Browsing by Author "Tune, Johnathan"
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Item Cardiovascular Response to Endotoxin-Mediated Sepsis: A Dose-Response Study(2022) Aguirre, David Salinas; Martinez, Richard; Warne, Cooper; Mallet, Robert T.; Dick, Gregory; Tune, Johnathan; Hodge, LisaPurpose: Our long-term goal is to advance our understanding and treatment of sepsis, a potentially life-threatening condition that occurs when the response to infection causes tissue and organ damage. Sepsis can be caused by lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria. We used a swine model of LPS-induced sepsis to study the impact of the lymphatic and immune systems on the disease progression. Our first experiments were aimed at determining the optimal dose of Escherichia coli LPS in order to study the effect of sepsis on the cardiovascular system. We hypothesized that 2-hour intravenous infusions of 1- 50 µg/kg LPS would reveal dose- and time-dependent changes in hemodynamic parameters that are consistent with sepsis. Methods: Yorkshire pigs (61 ± 4 kg, n = 4, 2 male) were sedated, intubated, and ventilated. Femoral artery and venous lines were placed to allow measurement of blood pressure, infusion of LPS, and blood gas sampling. A thoracotomy was performed in order to secure a Transonic flow probe around the left anterior descending coronary artery and to insert a sampling catheter in the anterior cardiac vein. A dose of LPS (1, 5, 25, and 50 µg/kg) was given to each pig over 2 hours. Blood samples were collected immediately before LPS infusion and for every 30 minutes during and after LPS infusion for blood gas measurements. Vital signs were recorded as the animals developed sepsis. Results: Only the pig given the lowest dose of LPS (1 µg/kg) survived the full 6 hours (mean survival time in remaining 3 pigs was 180 ± 30 min). At 150 min, a ≈55% decrease in mean arterial pressure was observed (107 ± 4 to 48 ± 13 mmHg), resulting in a ≈60% increase in heart rate (91 ± 9 to 146 ± 14 beats/min). Coronary blood flow and myocardial oxygen consumption decreased ≈28% (0.53 ± 0.06 to 0.38 ± 0.02 ml/min/g) and ≈33% (60 ± 6 to 44 ± 2 µl/min/g), respectively. Ventricular fibrillation was the cause of death in the 3 non-surviving pigs. Conclusion: A dose of 1 µg/kg appears to be an optimal dose for future studies, as this dose was survivable in the desired time frame, while causing hypotension and tachycardia. In future studies, this model will allow us to study the effect of novel therapeutics during acute sepsis.Item Cytokine Response in an Endotoxin-Mediated Sepsis Model(2022) Martinez, Richard; Aguirre, David Salinas; Warne, Cooper; Dick, Gregory; Mallet, Robert T.; Tune, Johnathan; Hodge, LisaPurpose: Sepsis is a life-threatening condition that develops secondary to infection and can manifest acute organ dysfunction due to the body's overactive systemic response. Sepsis affects approximately 1.7 million US adults and claims 270,000 lives as a result. The long-term goal of our project is to gain a better understanding of the roles of the lymphatic and immune systems in the progression of sepsis. The purpose of this study is to collect pilot data using a translational swine model of endotoxin-mediated sepsis. We chose a swine model because it closely mimics how sepsis progresses in humans. Sepsis was induced by infusion of lipopolysaccharide (LPS) from Escherichia coli. LPS was chosen because it is a key mediator in the activation of the immune system and the development of sepsis. We hypothesized that the administration of LPS would increase the concertation of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-?) in a dose-dependent manner over time. Methods: Yorkshire pigs (61 � 4 kg, n = 4, 2 male) were sedated, intubated, and ventilated. Thoracotomy was performed under anesthesia to record flow data and sample cardiac blood for use in another study. Femoral artery and venous lines were placed to allow measurement of blood pressure and infusion of LPS. Specifically, LPS was prepared at 1, 5, 25, or 50 ?g/kg (pig body weight) in sterile saline. LPS was infused into anesthetized pigs over a 2-hour period. Blood samples were collected immediately prior to LPS administration and at 30 min intervals during 2 hours of LPS infusion up to 4 hours following LPS infusion. The plasma was analyzed via enzyme-linked immunosorbent immunoassay (ELISA) for the concentrations of IL-6 and TNF-? using commercially available kits. Results: As hypothesized, the