat model of severe burn injury. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were randomized to receive either conventional buprenorphine (0.05 mg/kg) or buprenorphine-SR (1 mg/kg). Buprenorphine-SR was administered 24 h before the experiment. Buprenorphine was administered on the day of experiment. These groups were further randomized to control or scald burn (60% of total body surface area). Systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) were measured using a noninvasive blood pressure system before receiving analgesia and after 72 h. RESULTS: As expected, HR was significantly higher after burn injury regardless of analgesic (P <0.0001). Both SBP and DBP were significantly decreased in burned animals receiving conventional buprenorphine (P < 0.0001), but neither was altered in the buprenorphine-SR-treated burned animals. However, SBP, DBP, and HR were significantly increased after 72 h in control animals receiving buprenorphine-SR (P < 0.0001). CONCLUSIONS: These data indicate that buprenorphine-SR alters the hemodynamic response to injury and may not be an appropriate choice for a model of severe burn injury. If this analgesic is used, investigators must cautiously form conclusions, especially in experimental conditions that would be expected to alter cardiac hemodynamics.

Oxidative Stress and Cardiac Remodeling: An Updated Edge.

BACKGROUND: A common phenotype associated with heart failure is the development of cardiac hypertrophy. Cardiac hypertrophy occurs in response to stress, such as hypertension, coronary vascular disease, or myocardial infarction. The most critical pathophysiological conditions involved may include dilated hypertrophy, fibrosis and contractile malfunction. The intricate pathophysiological mechanisms of cardiac hypertrophy have been the core of several scientific studies, which may help in opening a new avenue in preventive and curative procedures. OBJECTIVES: To our knowledge from the literature, the development of cardiac remodeling and hypertrophy is multifactorial. Thus, in this review, we will focus and summarize the potential role of oxidative stress in cardiac hypertrophy development. CONCLUSION: Oxidative stress is considered a major stimulant for the signal transduction in cardiac cells pathological conditions, including inflammatory cytokines, and MAP kinase. The understanding of the pathophysiological mechanisms which are involved in cardiac hypertrophy and remodeling process is crucial for the development of new therapeutic plans, especially that the mortality rates related to cardiac remodeling/dysfunction remain high.

Biventricular differences in ß-adrenergic receptor signaling following burn injury.

Burn injury detrimentally affects the myocardium, primarily due to over-activation of ß-adrenergic receptors (ß-AR). Autopsy reports from our institution reveal that patients often suffer from right ventricle (RV) failure. Since burn injury affects ß-AR signaling in the left ventricle (LV), we proposed that ß-AR signaling may also be altered in the RV. A rodent model with a scald burn of 60% of the total body surface area was used to test this hypothesis. Ventricles were isolated 7 days post-burn. We examined the expression of ß-ARs via Western blotting and the mRNA expression of downstream signaling proteins via qRT-PCR. Cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity were measured in membrane and cytosolic fractions, respectively, using enzyme immunoassay kits. ß1-AR protein expression was significantly increased in the RV following burn injury compared to non-burned RV but not in the LV (p = 0.0022). In contrast, ß2-AR expression was unaltered among the groups while Gαi expression was significantly higher in the LV post-burn (p = 0.023). B-arrestin-1 and G-protein coupled receptor kinase-2 mRNA expression were significantly increased in the left ventricle post-burn (p = 0.001, p<0.0001, respectively). cAMP production and PKA activity were significantly lower in the LV post-burn (p = 0.0063, 0.0042, respectively). These data indicate that burn injury affects the ß-AR signaling pathway in the RV independently of the LV. Additionally, non-canonical ß-AR signaling may be activated in the RV as cAMP production and PKA activity were unchanged despite changes in ß1-AR protein expression.

The P50 Research Center in Perioperative Sciences: How the investment by the National Institute of General Medical Sciences in team science has reduced postburn mortality.

Since the inception of the P50 Research Center in Injury and Peri-operative Sciences (RCIPS) funding mechanism, the National Institute of General Medical Sciences has supported a team approach to science. Many advances in critical care, particularly burns, have been driven by RCIPS teams. In fact, burns that were fatal in the early 1970s, prior to the inception of the P50 RCIPS program, are now routinely survived as a result of the P50-funded research. The advances in clinical care that led to the reduction in postburn death were made by optimizing resuscitation, incorporating early excision and grafting, bolstering acute care including support for inhalation injury, modulating the hypermetabolic response, augmenting the immune response, incorporating aerobic exercise, and developing antiscarring strategies. The work of the Burn RCIPS programs advanced our understanding of the pathophysiologic response to burn injury. As a result, the effects of a large burn on all organ systems have been studied, leading to the discovery of persistent dysfunction, elucidation of the underlying molecular mechanisms, and identification of potential therapeutic targets. Survival and subsequent patient satisfaction with quality of life have increased. In this review article, we describe the contributions of the Galveston P50 RCIPS that have changed postburn care and have considerably reduced postburn mortality.

