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  • American Physiological Society  (33)
  • 1
    In: Journal of Applied Physiology, American Physiological Society, Vol. 134, No. 4 ( 2023-04-01), p. 868-878
    Abstract: Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we 1) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and 2) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: n = 7; OW/OB: n = 7) and 14 controls (CTRL; lean: n = 7, OW/OB: n = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 µg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, P 〈 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ± 0.9%, P = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only ( R 2 = 0.68, P = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ± 0.9 vs. 9.6 ± 1.7%, P 〈 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, P = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, P = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes. NEW & NOTEWORTHY We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is 1) associated with free testosterone levels, 2) impaired relative to overweight/obese women with AE-PCOS, and 3) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
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    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
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    SSG: 12
    SSG: 31
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  • 2
    Online Resource
    Online Resource
    American Physiological Society ; 2016
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 311, No. 4 ( 2016-10-01), p. G688-G698
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 311, No. 4 ( 2016-10-01), p. G688-G698
    Abstract: Anti-TNFα therapy decreases inflammation in Crohn's disease (CD). However, its ability to decrease fibrosis and alter the natural history of CD is not established. Anti-TNF-α prevents inflammation and fibrosis in the peptidoglycan-polysaccharide (PG-PS) model of CD. Here we studied anti-TNF-α in a treatment paradigm. PG-PS or human serum albumin (HSA; control) was injected into bowel wall of anesthetized Lewis rats at laparotomy. Mouse anti-mouse TNF-α or vehicle treatment was begun day (d)1, d7, or d14 postlaparotomy. Rats were euthanized d21-23. Gross abdominal and histologic findings were scored. Cecal levels of relevant mRNAs were measured by quantitative real-time PCR. There was a stepwise loss of responsiveness when anti-TNFα was begun on d7 and d14 compared with d1 that was seen in the percent decrease in the median gross abdominal score and histologic inflammation score in PG-PS-injected rats [as %decrease; gross abdominal score: d1 = 75% ( P = 0.003), d7 = 57% ( P = 0.18), d14 = no change ( P = 0.99); histologic inflammation: d1 = 57% ( P = 0.006), d7 = 50% ( P = 0.019), d14 = no change ( P = 0.99)]. This was also reflected in changes in IL-1β, IL-6, TNF-α, IGF-I, TGF-β1, procollagen I, and procollagen III mRNAs that were decreased or trended downward in PG-PS-injected animals given anti-TNF-α beginning d1 or d7 compared with vehicle-treated rats; there was no effect if anti-TNF-α was begun d14. This change in responsiveness to anti-TNFα therapy was coincident with a major shift in the cytokine milieu observed on d14 in the PG-PS injected rats (vehicle treated). Our data are consistent with the clinical observation that improved outcomes occur when anti-TNF-α therapy is initiated early in the course of CD.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477329-6
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  • 3
    Online Resource
    Online Resource
    American Physiological Society ; 1971
    In:  American Journal of Physiology-Legacy Content Vol. 220, No. 4 ( 1971-04-01), p. 986-992
    In: American Journal of Physiology-Legacy Content, American Physiological Society, Vol. 220, No. 4 ( 1971-04-01), p. 986-992
    Type of Medium: Online Resource
    ISSN: 0002-9513
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    Language: English
    Publisher: American Physiological Society
    Publication Date: 1971
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    detail.hit.zdb_id: 2065807-2
    detail.hit.zdb_id: 1477287-5
    detail.hit.zdb_id: 1477308-9
    detail.hit.zdb_id: 1477297-8
    detail.hit.zdb_id: 1477331-4
    detail.hit.zdb_id: 1477300-4
    detail.hit.zdb_id: 1477329-6
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  • 4
    Online Resource
    Online Resource
    American Physiological Society ; 1976
    In:  Journal of Applied Physiology Vol. 40, No. 4 ( 1976-04-01), p. 539-542
    In: Journal of Applied Physiology, American Physiological Society, Vol. 40, No. 4 ( 1976-04-01), p. 539-542
