414 results on '"Frisbee, Jefferson C."'
Search Results
2. Loss of fatty acid binding protein 3 ameliorates lipopolysaccharide-induced inflammation and endothelial dysfunction
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Nguyen, Hien C., Bu, Shuhan, Nikfarjam, Sepideh, Rasheed, Berk, Michels, David C.R., Singh, Aman, Singh, Shweta, Marszal, Caroline, McGuire, John J., Feng, Qingping, Frisbee, Jefferson C., Qadura, Mohammad, and Singh, Krishna K. more...
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- 2023
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3. The relationship between anxiety sensitivity and clinical outcomes in cardiac rehabilitation: A scoping review
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Osuji, Ebuka, Prior, Peter L., Suskin, Neville, Frisbee, Jefferson C., and Frisbee, Stephanie J.
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- 2022
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4. Regulation of Skeletal Muscle Resistance Arteriolar Tone: Temporal Variability in Vascular Responses.
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Halvorson, Brayden D., Ward, Aaron D., Murrell, Donna, Lacefield, James C., Wiseman, Robert W., Goldman, Daniel, and Frisbee, Jefferson C.
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MACHINE learning ,STIMULUS intensity ,STIMULUS & response (Psychology) ,SKELETAL muscle ,DATA analytics - Abstract
Introduction: A full understanding of the integration of the mechanisms of vascular tone regulation requires an interrogation of the temporal behavior of arterioles across vasoactive challenges. Building on previous work, the purpose of the present study was to start to interrogate the temporal nature of arteriolar tone regulation with physiological stimuli. Methods: We determined the response rate of ex vivo proximal and in situ distal resistance arterioles when challenged by one-, two-, and three-parameter combinations of five major physiological stimuli (norepinephrine, intravascular pressure, oxygen, adenosine [metabolism], and intralumenal flow). Predictive machine learning models determined which factors were most influential in controlling the rate of arteriolar responses. Results: Results indicate that vascular response rate is dependent on the intensity of the stimulus used and can be severely hindered by altered environments, caused by application of secondary or tertiary stimuli. Advanced analytics suggest that adrenergic influences were dominant in predicting proximal arteriolar response rate compared to metabolic influences in distal arterioles. Conclusion: These data suggest that the vascular response rate to physiologic stimuli can be strongly influenced by the local environment. Translating how these effects impact vascular networks is imperative for understanding how the microcirculation appropriately perfuses tissue across conditions. [ABSTRACT FROM AUTHOR] more...
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- 2024
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5. Early elevations in arterial pressure: a contributor to rapid depressive symptom emergence in female Zucker rats with metabolic disease?
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Konecny, Filip, Kamar, Lujaina, Zimmerman, Isabel, Whitehead, Shawn N., Goldman, Daniel, and Frisbee, Jefferson C.
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VASCULAR resistance ,INTERNAL carotid artery ,TRANSIENT ischemic attack ,LABORATORY rats ,CEREBRAL circulation - Abstract
One of the growing challenges to public health and clinical outcomes is the emergence of cognitive impairments, particularly depressive symptom severity, because of chronic elevations in metabolic disease and cerebrovascular disease risk. To more clearly delineate these relationships and to assess the potential for sexual dimorphism, we used lean (LZR) and obese Zucker rats (OZR) of increasing age to determine relationships between internal carotid artery (ICA) hemodynamics, cerebral vasculopathies, and the emergence of depressive symptoms. Male OZR exhibited progressive elevations in perfusion pressure within the ICA, which were paralleled by endothelial dysfunction, increased cerebral arterial myogenic activation, and reduced cerebral cortex microvessel density. In contrast, female OZR exhibited a greater degree of ICA hypertension than male OZR but maintained normal endothelial function, myogenic activation, and microvessel density to an older age range than did males. Although both male and female OZR exhibited significant and progressive elevations in depressive symptom severity, these were significantly worse in females. Finally, plasma cortisol concentration was elevated higher and at a younger age in female OZR as compared with males, and this difference was maintained to final animal usage at ∼17 wk of age. These results suggest that an increased severity of blood pressure waves may penetrate the cerebral circulation more deeply in female OZR than in males, which may predispose the females to a more severe emergence of depressive symptoms with chronic metabolic disease, whereas males may be more predisposed to more direct cerebral vasculopathies (e.g., stroke, transient ischemic attack). NEW & NOTEWORTHY: We provide novel insight that the superior maintenance of cerebrovascular endothelial function in female versus male rats with chronic metabolic disease buffers myogenic activation of cerebral resistance arteries/arterioles despite worsening hypertension. As hypertension development is earlier and more severe in females, potentially due to an elevated stress response, the blunted myogenic activation allows greater arterial pressure wave penetrance into the cerebral microcirculation and is associated with accelerated emergence/severity of depressive symptoms in obese female rats. [ABSTRACT FROM AUTHOR] more...
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- 2024
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6. Abstract 15377: Investigating the Role of Breast Cancer Susceptibility Gene 2 in High Glucose-Induced Endothelial Dysfunction
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Nikfarjam, Sepideh, Bu, Shuhan, Nguyen, Hien Chi, Rasheed, Berk, Frisbee, Jefferson C, and Singh, Krishna
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- 2022
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7. Abstract 15328: Investigating the Role of Endothelial Breast Cancer Susceptibility Gene 2 in Doxorubicin-Induced Cardiotoxicity
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Rasheed, Berk, Michels, David, Nikfarjam, Sepideh, Bu, Shuhan, Nguyen, Hien Chi, Frisbee, Jefferson C, Hess, David A, Gros, Robert, and Singh, Krishna K
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- 2022
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8. Abstract 15321: MicroRNA Mir-378-3p is a Novel Regulator of Endothelial Autophagy and Function
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Bu, Shuhan, Nikfarjam, Sepideh, Nguyen, Hien Chi, Rasheed, Berk, Singh, Rohan, Qadura, Mohammad, Frisbee, Jefferson C, and Singh, Krishna
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- 2022
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9. Exercise training prevents the perivascular adipose tissue-induced aortic dysfunction with metabolic syndrome
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DeVallance, Evan, Branyan, Kayla W., Lemaster, Kent C., Anderson, Ray, Marshall, Kent L., Olfert, I. Mark, Smith, David M., Kelley, Eric E., Bryner, Randy W., Frisbee, Jefferson C., and Chantler, Paul D. more...
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- 2019
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10. Complex Interplay between DNA Damage and Autophagy in Disease and Therapy.
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Singh, Aman, Ravendranathan, Naresh, Frisbee, Jefferson C., and Singh, Krishna K.
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BRCA genes ,DRUG resistance in cancer cells ,CYTOTOXINS ,CELL proliferation ,AUTOPHAGY ,DNA repair - Abstract
Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations. [ABSTRACT FROM AUTHOR] more...
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- 2024
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11. Laser Doppler Fluximetry in Cutaneous Vasculature: Methods for Data Analyses.
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Huang, Sophie J.Y., Wang, Xuan, Halvorson, Brayden D., Bao, Yuki, Frisbee, Stephanie J., Frisbee, Jefferson C., and Goldman, Daniel
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PERFUSION imaging ,DATA analytics ,BLOOD flow ,COMPUTER programming ,TRANSLATIONAL research - Abstract
Introduction: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators. Methods: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators. Conclusion: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science. [ABSTRACT FROM AUTHOR] more...
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- 2024
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12. Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology.
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Singh, Aman, Bhatt, Kriti S., Nguyen, Hien C., Frisbee, Jefferson C., and Singh, Krishna K.