The renaissance man of burn surgery: Basil A. Pruitt, Jr.

Dr. Basil A. Pruitt Jr., a consummate clinical and translational surgeon-scientist, has spent over half a century at the forefront of an advancing standard of burn care. Commanding the US Army Institute for Surgical Research in San Antonio, he trained generations of leading burn clinicians and allied scientists. At his direction, there were forged discoveries in resuscitation from shock, treatment of inhalation injury, control of burn-related infections, prevention of iatrogenic complications, and understanding the sympathetic, endocrine, and immune responses to burn injury. Most consequentially, this team was among the first to recognize and define alterations in the basal metabolic rate and thermoregulation consequent to burn injury. These investigations prompted groundbreaking insights into the coordinated nervous, autonomic, endocrine, immune, and metabolic outflows that a severely burned patient uses to remain alive and restore homeostasis. Marking his scientific consequence, many of his reports continue to bear fruit when viewed through a contemporary lens. This article summarizes some of the major findings of his career thus far and is intended to complement a Festschrift recently held in his honor.

Propranolol kinetics in plasma from severely burned adults.

OBJECTIVES: The aim of this study was to determine the appropriate propranolol dosing strategy for reducing heart rate in severely burned adults. METHODS: A total of 26 patients (≥18 years) with burns covering ≥30% of the total body surface area were included in this IRB-approved study. Plasma propranolol concentrations were determined in a placebo group (n=10) or following one of three dosing strategies: Q6 (n=4), Q8 (n=6), and Q24 (n=6). Blood was collected just before dosing and at regular intervals over two dosing periods with corresponding heart rate and blood pressure recordings. Statistical significance was determined by one-way ANOVA followed by the appropriate post-hoc test. RESULTS: Heart rate was 86±2 bpm for Q6, 93±3 bpm for Q8, and 90±4 bpm for Q24. The Q8 group had a significantly higher heart rate than the Q6 group (p=0.0001). Plasma propranolol concentrations were significantly higher in the Q6 dosing strategy than in the Q8 dosing strategy (p=0.02). CONCLUSIONS: Heart rate can be decreased to a similar degree with Q6 and Q24 dosing strategies, with the Q8 dosing strategy being less effective. Q6 dosing is recommended to maintain reduced heart rate throughout dosing periods.

Oxandrolone Coadministration Does Not Alter Plasma Propranolol Concentrations in Severely Burned Pediatric Patients.

The systemic impact of severe burn injury results in a variety of disorders that require therapeutic intervention. Propranolol, a nonselective ß1, ß2-adrenergic receptor antagonist, reduces resting heart rate and cardiac work caused by elevated circulating catecholamines. Oxandrolone, a testosterone mimetic, promotes protein synthesis and anabolism to counter muscle wasting. Coadministration of these drugs is expected to synergistically improve patient outcomes. Testosterone administration is known to alter ß-adrenergic receptor-mediated signaling. Here, we determined whether the coadministration of oxandrolone alters plasma propranolol concentrations. Ninety-two pediatric patients with burns covering ≥30% of the TBSA were enrolled in this institutional review board-approved study and randomized to receive propranolol (n = 49) or oxandrolone + propranolol (n = 43). Plasma propranolol concentrations were determined following two dosing strategies: Q6 (liquid formulation; n = 86) and Q24 (extended-release capsule; n = 22). Samples were drawn before drug administration and at regular intervals throughout the next two dosing periods. Heart rate and blood pressure were recorded throughout the study. Propranolol half-life was 3.3 hours for the Q6 drug dosing frequency (P < .0001) and 11.2 hours for the Q24 strategy (P < .0001). Percentage of predicted heart rate declined by 2.8% for each doubling of the propranolol concentration in the Q6 dosing schedule (P < .0001). Percentage of predicted heart rate declined by 2.5% for each doubling of propranolol concentration on the Q24 dosing schedule (P < .0001). Maximum and minimum propranolol plasma concentrations were similar with either dosing regimen. The addition of oxandrolone did not affect any of the measured parameters. Oxandrolone coadministration does not alter propranolol's plasma concentration, half-life, or effect on heart rate. This study is registered at clincialtrials.gov: NCT00675714.

Human herpes viruses in burn patients: A systematic review.