infusion of LPS increased the concentration of the inflammatory mediators IL-6 and TNF-? over time compared to pre-LPS infusion. Specifically, the greatest increase in IL-6 was seen at 180 minutes in both the 50 and 25 ?g/kg LPS infused pigs. TNF-? concentration peaked between 30 to 90 minutes during LPS infusion in both the 50 and 25 ?g/kg LPS infused pigs. The lower doses of 1 and 5 ?g/kg LPS produced little to no IL-6 or TNF-?. Furthermore, we discovered that the pigs who received 50 or 25 ?g/kg of LPS died from septic shock within 180 minutes of LPS infusion, whereas the pigs that received 1or 5 ?g/kg of LPS survived longer. Conclusion: In this study, we identified the impact of increasing the doses of LPS on the production of IL-6 and TNF-? in swine. Our preliminary results suggest a dose range of 10-20 ?g/kg of LPS may be ideal to study the inflammatory response in this model. The acquisition of these data are essential to pursue our long-term research objective, which is to identify the role of the lymphatic and immune systems during sepsis.Item The effects of esmolol on the control of coronary blood flow and myocardial oxygen supply-demand balance in sepsis(2024-03-21) Digilio, Michaela; Warne, Cooper; Heard, Michael; Tucker, Selina; Essajee, Sal; Bradford, Ni' Ja D.; Hodge, Lisa; Tune, Johnathan; Dick, GregoryPurpose: Sepsis is an acute organ dysfunction secondary to infection that results in tachycardia, tachypnea, fever, decreased blood pressure, and lactic acidosis. This results in an overall myocardial oxygen supply-demand imbalance leading to cardiac dysfunction and ultimately death. The current treatment for sepsis is antibiotic therapy, vasopressors, and fluid therapy. However, this regimen does not address the tachycardia that leads to cardiovascular decompensation. Beta-blocker therapy addresses this myocardial oxygen supply-demand imbalance and is expected to promote survival in sepsis. We hypothesize that treatment with beta-blocker therapy during acute sepsis will address the myocardial oxygen supply-demand imbalance to maintain coronary perfusion pressure, improve myocardial oxygen delivery, and promote survival. Methods: Female and male Yorkshire pigs were used as the animal model for this project. Pigs were anesthetized, intubated, and a rectal thermometer and oximeter were placed. Catheters placed in ear vein, great cardiac vein, femoral artery, and bilateral femoral veins. Pressure transducer placed in the femoral artery. A transonic flow transducer placed around the left anterior descending artery. After instrumentation, baseline values were collected. Then, infusion with Escherichia coli lipopolysaccharide (LPS) at 10 µg/kg over the course of 2 hours was used to induce sepsis. LPS was infused via the femoral vein at a rate of 0.5mL/min. After 2 hours, intervention began depending on the treatment group. Intervention lasted 4 hours. Experiment groups included Sham (without LPS, fluids, norepinephrine (NE), or esmolol), Control (with LPS, no fluids, NE, or esmolol), Standard (with LPS, fluids, and NE), and Experimental (with LPS, fluids, NE and esmolol). Doses: LPS 10 µg/kg, esmolol escalating from 100mg/hr, and NE escalating from 0.4 µg/kg/min. Goals during the intervention included keeping the mean arterial pressure (MAP) above 65mmHg and heart rate below 100. Results: All control pigs died during the 4-hour follow-up. 1 out of 3 standard treatment pigs survived. All esmolol-treated pigs survived. The esmolol group had better MAP, coronary blood flow, myocardial oxygen delivery, and oxygen extraction than the standard treatment group. Conclusion: Esmolol improves survival, coronary perfusion pressure, and myocardial oxygen delivery. This data provides support for our hypothesis and the clinical use of esmolol in sepsis.Item Effects of the thromboxane receptor antagonist S18886 in the porcine coronary circulation(2023) Tucker, Selina M.; Warne, Cooper; Essajee, Salman; Goulopoulou, Styliani; Dick, Gregory; Tune, JohnathanThromboxane A2 (TxA2) is a potent coronary vasoconstrictor that has been implicated in promoting decreases in myocardial perfusion in a variety of (patho)-physiologic conditions. S18886 is a promising orally-active TxA2 receptor antagonist currently approved for investigational clinical use. However, the coronary vascular effects of S18886 are unknown and its specificity and affinity for the thromboxane receptor in the coronary circulation remain unclear. We tested the hypothesis that