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HYPERTROPHIC scars ,CELL adhesion ,CELL adhesion molecules ,VON Willebrand factor ,ENDOTHELIAL cells ,PATHOLOGICAL physiology ,EMBRYOLOGY ,HEART fibrosis - Abstract
Under different pathophysiological conditions, endothelial cells lose endothelial phenotype and gain mesenchymal cell-like phenotype via a process known as endothelial-to-mesenchymal transition (EndMT). At the molecular level, endothelial cells lose the expression of endothelial cell-specific markers such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and gain the expression of mesenchymal cell markers such as α-smooth muscle actin, N-cadherin, vimentin, fibroblast specific protein-1, and collagens. EndMT is induced by numerous different pathways triggered and modulated by multiple different and often redundant mechanisms in a context-dependent manner depending on the pathophysiological status of the cell. EndMT plays an essential role in embryonic development, particularly in atrioventricular valve development; however, EndMT is also implicated in the pathogenesis of several genetically determined and acquired diseases, including malignant, cardiovascular, inflammatory, and fibrotic disorders. Among cardiovascular diseases, aberrant EndMT is reported in atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis, and cardiac fibrosis. Accordingly, understanding the mechanisms behind the cause and/or effect of EndMT to eventually target EndMT appears to be a promising strategy for treating aberrant EndMT-associated diseases. However, this approach is limited by a lack of precise functional and molecular pathways, causes and/or effects, and a lack of robust animal models and human data about EndMT in different diseases. Here, we review different mechanisms in EndMT and the role of EndMT in various cardiovascular diseases. [ABSTRACT FROM AUTHOR] more...
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- 2024
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13. Cerebrovascular dysfunction and depressive symptoms in preclinical models: insights from a scoping review.
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Menon, Nithin J., Sun, Clara, Chhina, Jashnoor, Halvorson, Brayden D., Frisbee, Jefferson C., and Frisbee, Stephanie J.
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MENTAL depression ,ANIMAL models in research ,COGNITION disorders ,SEROTONIN syndrome - Abstract
Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship. NEW & NOTEWORTHY: This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms. [ABSTRACT FROM AUTHOR] more...
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- 2024
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14. A constrained constructive optimization model of branching arteriolar networks in rat skeletal muscle.
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Bao, Yuki, Frisbee, Amelia C., Frisbee, Jefferson C., and Goldman, Daniel
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SKELETAL muscle ,CONSTRAINED optimization ,FRACTAL dimensions ,BLOOD flow ,RATS - Abstract
Blood flow regulation within the microvasculature reflects a complex interaction of regulatory mechanisms and varies spatially and temporally according to conditions such as metabolism, growth, injury, and disease. Understanding the role of microvascular flow distributions across conditions is of interest to investigators spanning multiple disciplines; however, data collection within networks can be labor-intensive and challenging due to limited resolution. To overcome these experimental challenges, computational network models that can accurately simulate vascular behavior are highly beneficial. Constrained constructive optimization (CCO) is a commonly used algorithm for vascular simulation, particularly well known for its adaptability toward vascular modeling across tissues. The present work demonstrates an implementation of CCO aimed to simulate a branching arteriolar microvasculature in healthy skeletal muscle, validated against literature including comprehensive rat gluteus maximus vasculature datasets, and reviews a list of user-specified adjustable model parameters to understand how their variability affects the simulated networks. Network geometric properties, including mean element diameters, lengths, and numbers of bifurcations per order, Horton's law ratios, and fractal dimension, demonstrate good validation once model parameters are adjusted to experimental data. This model successfully demonstrates hemodynamic properties such as Murray's law and the network Fahraeus effect. Application of centrifugal and Strahler ordering schemes results in divergent descriptions of identical simulated networks. This work introduces a novel CCO-based model focused on generating branching skeletal muscle microvascular arteriolar networks based on adjustable model parameters, thus making it a valuable tool for investigations into skeletal muscle microvascular structure and tissue perfusion. NEW & NOTEWORTHY: The present work introduces a CCO-based algorithm for generating branching arteriolar networks, with adjustable model parameters to enable modeling in varying skeletal muscle tissues. The geometric and hemodynamic parameters of the generated networks have been comprehensively validated using experimental data collected previously in-house and from literature. This is one of few validated CCO-based models to specialize in skeletal muscle microvasculature and acts as a beneficial tool for investigating the microvasculature for hypothesis testing and validation. [ABSTRACT FROM AUTHOR] more...
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- 2024
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15. Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival.
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Bu, Shuhan, Singh, Aman, Nguyen, Hien C., Peddi, Bharatsinai, Bhatt, Kriti, Ravendranathan, Naresh, Frisbee, Jefferson C., and Singh, Krishna K.
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PROTEIN disulfide isomerase ,ENDOTHELIAL cells ,ISOMERASES ,AUTOPHAGY ,PROTEIN expression - Abstract
Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of protein disulfide isomerase 4 (PDIA-4); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFβ-signaling, and inhibition of TGFβ-signaling suppressed EndMT in PDIA-4-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions. [ABSTRACT FROM AUTHOR] more...
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- 2024
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16. Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations.
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Nguyen, Hien C., Frisbee, Jefferson C., and Singh, Krishna K.
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BRCA genes , *HOMOLOGOUS recombination , *DOUBLE-strand DNA breaks , *GENE targeting , *DNA repair , *CELL death , *RECOMBINANT DNA , *CARDIOMYOPATHIES - Abstract
Germline mutations in Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) cause breast, ovarian, and other cancers, and the chemotherapeutic drug doxorubicin (Dox) is widely used to treat these cancers. However, Dox use is limited by the latent induction of severe cardiotoxicity known as Dox-induced cardiomyopathy, for which there are no specific treatments currently available. Dox is administered into the systemic circulation, where it readily translocates into sub-cellular compartments and disrupts the integrity of DNA. Accumulating evidence indicates that oxidative stress, DNA damage, inflammation, and apoptosis all play a central role in Dox-induced cardiomyopathy. The BRCA1 and BRCA2 proteins are distinct as they perform crucial yet separate roles in the homologous recombination repair of DNA double-strand breaks, thereby maintaining genomic integrity. Additionally, both BRCA1 and BRCA2 mitigate oxidative stress and apoptosis in both cardiomyocytes and endothelial cells. Accordingly, BRCA1 and BRCA2 are essential regulators of pathways that are central to the development of cardiomyopathy induced by Doxorubicin. Despite extensive investigations, there exists a gap in knowledge about the role of BRCA1 and BRCA2 in Doxorubicin-induced cardiomyopathy. Here, we review the previous findings and associations about the expected role and associated mechanisms of BRCA1 and 2 in Dox-induced cardiomyopathy and future perspectives. [ABSTRACT FROM AUTHOR] more...