OBJECTIVE: The contribution of human herpes viruses, including herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella zoster virus (VZV) to morbidity and mortality after burns remains controversial. This systematic review was undertaken to assess evidence of herpes virus-related morbidity and mortality in burns. MATERIALS AND METHODS: PubMed, Ovid, and Web of Science were searched to identify studies of HSV, CMV, or VZV infections in burn patients. Exclusion criteria included: A level of evidence (LoE) of IV or V; nonhuman in vivo studies; and non-English articles. There was no limitation by publication date. RESULTS: Fifty articles were subjected to full-text analysis. Of these, 18 had LoE between I-III and were included in the final review (2 LoE I, 16 LoE II-III). Eight had a prospective study design, 9 had a retrospective study design, and 1 included both. CONCLUSIONS: No direct evidence linked CMV and HSV infection with increased morbidity and mortality in burns. Following burn, CMV reactivation was more common than a primary CMV infection. Active HSV infection impaired wound healing but was not directly correlated to mortality. Infections with VZV are rare after burns but when they occur, VZV infections were associated with severe complications including mortality. The therapeutic effect of antiviral agents administered after burns warrants investigation via prospective randomized controlled trials.

Reversal of Growth Arrest With the Combined Administration of Oxandrolone and Propranolol in Severely Burned Children.

BACKGROUND: The hypercatabolic response in severely burned pediatric patients is associated with increased production of catecholamines and corticosteroids, decreased formation of testosterone, and reduced strength alongside growth arrest for up to 2 years after injury. We have previously shown that, in the pediatric burned population, the administration of the testosterone analog oxandrolone improves lean body mass accretion and bone mineral content and that the administration of the ß1-, ß2-adrenoceptor antagonist propranolol decreases cardiac work and resting energy expenditure while increasing peripheral lean mass. Here, we determined whether the combined administration of oxandrolone and propranolol has added benefit. METHODS: In this prospective, randomized study of 612 burned children [52% ±â€Š1% of total body surface area burned, ages 0.5-14 years (boys); ages 0.5-12 years (girls)], we compared controls to the individual administration of these drugs, and the combined administration of oxandrolone and propranolol at the same doses, for 1 year after burn. Data were recorded at discharge, 6 months, and 1 and 2 years after injury. RESULTS: Combined use of oxandrolone and propranolol shortened the period of growth arrest by 84 days (P = 0.0125 vs control) and increased growth rate by 1.7 cm/yr (P = 0.0024 vs control). CONCLUSIONS: Combined administration of oxandrolone and propranolol attenuates burn-induced growth arrest in pediatric burn patients. The present study is registered at clinicaltrials.gov: NCT00675714 and NCT00239668.

Cardiovascular Dysfunction Following Burn Injury: What We Have Learned from Rat and Mouse Models.

Severe burn profoundly affects organs both proximal and distal to the actual burn site. Cardiovascular dysfunction is a well-documented phenomenon that increases morbidity and mortality following a massive thermal trauma. Beginning immediately post-burn, during the ebb phase, cardiac function is severely depressed. By 48 h post-injury, cardiac function rebounds and the post-burn myocardium becomes tachycardic and hyperinflammatory. While current clinical trials are investigating a variety of drugs targeted at reducing aspects of the post-burn hypermetabolic response such as heart rate and cardiac work, there is still a paucity of knowledge regarding the underlying mechanisms that induce cardiac dysfunction in the severely burned. There are many animal models of burn injury, from rodents, to sheep or swine, but the majority of burn related cardiovascular investigations have occurred in rat and mouse models. This literature review consolidates the data supporting the prevalent role that ß-adrenergic receptors play in mediating post-burn cardiac dysfunction and the idea that pharmacological modulation of this receptor family is a viable therapeutic target for resolving burn-induced cardiac deficits.

Enhanced cardiac function in Gravin mutant mice involves alterations in the ß-adrenergic receptor signaling cascade.

Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (ß2-AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in ß-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute ß-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t) animals lacking functional protein compared to wild-type (WT) animals both at baseline and following acute isoproterenol (ISO) administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca(2+) in response to 1 µmol/L ISO stimulation. These physiological responses occurred in the presence of decreased ß2-AR phosphorylation in gravin-t/t hearts, where PKA-dependent ß2-AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC) phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20) was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin's scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute ß-AR stimulation by decreasing ß2-AR phosphorylation and thus attenuating receptor desensitization and perhaps by altering PKA localization to increase the phosphorylation of cMyBPC and the nonclassical PKA substrate Hsp20.

Protein kinase A and phosphodiesterase-4D3 binding to coding polymorphisms of cardiac muscle anchoring protein (mAKAP).