administration of S18886 dose-dependently attenuates coronary vasoconstriction to the TxA2 mimetic U46619 without influencing coronary responses to prostaglandin F2α, acetylcholine, or smooth muscle depolarization (K+). Experiments to test this hypothesis were performed in male (n = 5) and female (n = 6) domestic swine. Hearts were excised and the left circumflex coronary artery isolated, cleaned of periadventitial fat, and cut into 3 mm rings. Isometric tension of coronary artery rings was measured in response to log order increments of U46619 (1 nM to 1 µM) with and without S18886 (0.1-100 nM). Similar isometric studies were conducted with prostaglandin F2α (10 nM-10 µM), acetylcholine (0.1-10 µM), and KCl (5-90 mM). U46619 induced concentration dependent increases in tension development of isolated coronary artery rings (average EC50 of 42 ± 19 nM). Incubation of coronary arteries with S18886 (1 nM) significantly attenuated coronary vasoconstriction to U46619 resulting in a rightward shift of the EC50 to 187 ± 38 nM (P < 0.02). Vehicle had no effect on U46619-induced contractions. Higher concentrations of S18886 dose-dependently reduced U46619-induced contractions. S18886 (1 nM) antagonized coronary vasoconstriction of prostaglandin F2α (10 µM) by 68% ± 5 (P < 0.0001) but had no effect on either acetylcholine or KCl-induced contraction. Data from this investigation indicate that S18886 is an effective antagonist of U46619-induced vasoconstriction in the porcine coronary circulation. While S18886 does not influence coronary smooth muscle response to either acetylcholine or activation of L-type Ca2+ channels, attenuation of prostaglandin F2α suggests antagonists specificity may extend beyond TxA2 receptor signaling.Item Hypoxemia Augments the Local Metabolic Error Signal and Improves Coronary Pressure-Flow Autoregulation(2022) Warne, Cooper M.; Essajee, Sal; Dick, Gregory; Tune, JohnathanThe local metabolic hypothesis proposes that myocardial oxygen tension, indexed by coronary venous PO2 (CvPO2), determines the degree of coronary pressure-flow autoregulation by increasing the production of vasodilator metabolites as coronary perfusion pressure (CPP) is reduced. We tested this hypothesis by examining the extent to which exaggeration of the metabolic error signal influences coronary autoregulatory capability. Experiments were performed in anesthetized, open chest swine (n = 8) in which the left anterior descending coronary artery was cannulated and connected to a servo-controlled roller pump system. This allowed CPP to be reduced from 140 to 40 mmHg in increments of 10 mmHg before and during hypoxemia (PaO2 from 138 ± 5 to 34 ± 1 mmHg). Under control-normoxic conditions, CvPO2 decreased from 33 ± 1 to 20 ± 1 mmHg and coronary blood flow fell from 0.81 ± 0.09 to 0.35 ± 0.04 ml/min/g as CPP was reduced from 140 to 40 mmHg. Hypoxemia augmented myocardial oxygen consumption (P < 0.01), increased coronary blood flow (P < 0.0001), and reduced CvPO2 (22 ± 1 to 14 ± 1 mmHg; P < 0.0001) over the same range of CPPs. Increases in coronary blood flow during hypoxemia were sufficient to maintain myocardial oxygen delivery at values equivalent to normoxic conditions (P = 0.20). Calculation of closed-loop autoregulatory gain (Gc) over a CPP range of 120 to 60 mmHg (value of 1 represents perfect autoregulation) demonstrated that Gc was improved from 0.18 ± 0.05 to 0.45 ± 0.14 under normoxic vs. hypoxemic conditions respectively (P = 0.02). Gc was also inversely related to CvPO2 and the slope increased ~4-fold by hypoxemia. These findings support that coronary pressure-flow autoregulatory capability is augmented by hypoxemia-induced increases in the local metabolic error signal.Item Innate immune system stimulation during pregnancy induces upregulation of thromboxane synthesis in rat maternal heart(2022) Tucker, Selina; Cushen, Spencer; Bradshaw, Jessica L.; Gardner, Jennifer; Ricci, Contessa; Dick, Gregory; Tune, Johnathan; Goulopoulou, StylianiPurpose: Infections during pregnancy are associated with adverse clinical outcomes. We previously showed that exposure to immunostimulatory ODN2395 (synthetic Toll-like receptor 9 agonist) during pregnancy induces maternal vascular inflammation and enhances vascular tone in pregnant rats. These outcomes were mediated in part by activation of the cyclooxygenase/thromboxane A2 (COX/TxA2) pathway. The objective of this study was to investigate the impact of ODN2395-induced immune system stimulation on maternal hearts during