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- 2024
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17. The contribution of muscarinic-receptor-mediated responses to epineurial vascular diameter at the sciatic nerve
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Killey, Chelsa, Cleary, Shane, Orr, Julie, Frisbee, Jefferson C., Jackson, Dwayne, and Twynstra, Jasna
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Physiological aspects ,Muscarinic receptors -- Physiological aspects ,Blood vessels -- Physiological aspects ,Sciatic nerve -- Physiological aspects - Abstract
Introduction To maintain proper function, the peripheral nerves require sufficient blood flow. Decreases in peripheral nerve blood flow have been associated with decreased nerve conduction velocity, nerve atrophy, and cell [...], This study used an anaesthetized rat model to directly observe changes in diameter of the vessels supplying the sciatic nerve in response to acetylcholine ([10.sup.-4] M), a muscarinic receptor agonist, and atropine ([10.sup.- 5] M), a muscarinic receptor antagonist. Topical application of acetylcholine resulted in increases in vessel diameter (baseline: 22.0 [+ or -] 2.5 [micro]m, acetylcholine: 28.8 [+ or -] 3.3 [micro]m), while topical application of atropine resulted in a decrease in diameter (baseline: 26.6 [+ or -] 3.2 [micro]m, atropine: 15.5 [+ or -] 3.6 [micro]m) of the epineurial vessels. Mean arterial pressure was not affected by either acetylcholine (baseline: 103.8 [+ or -] 1.8 mm Hg, acetylcholine: 102.8 [+ or -] 3.2 mm Hg) or atropine (baseline: 104.0 [+ or - ] 1.9 mm Hg, atropine: 105.2 [+ or -] 2.2 mm Hg). These data suggest that muscarinic-receptor-mediated responses can affect the diameter of the epineurial vessels at the sciatic nerve. In addition, muscarinic-receptor-mediated responses appear to contribute to baseline diameter of epineurial vessels at the sciatic nerve. Key words: sciatic nerve, epineurial vasculature, intravital microscopy, muscarinic receptor, acetylcholine, atropine. Dans cette etude, nous avons utilise un modele de rat anesthesie en vue d'observer directement les variations du diametre des vaisseaux alimentant le nerf sciatique en reaction a l'acetylcholine ([10.sup.-4] M), un agoniste des recepteurs muscariniques, et a l'atropine ([10.sup.-5] M), un antagoniste des recepteurs muscariniques. L'application topique d'acetylcholine a entraine une augmentation du diametre des vaisseaux de l'epinerve (depart: 22,0 [+ or -] 2,5 [micro]m, acetylcholine : 28,8 [+ or -] 3,3 [micro]m), tandis que l'application topique d'atropine a entraine leur diminution (depart: 26,6 [+ or -] 3,2 [micro]m, atropine : 15,5 [+ or -] 3,6 [micro]m). La tension arterielle moyenne n'etait pas affectee par l'acetylcholine (depart : 103,8 [+ or -] 1,8 mm Hg, acetylcholine : 102,8 [+ or -] 3,2 mm Hg) ni par l'atropine (depart : 104,0 [+ or -] 1,9 mm Hg, atropine : 105,2 [+ or -] 2,2 mm Hg). Ces donnees laissent entrevoir que des reactions mediees par les recepteurs muscariniques peuvent affecter le diametre des vaisseaux de l'epinerve du nerf sciatique. De plus, des reactions mediees par les recepteurs muscariniques semblent participer a l'etablissement du diametre de depart des vaisseaux de l'epinerve du nerf sciatique. [Traduit par la Redaction] Mots-cles: nerf sciatique, vaisseaux de l'epinerve, microscopie intravitale, recepteur muscarinique, acetylcholine, atropine. more...
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- 2018
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18. Scoping Review: Integration of the Major Mechanisms Underlying the Regulation of Arteriolar Tone.
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Halvorson, Brayden D., Ahmed, Moeiz, Huang, Sophie J., and Frisbee, Jefferson C.
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BLOOD flow ,DATABASE searching ,MOLECULAR interactions ,CELLULAR signal transduction ,CARDIOVASCULAR diseases - Abstract
Background: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Arteriolar tone regulation plays a critical role in maintaining appropriate organ blood flow and perfusion distribution, which is vital for both vascular and overall health. Summary: This scoping review aimed to explore the interplay between five major regulators of arteriolar tone: metabolism (adenosine), adrenergic control (norepinephrine), myogenic activation (intravascular pressure), perivascular oxygen tension, and intraluminal flow rates. Specifically, the aim was to address how arteriolar reactivity changes in the presence of other vasoactive stimuli and by what mechanisms. The review focused on animal studies that investigated the impact of combining two or more of these stimuli on arteriolar diameter. Overall, 848 articles were identified through MEDLINE and EMBASE database searches, and 38 studies were included in the final review. Key Messages: The results indicate that arteriolar reactivity is influenced by multiple factors, including competitive processes, structural limitations, and indirect interactions among stimuli. Additionally, the review identified a lack of research involving female animal models and limited insight into the interaction of molecular signaling pathways, which represent gaps in the literature. [ABSTRACT FROM AUTHOR] more...
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- 2024
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19. Thromboxane-induced cerebral microvascular rarefaction predicts depressive symptom emergence in metabolic disease.
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Halvorson, Brayden D., Yuki Bao, Singh, Krishna K., Frisbee, Stephanie J., Hachinski, Vladimir, Whitehead, Shawn N., Melling, C. W. James, Chantler, Paul D., Goldman, Daniel, and Frisbee, Jefferson C. more...
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MENTAL depression ,LABORATORY rats ,PERIPHERAL circulation ,METABOLIC disorders ,SKELETAL muscle ,PENTOXIFYLLINE - Abstract
Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A
2 (TxA2 ). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA2 production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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20. Arterial Function in Cardio-Metabolic Diseases: From the Microcirculation to the Large Conduits
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Chantler, Paul D. and Frisbee, Jefferson C.
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- 2015
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21. Regulation of Skeletal Muscle Resistance Arteriolar Tone: Integration of Multiple Mechanisms.
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Halvorson, Brayden D., Bao, Yuki, Ward, Aaron D., Goldman, Daniel, and Frisbee, Jefferson C.
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SKELETAL muscle ,MACHINE learning ,SHEAR walls ,MATHEMATICAL analysis ,STATISTICS - Abstract
Introduction: Physiological system complexity represents an imposing challenge to gaining insight into how arteriolar behavior emerges. Further, mechanistic complexity in arteriolar tone regulation requires that a systematic determination of how these processes interact to alter vascular diameter be undertaken. Methods: The present study evaluated the reactivity of ex vivo proximal and in situ distal resistance arterioles in skeletal muscle with challenges across the full range of multiple physiologically relevant stimuli and determined the stability of responses over progressive alterations to each other parameter. The five parameters chosen for examination were (1) metabolism (adenosine concentration), (2) adrenergic activation (norepinephrine concentration), (3) myogenic activation (intravascular pressure), (4) oxygen (superfusate PO
2 ), and (5) wall shear rate (altered intraluminal flow). Vasomotor tone of both arteriole groups following challenge with individual parameters was determined; subsequently, responses were determined following all two- and three-parameter combinations to gain deeper insight into how stimuli integrate to change arteriolar tone. A hierarchical ranking of stimulus significance for establishing arteriolar tone was performed using mathematical and statistical analyses in conjunction with machine learning methods. Results: Results were consistent across methods and indicated that metabolic and adrenergic influences were most robust and stable across all conditions. While the other parameters individually impact arteriolar tone, their impact can be readily overridden by the two dominant contributors. Conclusion: These data suggest that mechanisms regulating arteriolar tone are strongly affected by acute changes to the local environment and that ongoing investigation into how microvessels integrate stimuli regulating tone will provide a more thorough understanding of arteriolar behavior emergence across physiological and pathological states. [ABSTRACT FROM AUTHOR] more...- Published
- 2023
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22. Impaired Tissue Oxygenation in Metabolic Syndrome Requires Increased Microvascular Perfusion Heterogeneity
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Mason McClatchey, P., Wu, Fan, Olfert, I. Mark, Ellis, Christopher G., Goldman, Daniel, Reusch, Jane E. B., and Frisbee, Jefferson C.
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- 2017
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23. Circulating leucocytes perpetuate stroke‐induced aortic dysfunction
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Asano, Shinichi, OʼConnell, Grant C., Lemaster, Kent C., DeVallance, Evan R., Branyan, Kayla W., Simpkins, James W., Frisbee, Jefferson C., Barr, Taura L., and Chantler, Paul D.
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- 2017
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24. Exercise Attenuates Chronic Unpredictable Mild Stress Induced Brain Microvascular Rarefaction In Obese Zucker Rat: Role Of Stat3 Signaling: 2501 Board #21 June 2 9: 30 AM - 11: 00 AM
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Asano, Shinichi, Dowson, Mariah L., Sheets, Whitney J., Seldomridge, Ashlee N., Branyan, Kayla W., DeVallance, Evan R., Frisbee, Jefferson C., and Chantler, Paul D.
