Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

Carotid body size measured by computed tomographic angiography in individuals born prematurely.

PURPOSE: We tested the hypothesis that the carotid bodies would be smaller in individuals born prematurely or exposed to perinatal oxygen therapy when compared individuals born full term that did not receive oxygen therapy. METHODS: A retrospective chart review was conducted on patients who underwent head/neck computed tomography angiography (CTA) at the Mayo Clinic between 10 and 40 years of age (n = 2503). Patients were identified as premature ( < 38 weeks) or receiving perinatal oxygen therapy by physician completion or billing codes (n = 16 premature and n = 7 receiving oxygen). Widest axial measurements of the carotid body images captured during the CTA were performed. RESULTS: Carotid body visualization was possible in 43% of patients and 52% of age, sex, and body mass index (BMI)-matched controls but only 17% of juvenile preterm subjects (p = .07). Of the carotid bodies that could be visualized, widest axial measurements of the carotid bodies in individuals born prematurely (n = 7, 34 ±â€¯4 weeks gestation, birth weight: 2460 ±â€¯454 g; average size: 2.5 ±â€¯0.2 cm) or individuals exposed to perinatal oxygen therapy (n = 3, 38 ±â€¯2 weeks gestation, Average size: 2.2 ±â€¯0.1 cm) were not different when compared to controls (2.3 ±â€¯0.2 cm and 2.3 ±â€¯0.2 cm, respectively, p > 0.05). CONCLUSIONS: Carotid body size, as measured using CTA, is not smaller in adults born prematurely or exposed to perinatal oxygen therapy when compared to sex, age, and BMI-matched controls. However, carotid body visualization was lower in juvenile premature patients. The decreased ability to visualize the carotid bodies in these individuals may be a result of their prematurity.

Effect of acute hypoxemia on cerebral blood flow velocity control during lower body negative pressure.

The ability to maintain adequate cerebral blood flow and oxygenation determines tolerance to central hypovolemia. We tested the hypothesis that acute hypoxemia during simulated blood loss in humans would cause impairments in cerebral blood flow control. Ten healthy subjects (32 ± 6 years, BMI 27 ± 2 kg·m-2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 min at 0, -15, -30, and -45 mmHg) during both normoxia and hypoxia (Fi O2  = 0.12-0.15 O2 titrated to an SaO2 of ~85%). Physiological responses during both protocols were expressed as absolute changes from baseline, one subject was excluded from analysis due to presyncope during the first stage of LBNP during hypoxia. LBNP induced greater reductions in mean arterial pressure during hypoxia versus normoxia (MAP, at -45 mmHg: -20 ± 3 vs. -5 ± 3 mmHg, P < 0.01). Despite differences in MAP, middle cerebral artery velocity responses (MCAv) were similar between protocols (P = 0.41) due to increased cerebrovascular conductance index (CVCi) during hypoxia (main effect, P = 0.04). Low frequency MAP (at -45 mmHg: 17 ± 5 vs. 0 ± 5 mmHg2 , P = 0.01) and MCAv (at -45 mmHg: 4 ± 2 vs. -1 ± 1 cm·s-2 , P = 0.04) spectral power density, as well as low frequency MAP-mean MCAv transfer function gain (at -30 mmHg: 0.09 ± 0.06 vs. -0.07 ± 0.06 cm·s-1 ·mmHg-1 , P = 0.04) increased more during hypoxia versus normoxia. Contrary to our hypothesis, these findings support the notion that cerebral blood flow control is not impaired during exposure to acute hypoxia and progressive central hypovolemia despite lower MAP as a result of compensated increases in cerebral conductance and flow variability.

Impact of sleep disordered breathing on carotid body size.

We tested the hypotheses that: (1) carotid body size can be measured by computed tomographic angiography (CTA) with high inter-observer agreement, and (2) patients with sleep apnea exhibit larger carotid bodies than those without sleep apnea. A chart review was conducted from patients who underwent neck CTA and polysomnography at the Mayo Clinic between January 2000 and February 2015. Widest axial measurements of the carotid bodies, performed independently by two radiologists, were possible in 81% of patients. Intra-class correlation coefficients ranged from 0.93 to 0.95 (Right carotid body: 0.93; Left: 0.94; Average: 0.95). Widest axial measurements of the carotid bodies were greater in patients with sleep apnea (n=32) compared to controls (n=46, P-value range 0.02-0.04). After adjusting for age, no differences in carotid body size were observed between the patient groups (P-value range 0.45-0.59). We conclude carotid body size can be detected by CTA with high inter-observer agreement; however, carotid body size is not increased in patients with sleep apnea.

Transglutaminase activity is decreased in large arteries from hypertensive rats compared with normotensive controls.

Transglutaminases (TGs) catalyze the formation of covalent cross-links between glutamine residues and amine groups. This cross-linking activity has been implicated in arterial remodeling. Because hypertension is characterized by arterial remodeling, we hypothesized that TG activity, expression, and functionality would be increased in the aorta, but not in the vena cava (which does not undergo remodeling), from hypertensive rats relative to normotensive rats. Spontaneously hypertensive stroke-prone rats (SHRSP) and DOCA-salt rats as well as their respective normotensive Wistar-Kyoto or Sprague-Dawley counterparts were used. Immunohistochemistry and Western blot analysis measured the presence and expression of TG1 and TG2, in situ activity assays quantified active TGs, and isometric contractility was used to measure TG functionality. Contrary to our hypothesis, the activity (52% DOCA-salt vs. control rats and 56% SHRSP vs. control rats, P < 0.05), expression (TG1: 54% DOCA-salt vs. control rats, P > 0.05, and TG2: 77% DOCA-salt vs. control rats, P < 0.05), and functionality of TG1 and TG2 were decreased in the aorta, but not in the vena cava, from hypertensive rats. Mass spectrometry identified proteins uniquely amidated by TGs in the aorta that play roles in cytoskeletal regulation, redox regulation, and DNA/RNA/protein synthesis and regulation and in the vena cava that play roles in cytoskeletal regulation, coagulation regulation, and cell metabolism. Consistent with the idea that growing cells lose TG2 expression, vascular smooth muscle cells placed in culture lost TG2 expression. We conclude that the expression, activity, and functionality of TG1 and TG2 are decreased in the aorta, but not in the vena cava, from hypertensive rats compared with control rats.