pregnancy. We hypothesize that exposure to TLR9-mediated immune system activation during pregnancy upregulates the COX/TxA2 signaling pathway in maternal cardiac tissues in rats. Methods: Rats were treated with a synthetic CpG DNA (ODN2395, 1 mg/kg, intraperitoneal injection) or vehicle (saline) in late pregnancy. Fetoplacental biometrics were recorded after euthanasia on gestational day 20 and maternal hearts were collected to assess COX-1 and COX-2 expression and 6-keto PGF1α (PGI2 metabolic byproduct) and TxB2 (TxA2 metabolic byproduct) production. Results: Left ventricular tissues from dams treated with ODN2395 released higher concentrations of TxB2 compared to tissues from vehicle-treated dams (ODN2395: 0.56 ± 0.06 ng/mg protein vs. Vehicle: 0.31 ± 0.04 ng/mg protein, n5, p=0.0041) but there were no differences in cardiac 6-keto PGF1α release between groups (p=0.16). COX-2 expression was lower in left ventricles from ODN2395-treated rats compared to vehicle-treated rats (p=0.009). There were no differences in cardiac COX-1 expression between groups (p=0.27). Exposure to ODN2395 during pregnancy increased fetal-placental weight ratio (ODN2395: 5.3 ± 0.22 vs. Vehicle: 4.7 ± 0.15, p = 0.04). COX-2 expression was greater in placental tissues from ODN2395-treated rats (p=0.004) but there were no differences in placental 6-keto PGF1α (p=0.51) and TxB2 release (p=0.32). Conclusion: TLR9 activation during pregnancy induces upregulation of TxB2 synthesis in maternal cardiac tissues coupled with a reduction in COX-2 expression. Maternal heart may have enhanced sensitivity to bacterial infections during pregnancy.Item The length-tension characteristics of small coronary arteries vary with transmural origin(2023) Essajee, Sal; Warne, Cooper; Tucker, Selina; Dick, Gregory; Tune, JohnathanThere are transmural differences in the structure of arteries across the left ventricular wall. For example, for arteries of the same size, wall thickness is greater in arteries of the epicardium than those from the endocardium. This observation suggests that there could be differences in their passive and active length-tension relationships, as different amounts of connective tissue or smooth muscle would be expected to alter these characteristics. We tested this hypothesis by studying similarly sized porcine coronary arteries from opposite transmural locations. Endocardial arteries had a diameter of 389 ± 33 µm (n = 8), while epicardial arteries measured 388 ± 50 µm (n = 6). A wire myograph was used to study the mechanical properties of these arteries under isometric conditions in KrebsHenseleit buffer at 37 oC. Arteries were cut into rings with an axial length of 2 mm. Rings were repetitively stimulated to contract at increasing lengths with the addition of high extracellular K + (80 mM). Coronary arteries developed active tension to a plateau level over approximately 3-5 min and K + -induced contractions readily washed out. Arteries from the epicardium were stiffer, as the passive-length tension curve of these vessels was elevated over arteries from the endocardium. Passive tensions at optimal length were 3.2 ± 0.4 vs. 5.6 ± 1.5 mN/mm (p < 0.05). The active tension developed in response to K + depolarization was greater in epicardial arteries. Active tensions at optimal length were 3.4 ± 1.1 vs. 2.4 ± 0.3 mN/mm (p < 0.05). Our results represent the first comparison of transmural differences in coronary arteries under isometric tension. Our findings support the hypothesis that differences exist in the passive and active length-tension relationships of epicardial and endocardial arteries that correlate with wall thickness.Item Phenotype of Pacing-Induced Heart Failure in Lean and Obese Ossabaw Swine(2022) Reagor, Caleb; Sweeney, Jonathan; Biggerstaff, Matthew; Tune, JohnathanCaleb Reagor*, Jonathan Sweeney*, Matthew Biggerstaff*, and Johnathan D. Tune *Authors contributed equally Purpose: There are numerous preclinical models of heart failure in large animals; however, almost all reflect heart failure with reduced ejection fraction (HFrEF). There are currently no suitable large animal models of heart failure with preserved ejection fraction (HFpEF). The lack of HFpEF models represents a significant gap in translational studies to understand pathophysiological mechanisms and elucidate potential treatments for approximately 50% of all heart failure cases. Obesity and its related comorbidities are more strongly associated with risk of future HFpEF versus HFrEF. We