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- 2017
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25. Oxidant stress and skeletal muscle microvasculopathy in the metabolic syndrome
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Goodwill, Adam G. and Frisbee, Jefferson C.
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- 2012
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26. Effects of Chronic Stress on Pancreatic Beta Cell Density in Obese and Lean Zucker Rats: 3190 Board #255 June 3, 2: 00 PM - 3: 30 PM
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Goudy, Gabriel, Mark Olfert, I., Frisbee, Jefferson C., Hoskinson, Hannah, Chantler, Paul, Branyan, Kayla, Skinner, Roy, Alway, Stephen E., and Bryner, Randy W.
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- 2016
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27. Microvascular perfusion heterogeneity contributes to peripheral vascular disease in metabolic syndrome
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Frisbee, Jefferson C., Goodwill, Adam G., Frisbee, Stephanie J., Butcher, Joshua T., Wu, Fan, and Chantler, Paul D.
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- 2016
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28. Rescue of a Trafficking Defective Human Pacemaker Channel via a Novel Mechanism: ROLES OF Src, Fyn, AND Yes TYROSINE KINASES
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Lin, Yen-Chang, Huang, Jianying, Kan, Hong, Frisbee, Jefferson C., and Yu, Han-Gang
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- 2009
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29. Application of a novel index for understanding vascular health following pharmacological intervention in a pre-clinical model of metabolic disease.
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Menon, Nithin J., Halvorson, Brayden D., Alimorad, Gabrielle H., Frisbee, Jefferson C., Lizotte, Daniel J., Ward, Aaron D., Goldman, Daniel, Chantler, Paul D., and Frisbee, Stephanie J.
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- 2023
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30. Obesity and vascular dysfunction
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Stapleton, Phoebe A., James, Milinda E., Goodwill, Adam G., and Frisbee, Jefferson C.
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- 2008
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31. Mitochondrial dysfunction in the type 2 diabetic heart is associated with alterations in spatially distinct mitochondrial proteomes
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Dabkowski, Erinne R., Baseler, Walter A., Williamson, Courtney L., Powell, Matthew, Razunguzwa, Trust T., Frisbee, Jefferson C., and Hollander, John M.
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Diabetics -- Health aspects ,Mitochondrial diseases -- Risk factors ,Mitochondrial diseases -- Care and treatment ,Mitochondrial diseases -- Research ,Proteomics -- Research ,Biological sciences - Abstract
Cardiac complications and heart failure are the leading cause of death in type 2 diabetic patients. Mitochondrial dysfunction is central in the pathogenesis of the type 2 diabetic heart. However, it is unclear whether this dysfunction is specific for a particular subcellular region. The purpose of this study was to determine whether mitochondrial dysfunction in the type 2 diabetic heart is specific to a spatially distinct subset of mitochondria. We investigated mitochondrial morphology, function, and proteomic composition of subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) in 18-wk-old db/db mice. Oxidative damage was assessed in subpopulations through the measurement of lipid peroxidation byproducts and nitrotyrosine residues. Proteomic profiles and posttranslational modifications were assessed in mitochondrial subpopulations using iTRAQ and multi-dimensional protein identification technologies, respectively. SSM from db/db hearts had altered morphology, including a decrease in size and internal complexity, whereas db/db IFM were increased in internal complexity. Db/db SSM displayed decreased state 3 respiration rates, electron transport chain activities, ATP synthase activities, and mitochondrial membrane potential and increased oxidative damage, with no change in IFM. Proteomic assessment revealed a greater impact on db/db SSM compared with db/db IFM. Inner mitochondrial membrane proteins, including electron transport chain, ATP synthesis, and mitochondrial protein import machinery, were predominantly decreased. We provide evidence that mitochondrial dysfunction in the type 2 diabetic heart is associated with a specific subcellular locale. Furthermore, mitochondrial morphological and functional indexes are impacted differently during type 2 diabetic insult and may result from the modulation of spatially distinct mitochondrial proteomes. mitochondria; diabetes; proteomics doi: 10.1152/ajpheart.00267.2010. more...
- Published
- 2010
32. Inactivation of L-type calcium channel modulated by HCN2 channel
- Author
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Lin, Yen-Chang, Huang, Jianying, Zhang, Qi, Hollander, John M., Frisbee, Jefferson C., Martin, Karen H., Nestor, Casey, Goodman, Robert, and Yu, Han-Gang
- Subjects
Calmodulin -- Properties ,Calcium channels -- Research ,Neurons -- Properties ,Biological sciences - Abstract
[Ca.sup.+] entry is delicately controlled by inactivation of L-type calcium channel (LTCC) composed of the pore-forming subunit [alpha]1C and the auxiliary subunits [beta]1 and [alpha]2[delta]. Calmodulin is the key protein that interacts with the COOH-terminal motifs of [alpha]1C, leading to the fine control of LTCC inactivation. In this study we show evidence that a hyperpolarization-activated cyclic nucleotide-gated channel, HCN2, can act as a non-channel regulatory protein to narrow the L-type [Ca.sup.2+] channel current-voltage curve. In the absence of LTCC auxiliary subunits, HCN2 can induce [alpha]1C inactivation. Without [alpha]2[delta], HCN2-induced fast inactivation of [alpha]1C requires calmodulin. With [alpha]2[delta], the [alpha]1C/HCN2/[alpha]2[delta] channel inactivation does not require calmodulin. In contrast, [beta]1-subunit plays a relatively minor role in the interaction of [alpha]1C with HCN2. The N[H.sub.2] terminus of HCN2 and the IQ motif of [alpha]1C subunit are required for [alpha]1C/HCN2 channel interaction. [Ca.sup.+] channel inactivation is significantly slowed in hippocampus neurons (HNs) over-expressing HCN2 mutant lacking NH2 terminus and accelerated in HNs overexpressing the wild-type HCN2 compared with HN controls. Collectively, these results revealed a potentially novel protection mechanism for achieving the LTCC inactivation via interaction with HCN2. L-type calcium channel inactivation; hyperpolarization-activated cyclic nucleotide-gated channels; calmodulin; hippocampal neuron doi: 10.1152/ajpcell.00355.2009. more...
- Published
- 2010
33. Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity
- Author
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Kelley, Eric E., Baust, Jeff, Bonacci, Gustavo, Golin-Bisello, Franca, Devlin, Jason E., St. Croix, Claudette M., Watkins, Simon C., Gor, Sonia, Cantu-Medellin, Nadiezhda, Weidert, Eric R., Frisbee, Jefferson C., Gladwin, Mark T., Champion, Hunter C., Freeman, Bruce A., and Khoo, Nicholas K.H. more...
- Published
- 2014
- Full Text
- View/download PDF
34. Integration of skeletal muscle resistance arteriolar reactivity for perfusion responses in the metabolic syndrome
- Author
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Frisbee, Jefferson C., Hollander, John M., Brock, Robert W., Yu, Han-Gang, and Boegehold, Matthew A.