Protein kinase A (PKA) substrate phosphorylation is facilitated through its co-localization with its signaling partner by A-kinase anchoring proteins (AKAPs). mAKAP (muscle-selective AKAP) localizes PKA and its substrates such as phosphodiesterase-4D3 (PDE4D3), ryanodine receptor, and protein phosphatase 2A (PP2A) to the sarcoplasmic reticulum and perinuclear space. The genetic role of mAKAP, in modulating PKA/PDE4D3 molecular signaling during cardiac diseases, remains unclear. The purpose of this study was to examine the effects of naturally occurring mutations in human mAKAP on PKA and PDE4D3 signaling. We have recently identified potentially important human mAKAP coding non-synonymous polymorphisms located within or near key protein binding sites critical to ß-adrenergic receptor signaling. Three mutations (P1400S, S2195F, and L717V) were cloned and transfected into a mammalian cell line for the purpose of comparing whether those substitutions disrupt mAKAP binding to PKA or PDE4D3. Immunoprecipitation study of mAKAP-P1400S, a mutation located in the mAKAP-PDE4D3 binding site, displayed a significant reduction in binding to PDE4D3, with no significant changes in PKA binding or PKA activity. Conversely, mAKAP-S2195F, a mutation located in mAKAP-PP2A binding site, showed significant increase in both binding propensity to PKA and PKA activity. Additionally, mAKAP-L717V, a mutation flanking the mAKAP-spectrin repeat domain, exhibited a significant increase in PKA binding compared to wild type, but there was no change in PKA activity. We also demonstrate specific binding of wild-type mAKAP to PDE4D3. Binding results were demonstrated using immunoprecipitation and confirmed with surface plasmon resonance (Biacore-2000); functional results were demonstrated using activity assays, Ca(2+) measurements, and Western blot. Comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate signaling.

The pre-synaptic Munc13-1 binds alcohol and modulates alcohol self-administration in Drosophila.

Munc13-1 is a pre-synaptic active-zone protein essential for neurotransmitter release and involved in pre-synaptic plasticity in brain. Ethanol, butanol, and octanol quenched the intrinsic fluorescence of the C1 domain of Munc13-1 with EC50 s of 52 mM, 26 mM, and 0.7 mM, respectively. Photoactive azialcohols photolabeled Munc13-1 C1 exclusively at Glu-582, which was identified by mass spectrometry. Mutation of Glu-582 to alanine, leucine, and histidine reduced the alcohol binding two- to five-fold. Circular dichroism studies suggested that binding of alcohol increased the stability of the wild-type Munc13-1 compared with the mutants. If Munc13-1 plays some role in the neural effects of alcohol in vivo, changes in the activity of this protein should produce differences in the behavioral responses to ethanol. We tested this prediction with a loss-of-function mutation in the conserved Dunc-13 in Drosophila melanogaster. The Dunc-13(P84200) /+ heterozygotes have 50% wild-type levels of Dunc-13 mRNA and display a very robust increase in ethanol self-administration. This phenotype is reversed by the expression of the rat Munc13-1 protein within the Drosophila nervous system. The present studies indicate that Munc13-1 C1 has binding site(s) for alcohols and Munc13-1 activity is sufficient to restore normal self-administration to Drosophila mutants deficient in Dunc-13 activity. The pre-synaptic Mun13-1 protein is a critical regulator of synaptic vesicle fusion and may be involved in processes that lead to ethanol abuse and addiction. We studied its interaction with alcohol and identified Glu-582 as a critical residue for ethanol binding. Munc13-1 can functionally complement the Dunc13 haploinsufficient ethanol self-administration phenotype in Drosophila melanogaster, indicating that this protein participates in alcohol-induced behavioral plasticity.

Delta-opioid augments cardiac contraction through ß-adrenergic and CGRP-receptor co-signaling.

Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist DPDPE (100 µg/kg) with or without 10-min pretreatment with either ß-adrenergic receptor (ß-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP(8-37) (300 µg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after DPDPE infusion. At 5-min DPDPE induced a 36 ± 18% (p<0.001) increase of the LVFS, which continues to increase to 51 ± 24% (p<0.0001) by 10 min, and 68 ± 19% (p<0.001) by 20 min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5 min and 11 ± 6% (p<0.001) by 15 min post DPDPE infusion. This magnitude of HR reduction was observed for the remainder of the 20 min. Despite the HR-reduction, cardiac output was increased by 17 ± 8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post DPDPE administration, respectively. There was a modest (9 ± 9%, p=0.03) decrease in SBP that was not apparent until 20 min post DPDPE infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol, CGRP(8-37), or combined propranolol+CGRP(8-37). Furthermore, in whole animal and cardiomyocyte cell culture preparations, DPDPE induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP(8-37). DOR agonists augment myocardial contraction through enhanced ß-AR and CGRPR co-signaling.