hypothesized that obese animals would develop HFpEF in response to 4 weeks of tachypacing, whereas lean animals would develop HFrEF in response to the same stimulus. Methods: Three groups of Ossabaw swine were studied, including lean swine without pacing (n = 9; control), lean swine with pacing (n = 5), and obese swine with pacing (n = 5). Ossabaw swine are an ideal model for these studies, as they demonstrate a human-like response to a high calorie, high fat diet (e.g., obesity, insulin resistance, and dyslipidemia). Swine were anesthetized and pacemakers were implanted to drive the right ventricle at 180 beats/min. After recovery and 4 weeks of pacing, animals were anesthetized, and a pressure-volume catheter was inserted into the left ventricle to assess the type and degree of heart failure. Results: Paced animals had grossly enlarged heart chambers and significant abdominal ascites. Tachypacing increased heart weight (176 ± 11, 229 ± 13, and 234 ± 14 g in control, lean, and obese swine, respectively; p < 0.01). Ejection fraction was not different between groups (58 ± 6, 53 ± 6, and 59 ± 6% in control, lean, and obese swine, respectively; p = 0.86). Tachypacing increased left ventricular end diastolic pressure (LVEDP), a hallmark of heart failure (12 ± 1, 28 ± 4, and 26 ± 1 mmHg in control, lean, and obese swine, respectively; p < 0.001). Conclusions: The data indicate that we have created a tachypacing-induced model of HFpEF in Ossabaw swine. However, in direct contrast to our prediction, tachypacing produced HFpEF in both lean and obese Ossabaw swine. Tachypacing significantly elevated filling pressure (LVEDP) to pathophysiological levels, but ventricular performance (ejection fraction) was maintained. Our findings support the idea that Ossabaw swine subjected to tachypacing represent a clinically relevant large animal model of HFpEF.Item Smooth Muscle Contraction Is Regulated by Chloride Channels: Functional Evidence for TMEM16A in Porcine Coronary Arteries(2021) Dick, Gregory; Tune, JohnathanPurpose: Contraction of coronary smooth muscle is influenced by ion channels controlling membrane potential (Em) and Ca2+ influx. A great deal of attention has been focused on K+ channels, as their opening makes Em more negative, reduces Ca2+, and causes relaxation. We investigated ion channels whose opening would depolarize Em, increase Ca2+, and promote contraction. A candidate for study is TMEM16A, a Ca2+-activated Cl- channel expressed in a variety of smooth muscles. We tested the hypothesis that drugs which influence TMEM16A would alter contraction. We predicted that contraction would be enhanced by a TMEM16A activator (Eact), whereas it would be attenuated by a TMEM16A inhibitor (T16Ainh-A01). Methods: We used isometric tension recording methods on epicardial coronary artery segments from domestic swine. Contractions to K+ were recorded before and after treatment with 5 µM Eact or 5 µM T16Ainh-01. Extracellular K+ was varied by adding K-gluconate, rather than KCl, to keep Cl- constant. Results: K+ contracted rings with an EC50 of 19.1 ± 0.6 mM and a maximum of 11.8 ± 1.4 g. Drug vehicle had no effect on EC50 or maximum. Eact shifted contraction to the left (17.8 ± 0.9 mM; P < 0.05) but did not affect the maximum (105 ± 3% of control). T16Ainh-A01 shifted contraction to the right (20.4 ± 0.6 mM; P < 0.05) but did not affect the maximum (90 ± 1% of control). Conclusions: These data suggest that TMEM16A is expressed in porcine coronary arteries and influences electromechanical coupling.Item The Effect of Osteopathic Manipulation Techniques on the Lymphatic System(2021) Parker, Madison; Williams, Arthur; Mallet, Robert T.; Tune, Johnathan; Hodge, LisaPurpose: Osteopathic manipulation techniques (OMT) have been utilized by osteopathic physicians to treat a variety of conditions. However, the mechanisms by which OMT aides the body in healing are not well understood. The long-term goal of our research is to advance our understanding of the impact of OMT during disease, such as sepsis. The purpose of this study is to develop a large animal model and to establish surgical techniques that will be used in these future studies. We hypothesized that the abdominal lymphatic pump technique (LPT) will enhance thoracic duct lymph (TDL) flow. Methods: The thoracic duct was exposed via thoracotomy then cannulated using an angio-catheter. TDL was collected from 2 swine (1 male, 1 female) during 10-minutes of baseline, 4-minutes of LPT, and 10-minutes post-LPT. TDL