    Abstract: The effective elastance of the respiratory system (E‣rs) is a measure of its ability to resist a change in tidal volume under conditions of changing elastic loads. E‣rs was measured while subjects breathed air and 2% CO2 and 4% CO2 in air in two groups of premature infants of different gestational ages at 1 day 3–4 days, and 7–10 days of age. E‣rs was shown to decrease with increasing maturation and was independent of changes in control tidal volume. The decrease of E‣rs with increased gestational age could be accounted for by differences in calculated thoracic gas volumes in all but one instance, where E‣rs was lower in one group on the 3rd day of life. The activity of the Hering-Breuer reflex, as measured by the degree of slowing of inspiratory time after occlusion at FRC, has been previously reported to be normal to increased in similar infants. This suggests that differences related to size account for most of the maturational changes of E‣rs in newborns.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
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    Language: English
    Publisher: American Physiological Society
    Publication Date: 1976
    detail.hit.zdb_id: 1404365-8
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  • 5
    Online Resource
    Online Resource
    American Physiological Society ; 1984
    In:  American Journal of Physiology-Cell Physiology Vol. 247, No. 3 ( 1984-09-01), p. C188-C196
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 247, No. 3 ( 1984-09-01), p. C188-C196
    Abstract: To determine intracellular pH gradients rabbit renal cortical tubular cells were prepared by collagenase separation, suspended in a Krebs-Ringer buffer solution, and gassed with 95% O2-5% CO2 in a special nuclear magnetic resonance (NMR) probe. Renal tubular cellular pH was determined simultaneously from the distribution of 14C-dimethadione (DMO) (pHDMO) or the chemical shift of inorganic phosphate (pHNMR). Experiments were performed at different external pH values (pHe) ranging between 6.52 and 7.20. pHNMR, a measure of cytoplasmic pH, changed by an amount equal to the change in pHe. pHDMO, however, a measure of cytoplasmic plus mitochondrial pH, changed less than pHe as the latter increased. pHDMO, higher than pHNMR at low pHe, became equal to pHNMR at higher pHe values. By use of assumed mitochondrial volumes of 30-40% mitochondrial pH was calculated from pHDMO and pHNMR. Mitochondrial pH remained relatively constant over the entire pHe range studied. Since cytoplasmic pH fell as pHe was lowered, the transmitochondrial pH gradient increased at low pHE values. These findings suggest that the transmitochondrial pH gradient may be important in regulating metabolism.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1984
    detail.hit.zdb_id: 1477334-X
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  • 6
    Online Resource
    Online Resource
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 315, No. 4 ( 2018-10-01), p. H925-H933
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 315, No. 4 ( 2018-10-01), p. H925-H933
    Abstract: Hypertension, obesity, and endothelial function predict cardiovascular disease in women, and these factors are interrelated. We hypothesized that hypertension and obesity are associated with endothelial dysfunction in young women and that short-term ethinyl estradiol exposure mitigates this dysfunction. We examined flow-mediated dilation (FMD) responses before and during 7 days of oral ethinyl estradiol (30 µg/day) in 19 women (25 ± 5, 18–35 yr). We divided our sample into two groups based on two criteria: blood pressure and obesity. Women were divided into normal blood pressure (NBP; mean arterial pressure range: 78–91 mmHg, n = 7) and high blood pressure (HBP; mean arterial pressure range: 95–113 mmHg, n = 9) groups. We also stratified our subjects by body composition (lean: 18–31%, n = 8; obese: 38–59%, n = 9). We evaluated brachial FMD after two distinct shear stress stimuli: occlusion alone and occlusion with ischemic handgrip exercise. Obesity was unrelated to both FMD responses. Before ethinyl estradiol administration, the HBP group had blunted ischemic exercise responses relative to the NBP group (8.0 ± 3.5 vs. 12.3 ± 3.2%, respectively, P = 0.05). However, during ethinyl estradiol administration, ischemic exercise responses increased in the HBP group (12.8 ± 6.1%, P = 0.04) but decreased in the NBP group (5.6 ± 2.4%, P = 0.01). Standard FMD did not reveal differences between groups. In summary, 1) moderate HBP predicted endothelial impairment, 2) ethinyl estradiol administration had divergent effects on FMD in women with NBP versus HBP, and 3) enhanced FMD (ischemic handgrip exercise) revealed differences in endothelial function, whereas standard FMD (occlusion alone) did not. NEW & NOTEWORTHY We are the first to show that mild hypertension is a stronger predictor of endothelial dysfunction than obesity in healthy women without overt cardiovascular dysfunction. Importantly, the standard 5-min flow-mediated vasodilation stimulus did not detect endothelial dysfunction in our healthy population; only an enhanced ischemic handgrip exercise shear stress stimulus detected endothelial impairment. Estradiol administration increased flow-mediated dilation in women with high blood pressure, so it may be a therapeutic intervention to improve endothelial function.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