- Subjects
Metabolic syndrome X -- Drug therapy ,Metabolic syndrome X -- Patient outcomes ,Metabolic syndrome X -- Research ,Perfusion (Physiology) -- Research ,Muscles -- Physiological aspects ,Muscles -- Research ,Biological sciences - Abstract
Previous study suggests that with evolution of the metabolic syndrome, patterns of arteriolar reactivity are profoundly altered and may constrain functional hyperemia. This study investigated interactions between parameters of vascular reactivity at two levels of resistance arterioles in obese Zucker rats (OZR), translating these observations into perfusion regulation for in situ skeletal muscle. Dilation of isolated and in situ resistance arterioles from OZR to acetylcholine, arachidonic acid (AA), and hypoxia (isolated arterioles only) were blunted vs. lean Zucker rats (LZR), although dilation to adenosine was intact. Increased adrenergic tone (phenylephrine) or intralumenal pressure (ILP) impaired dilation in both strains (OZR>LZR). Treatment of OZR arterioles with Tempol (superoxide dismutase mimetic) or SQ-29548 (prostaglandin [H.sub.2]/thromboxane [A.sub.2] receptor antagonist) improved dilator reactivity under control conditions and with increased ILP, but had minimal effect with increased adrenergic tone. Arteriolar dilation to adenosine was well maintained in both strains under all conditions. For in situ cremasteric arterioles, muscle contraction-induced elevations in metabolic demand elicited arteriolar dilations and hyperemic responses that were blunted in OZR vs. LZR, although distal parallel arterioles were characterized by heterogeneous dilator and perfusion responses, [alpha]-Adrenoreceptor blockade improved outcomes at rest but had minimal effect with elevated metabolic demand. Treatment with Tempol or SQ-29548 had minimal impact at rest, but lessened distal arteriolar perfusion heterogeneity with increased metabolic demand. In blood-perfused gastrocnemius of OZR, perfusion was constrained primarily by adrenergic tone, while myogenic activation and endothelium-dependent dilation did not appear to contribute significantly to ischemia. These results of this novel, integrated approach suggest that adrenergic tone and metabolic dilation are robust determinants of bulk perfusion to skeletal muscle of OZR, while endothelial dysfunction may more strongly regulate perfusion distribution homogeneity via the impact of oxidant stress and AA metabolism. peripheral vascular disease; microcirculation; regional blood flow; obesity more...
- Published
- 2009
35. Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension
- Author
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Goodwill, Adam G., James, Milinda E., and Frisbee, Jefferson C.
- Subjects
Muscles -- Properties ,Microcirculation -- Evaluation ,Endothelium -- Properties ,Obesity -- Complications and side effects ,Blood vessels -- Dilatation ,Blood vessels -- Evaluation ,Biological sciences - Abstract
This study determined if altered vascular prostacyclin ([PGI.sub.2]) and/or thromboxane [A.sub.2] (Tx[A.sub.2]) production with reduced [Po.sub.2] contributes to impaired hypoxic dilation of skeletal muscle resistance arterioles of obese Zucker rats (OZRs) versus lean Zucker rats (LZRs). Mechanical responses were assessed in isolated gracilis muscle arterioles following reductions in [Po.sub.2] under control conditions and following pharmacological interventions inhibiting arachidonic acid metabolism and nitric oxide synthase and alleviating elevated vascular oxidant stress. The production of arachidonic acid metabolites was assessed using pooled arteries from OZRs and LZRs in response to reduced [Po.sub.2]. Hypoxic dilation, endothelium-dependent in both strains, was attenuated in OZRs versus LZRs. Nitric oxide synthase inhibition had no significant impact on hypoxic dilation in either strain. Cyclooxygenase inhibition dramatically reduced hypoxic dilation in LZRs and abolished responses in OZRs. Treatment of arterioles from OZRs with polyethylene glycol-superoxide dismutase improved hypoxic dilation, and this improvement was entirely cyclooxygenase dependent. Vascular [PGI.sub.2] production with reduced [Po.sub.2] was similar between strains, although Tx[A.sub.2] production was increased in OZRs, a difference that was attenuated by treatment of vessels from OZRs with polyethylene glycol-superoxide dismutase. Both blockade of [PGH.sub.2]/Tx[A.sub.2] receptors and inhibition of thromboxane synthase increased hypoxic dilation in OZR arterioles. These results suggest that a contributing mechanism underlying impaired hypoxic dilation of skeletal muscle arterioles of OZRs may be an increased vascular production of Tx[A.sub.2], which competes against the vasodilator influences of [PGI.sub.2]. These results also suggest that the elevated vascular oxidant stress inherent in metabolic syndrome may contribute to the increased vascular Tx[A.sub.2] production and may blunt vascular sensitivity to [PGI.sub.2]. skeletal muscle microcirculation; endothelium-dependent dilation; vascular reactivity; rodent models of obesity more...
- Published
- 2008
36. Increased myogenic responsiveness of skeletal muscle arterioles with juvenile growth
- Author
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Samora, Julie Balch, Frisbee, Jefferson C., and Boegehold, Matthew A.
- Subjects
Arteries -- Properties ,Muscles -- Properties ,Microcirculation -- Evaluation ,Endothelium -- Properties ,Myogenesis -- Evaluation ,Physiological research ,Biological sciences - Abstract
Previous studies from this laboratory suggest that during juvenile growth, structural changes in the arteriolar network are accompanied by changes in some of the mechanisms responsible for regulation of tissue blood flow. To test the hypothesis that arteriolar myogenic behavior is altered with growth, we studied gracilis muscle arterioles isolated from Sprague-Dawley rats at two ages: 21-28 and 42-49 days. When studied at their respective in vivo pressures, the myogenic index (instantaneous slope of the active pressure-diameter curve) of arterioles from 42-49-day-old rats was more negative than that of arterioles from 21-28-day-old rats, indicating greater myogenic responsiveness. Endothelial denudation, or prostaglandin [H.sub.2] (PG[H.sub.2])/thromboxane [A.sub.2] (Tx[A.sub.2]) receptor antagonism without denudation, significantly reduced the myogenic responsiveness of arterioles from the older rats over a wide range of pressures but had no consistent effects on the myogenic responsiveness of arterioles from the younger rats. The heme oxygenase inhibitor chromium (III) mesoporphyrin IX chloride had no effect on the myogenic activity of arterioles from either age group. These findings indicate that microvascular growth in young animals is accompanied by an increase in the myogenic behavior of arterioles, possibly because PG[H.sub.2] or Tx[A.sub.2] assumes a role in reinforcing myogenic activity over this period. As a result, the relative contribution of myogenic activity to blood flow regulation in skeletal muscle may increase during rapid juvenile growth. skeletal muscle microcirculation; endothelium; postnatal growth; myogenic response more...
- Published
- 2008
37. Altered mechanisms of endothelium-dependent dilation in skeletal muscle arterioles with genetic hypercholesterolemia
- Author
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Stapleton, Phoebe A., Goodwill, Adam G., James, Milinda E., and Frisbee, Jefferson C.
- Subjects
Vascular resistance -- Research ,Vascular endothelium -- Research ,Microcirculation -- Research ,Muscles -- Research ,Hypercholesterolemia -- Research ,Blood vessels -- Dilatation ,Blood vessels -- Research ,Cardiovascular research ,Biological sciences - Abstract
With most cardiovascular disease risk factors, endothelium-dependent dilation of skeletal muscle resistance arterioles is compromised, although with hypercholesterolemia, impairments to reactivity are not consistently observed. Using apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion male mouse models of hypercholesterolemia at 20 wk of age, we tested the hypothesis that arteriolar dilation would be maintained due to an increased stimulus-induced production of dilator metabolites via cyclooxygenase and cytochrome P-450 epoxygenase pathways. Arterioles from both strains demonstrated mild reductions in dilation to hypoxia and acetylcholine versus responses in C57/B1/6J (C57) controls. However, although inhibition of nitric oxide synthase (NOS) attenuated dilation in arterioles from C57 controls, this effect was absent in ApoE or LDLR strains. In contrast, cyclooxygenase-dependent portions of dilator reactivity were maintained across the three strains. Notably, although combined NOS and cyclooxygenase inhibition abolished arteriolar responses to hypoxia and acetylcholine in C57 controls, significant reactivity remained in ApoE and LDLR strains. Whereas inhibition of cytochrome P-450 [omega]-hydroxylase and epoxygenases had no effect on this residual reactivity in ApoE and LDLR strains, inhibition of 12/15-lipoxygenase with nordihydroguaiaretic acid abolished the residual reactivity. With both hypoxic and methacholine challenges, arteries from ApoE and LDLR strains demonstrated an increased production of both 12(S)- and 15(S)-hydroxyeicosatetraenoic acid, end products of arachidonic acid metabolism via 12/15-lipoxygenase, a response that was not present in C57 controls. These results suggest that with development of hypercholesterolemia, mechanisms contributing to dilator reactivity in skeletal muscle arterioles are modified such that net reactivity to endothelium-dependent stimuli is largely intact. skeletal muscle microcirculation; mouse models of cardiovascular disease more...