flow was measured by timed collection during each condition. TDL was centrifuged to remove the cellular components, and the supernatant was stored for biomarker analysis. Results: TDL flow increased from an average of 1.68 mL/min to 3.25 mL/min during LPT administration. Immunological assays will be performed to identify changes in lymph composition during OMT. Conclusion: In our pilot study, LPT increased TDL flow in both our swine subjects and demonstrated surgical feasibility. In future studies we will study the physiological effects of OMT during sepsis. This knowledge would provide an evidence-based foundation for the use, or contraindication, of OMT during sepsis and aid osteopathic physicians during their therapeutic decision making.Item The Effects of Osteopathic Manipulation Techniques on the Lymphatic System(2021-05) Parker, Madison A.; Hodge, Lisa M.; Tune, Johnathan; Mallet, Robert T.Osteopathic manipulation techniques (OMT) have been utilized by osteopathic physicians to treat a variety of conditions including musculoskeletal dysfunctions, edema, inflammation, and disease. However, the mechanisms by which OMT aides the body in healing are not well understood. The long-term goal of our research is to advance our understanding of the impact of OMT during inflammatory disease, such as sepsis. The purpose of this study was to develop a swine model and to establish surgical techniques that will be used in future studies investigating the impact of OMT on the lymphatic system during disease. We hypothesized that the abdominal lymphatic pump technique (LPT) would enhance thoracic duct lymph (TDL) flow. Four swine subjects (two male and two female) were placed under anesthesia. The thoracic duct was exposed via thoracotomy then cannulated using an angio-catheter. TDL was collected from the four pigs during four-minutes of baseline, four-minutes of LPT, and four minutes post-LPT. TDL flow was measured by timed collection during each condition. TDL was centrifuged to remove the cellular components, and the supernatant was stored for biomarker analysis. Results: TDL flow at baseline was 2.2 ± 1.0 mL/min and LPT increased lymph flow rate to 5.58 ± 1.8 mL/min. In two experiments, thoracic lymph nodes and thoracic duct lymph were collected, and leukocyte were isolated to optimize the flow cytometry staining protocol. In our pilot study, LPT increased TDL flow approximately 2-fold in our swine subjects and demonstrated surgical feasibility. In future studies we will study the physiological effects of OMT, including LPT, during sepsis. This knowledge would provide an evidence-based foundation for the use, or contraindication, of OMT during sepsis and aid osteopathic physicians during their therapeutic decision making.Item The wall stress hypothesis for myogenic responses in the coronary circulation(2021) Bale, Alexander; Dick, Gregory; Tune, JohnathanPurpose: Coronary arterioles demonstrate myogenic reactivity, as the caliber of the arteriole is actively adjusted in response to the intraluminal distending pressure. The teleological purpose of myogenic reactivity remains unclear, but it has been proposed that myogenic responses act to mitigate pressure-induced changes in circumferential wall stress (σ). We investigated pressure-induced variations in σ with and without myogenic reactivity. Methods: Using previously published data, we calculated σ in coronary arterioles in both the longitudinal (branch order) and transmural (epicardial vs endocardial) directions with and without myogenic tone. Results: Active constriction from the myogenic response reduced σ in all arterioles examined. Arteriolar σ was higher in the endocardium in both the passive and active state, but the percent change from passive σ to active σ was similar when compared to epicardial arterioles of the same branch order. There was no major change in active arteriole σ in the longitudinal direction, except for branch order 5 epicardial arterioles, which had a larger reduction in σ and a larger change from passive when compared to other epicardial branch orders. Conclusions: The results indicate that the myogenic response reduces arteriole wall stress. The greater passive and active σ seen in endocardial arterioles compared to epicardial arterioles is due to transmural differences in wall thickness. Yet, the fact that the thinner endocardial arterioles were able to produce the same degree of reduction in active σ may indicate that these vessels have more myogenic activity.