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    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477308-9
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  • 7
    Online Resource
    Online Resource
    American Physiological Society ; 1988
    In:  Journal of Applied Physiology Vol. 64, No. 5 ( 1988-05-01), p. 1829-1836
    In: Journal of Applied Physiology, American Physiological Society, Vol. 64, No. 5 ( 1988-05-01), p. 1829-1836
    Abstract: Buffering capacity of most tissues is composed of both rapid and slow phases, the latter presumably due to active acid extrusion. To examine the time course of brain buffering the brain pH of Sprague-Dawley rats was measured using 31P-nuclear magnetic resonance. The effect on brain pH of 30- or 58-min exposures to 20% CO2 followed by 30- or 38-min recovery periods, respectively, was studied. Brain pH reached its lowest value after a 15-min exposure to elevated CO2, thereafter slowly and steadily increasing. During recovery brain pH rose rapidly in the first 5 min exceeding control brain pH by 0.08 pH units. Brain pH fell during the next 30 min despite increases in blood pH and decreases in blood CO2 tension. Calculated intrinsic brain buffering rose steadily threefold during the last 40 min of CO2 exposure and during the final 30 min of recovery. These data show that in rat brain there is a temporally late buffering process, most likely active acid extrusion, requiring greater than 30 min for full activation and at least 30 min for discontinuation.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
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    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1988
    detail.hit.zdb_id: 1404365-8
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  • 8
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 301, No. 1 ( 2011-07), p. H41-H47
    Abstract: Experimental studies have suggested a role for the local renin-angiotensin-aldosterone system in the response to vascular injury. Clinical data support that aldosterone, via activation of the mineralocorticoid receptor (MR), is an important mediator of vascular damage in humans with cardiovascular disease. In mineralocorticoid-sensitive target tissue, aldosterone specificity for MR is conferred enzymatically by the cortisol-inactivating enzyme 11β-hydroxysteroid-dehydrogenase-2 (11βHSD2). However, the role of MR/aldosterone signaling in the venous system has not been explored. We hypothesized that MR expression and signaling in venous smooth muscle cells contributes to the arterialization of venous conduits and the injury response in vein bypass grafts. MR immunostaining was observed in all samples of excised human peripheral vein graft lesions and in explanted experimental rabbit carotid interposition vein grafts, with minimal staining in control greater saphenous vein. We also found upregulated transcriptional expression of both MR and 11βHSD2 in human vein graft and rabbit vein graft, whereas control greater saphenous vein expressed minimal MR and no detectable 11βHSD2. The expression of MR and 11βHSD2 was confirmed in cultured human saphenous venous smooth muscle cells (hSVSMCs). Using an adenovirus containing a MR response element-driven reporter gene, we demonstrate that MR in hSVSMCs is capable of mediating aldosterone-induced gene activation. The functional significance for MR signaling in hSVSMCs is supported by the aldosterone-induced increase of angiotensin II type-1 receptor gene expression that was inhibited by the MR antagonist spironolactone. The upregulation of MR and 11βHSD2 suggests that aldosterone-mediated tissue injury plays a role in vein graft arterialization.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
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    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477308-9
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  • 9
    Online Resource
    Online Resource
    American Physiological Society ; 1994
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 266, No. 4 ( 1994-04-01), p. H1657-H1671
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 266, No. 4 ( 1994-04-01), p. H1657-H1671