- Published
- 2007
38. Growth-dependent changes in endothelial factors regulating arteriolar tone
- Author
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Samora, Julie Balch, Frisbee, Jefferson C., and Boegehold, Matthew A.
- Subjects
Endothelial growth factors -- Research ,Muscles -- Research ,Endothelium -- Research ,Nitric oxide -- Research ,Biological sciences - Abstract
Previous studies from this laboratory suggest that during maturation, rapid microvascular growth is accompanied by changes in the mechanisms responsible for regulation of tissue blood flow. To further define these changes, we studied isolated gracilis muscle arterioles from weanling (~25 days) and juvenile (~44 days) Sprague-Dawley rats to test the hypothesis that endothelial mechanisms for the control of arteriolar tone are altered with growth. Responses to the endothelium-dependent dilator acetylcholine (ACh) were greater in weanling arterioles (WA) than in juvenile arterioles (JA), whereas there were no consistent differences between age groups in arteriolar responses to other endothelium-dependent agonists (A-23187, vascular endothelial growth factor, and simvastatin). Inhibition of nitric oxide synthase (NOS) with [N.sup.[omega]]-nitroL-arginine methyl ester (L-NAME) attenuated ACh-induced dilation in JA but not in WA. In JA, combined inhibition of NOS and cyclooxygenase (with indomethacin) reduced the dilator responses to ACh and simvastatin by ~90% and ~70%, respectively, but had no effect in WA. Cytochrome P450 epoxygenase inhibition [with 2-(propargyloxyphenyl) hexanoic acid] had no effect on responses to ACh or simvastatin in either age group. Inhibition of [Ca.sup.+]-activated or ATP-dependent potassium channels (with tetraethylammonium or glibenclamide, respectively) reduced these arteriolar responses in JA but not those in WA. These findings suggest that in fully grown microvascular networks, endothelium-dependent arteriolar dilation is mediated by the combined release of endothelial nitric oxide and vasodilator prostanoids, and in part through activation of [Ca.sup.2+]-activated and ATP-dependent potassium channels. However, during earlier microvascular growth, this dilation is mediated by other factors yet to be identified. This may have significant implications for the regulation of tissue perfusion during microvascular development. skeletal muscle microcirculation; endothelium; postnatal growth; nitric oxide; endothelium-derived hyperpolarizing factor more...
- Published
- 2007
39. Exercise training blunts microvascular rarefaction in the metabolic syndrome
- Author
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Frisbee, Jefferson C., Samora, Julie Balch, Peterson, Jonathan, and Byner, Randall
- Subjects
Metabolic syndrome X -- Research ,Exercise -- Health aspects ,Vascular endothelium -- Research ,Biological sciences - Abstract
Reduced skeletal muscle microvessel density (MVD) in the obese Zucker rat (OZR) model of the metabolic syndrome is a function of a chronic reduction in vascular nitric oxide (NO) bioavailability. Previous studies suggest that exercise can improve NO bioavailability and reduce chronic inflammation and that low vascular NO bioavailability may be associated with impaired angiogenic responses via increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. As such, we hypothesized that chronic exercise (EX) would increase NO bio-availability in OZR and blunt microvascular rarefaction through reduced MMP activity, and potentially via altered plasma cytokine levels. Ten weeks of treadmill exercise (1 h/day, 5 days/wk, 22 m/min) reduced body mass and fasting insulin and triglyceride levels in EX-OZR vs. sedentary (SED) OZR. In EX-OZR, gastrocnemius muscle MVD was improved by 19 [plus or minus] 4%, whereas skeletal muscle arteriolar dilation and conduit arterial methacholine-induced NO release were increased. In EX-OZR, functional hyperemia was improved vs. SED-OZR, and minimum vascular resistance within perfused gastrocnemius muscle was reduced, although no change in arteriolar stiffness was identified. Western blotting and gelatin zymography demonstrated that neither expression nor activity of MMP-2 or MMP-9 was altered in skeletal muscle of EX vs. SED animals. Plasma markers of inflammation associated with angiogenesis, monocyte chemoattractant protein- 1 and IL- 1 [beta], were increased in SED-OZR and were reduced with training, whereas IL-13 was reduced in SED-OZR and increased with exercise. These data suggest that exercise-induced improvements in skeletal muscle MVD in OZR are associated with increased NO bioavailability and may stem from altered inflammatory profiles rather than MMP function. skeletal muscle microcirculation; regulation of skeletal muscle perfusion; microvessel density; vascular remodeling; vascular resistance more...
- Published
- 2006
40. Vascular adrenergic tone and structural narrowing constrain reactive hyperemia in skeletal muscle of obese Zucker rats
- Author
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Frisbee, Jefferson C.
- Subjects
Blood flow -- Research ,Microcirculation -- Research ,Rats -- Physiological aspects ,Rats -- Research ,Rattus -- Physiological aspects ,Rattus -- Research ,Biological sciences - Abstract
Previous studies have demonstrated that skeletal muscle perfusion is impaired in obese Zucker rats (OZR) under control conditions and with elevated metabolic demand versus responses in lean Zucker rats (LZR). To further our understanding of processes contributing to impaired perfusion, we determined whether hyperemic responses following periods of occlusion were altered in skeletal muscle of OZR versus LZR. In isolated hindlimbs, basal blood flow in OZR was less than in LZR, and total perfusion responses after 30, 90, and 180 s of occlusion were reduced. Treatment of animals with an antioxidant (polythethylene glycol-superoxide dismutase) had no effect on reactive hyperemia, although blockade of [alpha]-adrenoreceptors ([[alpha].sub.1] > [[alpha].sub.2]) improved responses to 30 and 90 s of occlusion; responses to 180 s of occlusion were unaltered. Pump perfusion of a dilated distal hindlimb demonstrated that increased volume flow elicited a greater increase in perfusion pressure in OZR versus LZR, suggesting structural contributions to an increased vascular resistance. Responses were comparable for in situ cremaster muscle because reactive hyperemia following serial arteriolar occlusion was attenuated in OZR versus LZR, treatment with polythethylene glycol-superoxide dismutase was ineffective, and hyperemic responses were improved following inhibition of [alpha]-adrenoreceptors ([[alpha].sub.1] > [[alpha].sub.2]). Treatment of cremaster muscle with adenosine ([10.sup.-3] M) caused flow to increase to a level comparable to that following 180 s of occlusion in both strains, although this level was reduced in OZR versus LZR. These results suggest that increased adrenergic tone may constrain reactive hyperemia in OZR with brief occlusion, although structural increases in vascular resistance can contribute to constrained perfusion after longer periods of occlusion. microcirculation; blood flow regulation; rodent models of metabolic syndrome more...
- Published
- 2006
41. Enhanced skeletal muscle arteriolar reactivity to ANG II after recovery from ischemic acute renal failure
- Author
-
Basile, David P., Donohoe, Deborah L., Phillips, Shane A., and Frisbee, Jefferson C.
- Subjects
Muscles -- Research ,Acute renal failure -- Risk factors ,Acute renal failure -- Health aspects ,Angiotensin -- Health aspects ,Biological sciences - Abstract
In addition to the long-term renal complications, previous studies suggested that after acute renal failure (ARF), rats manifest an increased pressor response to an overnight infusion of ANG II. The present study tested whether recovery from ARF results in alterations in sensitivity to the peripheral vasculature. ARF was induced in Sprague-Dawley rats by 45 min of bilateral renal ischemia and reperfusion. Animals were allowed to recover renal structure and function for 5-8 wk, after which the acute pressor responses to ANG II were evaluated either in vivo in in situ skeletal muscle arterioles or in isolated gracilis muscle arteries in vitro. Baseline arterial pressure was not different in ARF rats vs. sham-operated controls, although ARF rats exhibited an enhanced pressor response to bolus ANG II infusion compared with control rats. Steady-state plasma ANG II concentration and plasma renin activity were similar between ARF and control rats. Constrictor reactivity of in situ cremasteric arterioles from ARF rats was enhanced in response to increasing concentrations of ANG II; however, no difference was observed in arteriolar responses to elevated P[O.sub.2], norepinephrine, acetylcholine, or sodium nitroprusside. Isolated gracilis muscle arteries from ARF rats also showed increased vasoconstriction in response to ANG II but not norepinephrine. In conclusion, recovery from ischemic ARF is not associated with hypertension but is associated with increased arteriolar constrictor reactivity to ANG II. Although the mechanisms of this altered responsiveness are unclear, such changes may relate, in part, to cardiovascular complications in patients with ARF and/or after renal transplant. ischemia; blood pressure more...
- Published
- 2005
42. Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome
- Author
-
Frisbee, Jefferson C.
- Subjects
Rats -- Physiological aspects ,Rats -- Case studies ,Rattus -- Physiological aspects ,Rattus -- Case studies ,Microcirculation -- Case studies ,Blood flow -- Case studies ,Muscles -- Case studies ,Biological sciences - Abstract
This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine l-oxyl (tempol) in the drinking water for ~4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with [N.sup.[omega]]-nitro-L-arginine methyl ester (L-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperernia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand. microcirculation; regulation of skeletal muscle blood flow; functional hyperemia; active hyperemia more...
- Published
- 2005
43. Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker rats
- Author
-
Phillips, Shane A., Sylvester, Francis A., and Frisbee, Jefferson C.
- Subjects
Rats -- Research ,Rattus -- Research ,Metabolic syndrome X -- Research ,Microcirculation ,Cerebral circulation ,Blood circulation ,Biological sciences - Abstract
This study tested the hypothesis that evolution of the metabolic syndrome in obese Zucker rats (OZR) leads to impaired dilator reactivity of cerebral resistance arteries vs. responses determined in lean Zucker rats (LZR). Middle cerebral arteries (MCA) from 17-wk-old male LZR and OZR were isolated and cannulated with glass micropipettes. Vascular reactivity was assessed in response to challenge with ACh, sodium nitroprusside (SNP), reductions and elevations in P[O.sub.2], 5-HT, and increased intralumenal pressure. Vessels were treated with the free radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) to assess the role of superoxide production in altering reactivity, and passive vascular wall mechanics was assessed in each vessel. Vascular superoxide production was assessed in isolated arteries using fluorescence microscopy. Vessel dilation to ACh and hypoxia was impaired in OZR vs. LZR, although responses to SNP were normal. Vessel constriction to 5-HT, elevated P[O.sub.2], and elevated intralumenal pressure was enhanced in OZR vs. LZR. Fluorescence microscopy demonstrated an increased superoxide production in arteries of OZR vs. LZR, correctable by incubation with tempol. Although treatment of vessels from OZR with tempol improved dilation to ACh and hypoxia, constrictor responses to 5-HT, elevated P[O.sub.2], and pressure were not altered by tempol treatment. Indexes of vessel wall mechanics were comparable between groups. These results suggest that vasodilator reactivity of MCA of OZR in response to endothelium-dependent dilator stimuli is impaired vs. LZR and that this may represent a reduced bioavailability of signaling molecules due to oxidant scavenging. However, oxidative stress-independent increases in myogenic tone and constrictor reactivity may contribute to blunted dilator responses of cerebral microvessels. rat models of metabolic syndrome; microcirculation; cerebral circulation; vascular reactivity more...
- Published
- 2005
44. Exercise reveals impairments in left ventricular systolic function in patients with metabolic syndrome
- Author
-
Fournier, Sara B., Reger, Brian L., Donley, David A., Bonner, Daniel E., Warden, Bradford E., Gharib, Wissam, Failinger, Conard F., Olfert, Melissa D., Frisbee, Jefferson C., Olfert, Mark I., and Chantler, Paul D. more...
- Published
- 2014
- Full Text
- View/download PDF
45. Chronic A[T.sub.1] receptor blockade alters mechanisms mediating responses to hypoxia in rat skeletal muscle resistance arteries
- Author
-
Phillips, Shane A., Drenjancevic-Peric, Ines, Frisbee, Jefferson C., and Lombard, Julian H.
- Subjects
Smooth muscle -- Research ,Angiotensin -- Research ,Biological sciences - Abstract
The goal of this study was to determine the effect of angiotensin type 1 (A[T.sub.1]) receptor antagonism on vasodilator responses in isolated skeletal muscle resistance arteries. Normotensive Sprague-Dawley rats were fed normal rat chow with the A[T.sub.1] receptor antagonist losartan (1mg/ml) in the drinking water for 7 days and compared with untreated control rats. Changes in the diameter of isolated resistance arteries supplying the gracilis muscle were assessed with a video micrometer. Arteriolar responses to acetylcholine, iloprost, and sodium nitroprusside were unaffected by losartan administration, whereas dilation to reduced P[O.sub.2] was converted into a constriction. Hypoxia-induced constriction of vessels from losartan-treated rats was inhibited by endothelium removal or indomethacin (1 [micro]M). Blockade of the PG[H.sub.2]-thromboxane A2 receptor with SQ-29548 (10 [micro]M), thromboxane synthase inhibition with dazoxiben (10 [micro]M), or the addition of the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL, 100 [micro]M) converted hypoxic vasoconstriction to a dilation that was blocked by inhibiting nitric oxide synthase with [N.sup.[omega]]-nitro-L-arginine methyl ester (100 [micro]M). These data suggest that A[T.sub.1] receptor activation has an important role in maintaining the vascular release of prostaglandins responsible for mediating hypoxic dilation in skeletal muscle microvessels. angiotensin II; angiotensin II receptors; vascular smooth muscle; endothelium; microcirculation more...
- Published
- 2004
46. Low-flow vascular remodeling in the metabolic syndrome X
- Author
-
Stepp, David W., Pollock, David M., and Frisbee, Jefferson C.
- Subjects
Physiology -- Research ,Rattus -- Research ,Rattus -- Physiological aspects ,Rats -- Research ,Rats -- Physiological aspects ,Peripheral vascular diseases -- Research ,Peripheral vascular diseases -- Physiological aspects ,Biological sciences - Abstract
Peripheral microvascular dysfunction is a common affliction in patients with the metabolic syndrome X. Previous studies have described a number of vascular impairments in vasomotor control in both human patients and animal models of syndrome X, but the net effect of these impairments on microvascular structure has not been examined. The goal of the current study was to test the hypothesis that syndrome X reduces muscle perfusion and induces vascular remodeling. The obese Zucker rat was used as a model of syndrome X, and the microcirculation of the hindlimb and brain were examined. Obese Zucker rats were obese, hyperlipidemic, hyperinsulinemic, and hyperglycemic. Blood flow to the hindlimb was reduced by 59% in obese rats relative to lean rats. Skeletal muscle resistance arteries of the hindlimb microcirculation of obese rats had thinner walls, smaller lumens, and reduced distensibility. Hindlimb microvessels from obese rats also demonstrated reduced expression of vascular smooth muscle cell markers. Each of these traits is consistent with low-flow remodeling. In contrast, the cerebral microcirculation, where flow is vigorously autoregulated, showed no vascular remodeling nor were there changes in microvascular smooth muscle marker expression. Neither physical activity nor muscle mass were significantly different between lean and obese rats. Taken together, these findings suggest that syndrome X, by reducing hindlimb blood flow, induces a marked remodeling of microcirculation to favor smaller, less distensible vessels. This remodeling may result in an architectural limitation of maximum perfusion capacity and may be an important maladaption in the progression of peripheral microvascular disease. peripheral vascular disease; microcirculation; smooth muscle cell markers more...