    Abstract: Discrete theoretical methods, compatible with the discrete features of the beating heart, are used together with experimental study to attain a quantitative understanding of the transient response to a volume perturbation and of sustained mechanical alternans (SMA) in the beating heart. This is done in three stages. In stage A, a first-order difference equation describes the stroke volume (SV) response due to the Frank-Starling mechanism. It is shown that the value of gamma, the slope of the SV-end-diastolic volume curve, determines the type of response obtained because of a perturbation: 1) nonoscillatory decay for gamma 〈 1,2) oscillatory decay for 1 〈 gamma 〈 2, 3) SMA for gamma = 2, and 4) chaotic response for gamma 〉 2. In stage B, when the effect of each SV change on the successive end-diastolic aortic pressure (P) is considered, SV response to a perturbation is determined by a second-order difference equation. The solution of this equation shows that the response is determined by gamma and by the afterload factor lambda 1 = alpha 1.delta, where alpha 1 = delta Pj + 1/delta SVj and delta = delta SVj + 1/delta Pj + 1. The responses are a nonoscillatory decay for lambda 1 〈 1 - gamma (type 1), oscillatory decay for 1 - (gamma/2) 〉 lambda 1 〉 1 - gamma (type 2), SMA for lambda 1 = 1 - gamma/2 (type 3), and 2:1 electrical-mechanical response for lambda 1 〉 1 - gamma/2 (type 4). In stage C, a single volume perturbation, delta SVj, will directly affect not only Pj + 1 but also the subsequent values of P. Filling volume perturbations performed with a mitral valve occluder in eight anesthetized dogs led only to type 1 and 2 responses. The responses predicted by the model (using the experimental values of gamma and lambda 1) in each of the eight open-chest dogs are compatible with the experimental responses, suggesting that it is unlikely that SMA is initiated and maintained by variations in preload and afterload.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 1994
    detail.hit.zdb_id: 1477308-9
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  • 10
    Online Resource
    Online Resource
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 318, No. 3 ( 2020-03-01), p. H581-H589
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 318, No. 3 ( 2020-03-01), p. H581-H589
    Abstract: Preeclampsia is associated with the development of cardiovascular diseases later in life. To investigate this phenomenon, we compared established markers of cardiovascular dysregulation between previously preeclamptic women (PPE; n = 12, 13 ± 6 mo postpartum, 34 ± 6 yr) and women who had previously had an uncomplicated pregnancy [control (CTRL); n = 12, 15 ± 4 mo postpartum; 29 ± 3 yr]. We hypothesized that PPE would present with elevated arterial stiffness (assessed as central and peripheral pulse wave velocity) and muscle sympathetic nerve activity (MSNA; microneurography) and blunted baroreflex sensitivity (BRS) relative to CTRL. Blood pressure (Finometer) was similar between PPE and CTRL (mean arterial pressure: 94 ± 11 vs. 89 ± 9, P = 0.16). Central (6.92 ± 0.21 vs. 6.24 ± 0.22 m/s, P = 0.04) but not peripheral arterial stiffness (7.52 ± 0.19 vs. 7.09 ± 0.19 m/s, P = 0.13) was elevated in PPE versus CTRL (values normalized to MAP). MSNA was also elevated in PPE versus CTRL (22 ± 7 vs. 13 ± 5 bursts/min, P = 0.01), although this was independent of arterial stiffness (central: r 2  = 0.01, P = 0.74; peripheral: r 2  = 0.01, P = 0.74). Cardiovagal BRS was blunted in PPE versus CTRL (15 ± 5 vs. 28 ± 1 ms/mmHg, P = 0.01), whereas sympathetic vascular BRS was similar (−3.2 ± 0.9 vs. −3.1 ± 1.4 bursts·100 hb −1 ·mmHg −1 , P  = 0.88). Cardiovagal and sympathetic BRS were inversely correlated in both CTRL ( r 2  = 0.43; P = 0.05) and PPE ( r 2  = 0.69; P = 0.04), supporting a compensatory mechanism resulting in normal blood pressures in both groups. Overall, these data indicate that PPE retain their ability to buffer elevated MSNA. We propose that the higher incidence of cardiovascular disease observed later in life in PPE results from this arterial stiffness, combined with the loss of protective vascular mechanisms and the “unmasking” of high MSNA. NEW & NOTEWORTHY We demonstrate that resting muscle sympathetic nerve activity is elevated in women with a recent history of preeclampsia relative to women who have recently had uncomplicated pregnancies and without a history of preeclampsia. Structural changes in the central arteries are associated with arterial stiffness following preeclampsia, independent of changes in the sympathetic nervous system. The structural changes are observed in these relatively young previously preeclamptic women, indicating elevated cardiovascular risk. Our data suggest that with aging (and the gradual loss of vascular protection for women, as established by others), this risk will become exaggerated compared with women who have had normal pregnancies. Listen to this article’s corresponding podcast at: https://ajpheart.podbean.com/e/behind-the-bench-episode-4/ .
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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