- Published
- 2004
47. Impaired skeletal muscle perfusion in obese Zucker rats
- Author
-
Frisbee, Jefferson C.
- Subjects
Muscles -- Research ,Biological sciences - Abstract
Frisbee, Jefferson C. Impaired skeletal muscle perfusion in obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 285: R1124-R1134, 2003. First published July 10, 2003; 10.1152/ajpregu.00239.2003.--Skeletal muscle arterioles from obese Zucker rats (OZR) exhibit oxidant stressbased alterations in reactivity, enhanced [alpha]-adrenergic constriction, and reduced distensibility vs. microvessels of lean Zucker rats (LZR). The present study determined the impact of these alterations for perfusion and performance of in situ skeletal muscle during periods of elevated metabolic demand. During bouts of isometric tetanic contractions, fatigue of in situ gastrocnemius muscle of OZR was increased vs. LZR; this was associated with impaired active hyperemia. In OZR, vasoactive responses of skeletal muscle arterioles from the contralateral gracilis muscle were impaired, due in part to elevated oxidant tone; reactivity was improved after treatment with polyethylene glycol-superoxide dismutase (PEG-SOD). Arterioles of OZR also exhibited increased [alpha]-adrenergic sensitivity, which was abolished by treatment with phentolamine ([10.sup.-5] M). Intravenous infusion of phentolamine (10 mg/kg) or PEG-SOD (2,000 U/kg) in OZR altered neither fatigue rates nor active hyperemia from untreated levels; however, combined infusion improved performance and hyperemia, although not to levels in LZR. Microvessel density in the contralateral gastrocnemius muscle, determined via histological analyses, was reduced by ~25% in OZR vs. LZR, while individual arterioles from the contralateral gracilis muscle demonstrated reduced distensibility. These data suggest that altered arteriolar reactivity contributes to reduced muscle performance and active hyperemia in OZR. Further, despite pharmacological improvements in arteriolar reactivity, reduced skeletal muscle microvessel density and arteriolar distensibility also contribute substantially to reduced active hyperemia and potentially to impaired muscle performance. skeletal muscle microcirculation; skeletal muscle fatigue; obesity; models of syndrome X more...
- Published
- 2003
48. Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats
- Author
-
Frisbee, Jefferson C.
- Subjects
Heart diseases -- Research ,Biological sciences - Abstract
Whereas previous studies have demonstrated that the development of syndrome X in obese Zucker rats (OZR) is associated with impaired arteriolar reactivity to vasoactive stimuli, additional results from these studies indicate that the passive diameter of skeletal muscle arterioles is reduced in OZR versus lean Zucker rats (LZR). On the basis of these prior observations, the present study evaluated structural alterations to the skeletal muscle microcirculation as potential contributors to an elevated vascular resistance. Isolated skeletal muscle resistance arterioles exhibited a reduced passive diameter at all levels of intralumenal pressure and a left-shifted stress-strain curve in OZR versus LZR, indicative of structural remodeling of individual arterioles. Histological analyses using Griffonia simplicifolia I lectin-stained sections of skeletal muscle demonstrated reduced microvessel density (rarefaction) in OZR versus LZR, suggesting remodeling of entire microvascular networks. Finally, under maximally dilated conditions, constant fiow-perfused skeletal muscle of OZR exhibited significant elevations in perfusion pressure versus LZR, indicative of an increased resistance to perfusion within the microcirculation. These data suggest that developing structural alterations to the skeletal muscle microcirculation in OZR result in elevated vascular resistance, which may, acting in concert with impaired arteriolar reactivity, contribute to blunted active hyperemic responses and compromised performance of in situ skeletal muscle with elevated metabolic demand. microvessel rarefaction; vascular wall mechanics; passive vascular mechanics; models of syndrome X; obesity; diabetes mellitus more...
- Published
- 2003
49. High-salt diet impairs vascular relaxation mechanisms in rat middle cerebral arteries
- Author
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Lombard, Julian H., Sylvester, Francis A., Phillips, Shane A., and Frisbee, Jefferson C.
- Subjects
Rats as laboratory animals -- Physiological aspects ,Sodium in the body -- Physiological aspects ,Muscle contraction -- Physiological aspects ,Hypertension -- Physiological aspects ,Cookery for hypertensives ,Biological sciences - Abstract
Male Sprague-Dawley rats were maintained on a low-salt (LS) diet (0.4% NaC1) or a high-salt (HS) diet (4% NaC1) for 3 days or 4 wk. [Po.sub.2] reduction to 40-45 mmHg, the stable prostacyclin analog iloprost (10 pg/ml), and stimulatory G protein activation with cholera toxin (1 ng/ml) caused vascular smooth muscle (VSM) hyperpolarization, increased cAMP production, and dilation in cerebral arteries from rats on a LS diet. Arteries from rats on a HS diet exhibited VSM depolarization and constriction in response to hypoxia and iloprost, failed to dilate or hyperpolarize in response to cholera toxin, and cAMP production did not increase in response to hypoxia, iloprost, or cholera toxin. Low-dose angiotensin II infusion (5 ng*[kg.sup.-1]*[mini.sup.-1] iv) restored normal responses to reduced [Po.sub.2] and iloprost in arteries from animals on a HS diet. These observations suggest that angiotensin II suppression with a HS diet leads to impaired relaxation of cerebral arteries in response to vasodilator stimuli acting at the cell membrane. salt intake; hypertension; angiotensin; hypoxia; vascular smooth muscle; endothelium more...
- Published
- 2003
50. Integration of hypoxic dilation signaling pathways for skeletal muscle resistance arteries
- Author
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Frisbee, Jefferson C., Maier, Kristopher G., Falck, John R., Roman, Richard J., and Lombardi, Julian H.
- Subjects
Striated muscle -- Physiological aspects ,Cellular control mechanisms -- Research ,Hypoxia -- Physiological aspects ,Vascular resistance -- Physiological aspects ,Biological sciences - Abstract
Mediator contributions to hypoxic dilation of rat gracilis muscle resistance arteries were determined by measuring dilation, vascular smooth muscle hyperpolarization, and metabolite production after incremental hypoxia. Nitric oxide (NO) synthase inhibition abolished responses to mild hypoxia, whereas COX inhibition impaired responses to more severe hypoxia by 77%. Blocking 20-hydroxyeicosatetraenoic acid (20-HETE) impaired responses to moderate hypoxia. With only NO systems intact, responses were maintained with mild hypoxia (88% normal) mediated via [K.sub.Ca] channels. When only COX pathways were intact, responses to moderate-severe hypoxia were largely retained (79% of normal) mediated via KATP channels. Vessel responses to moderate hypoxia were retained with only 20-HETE systems intact mediated via [K.sub.Ca] channels. NO production increased 5.6-fold with mild hypoxia; greater hypoxia was without further effect. With increased hypoxia, 20-HETE levels fell to 40% of control values. 6-keto-PG[F.sub.1[alpha]] levels were not altered with mild hypoxia, but increased 4.6-fold with severe hypoxia. These results suggest vascular reactivity to progressive hypoxia represents an integration of NO production (mild hypoxia), PG[I.sub.2] production (severe hypoxia), and reduced 20-HETE levels (moderate hypoxia). nitric oxide; prostacyclin; skeletal muscle microcirculation; oxygen-induced vascular reactivity; cytochrome P-450 4a enzymes; microvessels; 20-hydroxyeicosatetraenoic acid more...
- Published
- 2002
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