Harper, Jennifer L.

AbstractEndothelin‐1 (ET‐1) and its receptors are linked to increases in sensitivity of the chemoreceptors to hypoxic stress and the development of hypertension in preclinical models. We hypothesized ET receptor antagonism would lower resting blood pressure (BP) as well as the acute BP response to chemoreflex stress. Twenty‐four men (31 ± 5 years, 26 ± 3 kg/m2) completed two study visits (control, bosentan). On each visit, BP was assessed under three conditions: (1) normoxia (FiO2 0.21), (2) chemoreflex excitation via hypoxia (FiO2 0.05–0.21), (3) chemoreflex inhibition via hyperoxia (FiO2 1.00). Bosentan increased plasma ET‐1 (0.94 ± 0.90 to 1.27 ± 0.62 pg/mL, p = 0.004), supporting receptor blockade. Resting diastolic (73 ± 5 to 69 ± 7 mmHg, p = 0.007) and mean (93 ± 7 to 88 ± 7 mmHg, p = 0.005) BP were reduced following bosentan compared to control with no change in systolic BP (p = 0.507). The mean BP response to both acute hypoxia (−0.48 ± 0.38 to −0.25 ± 0.31 mmHg/%, p = 0.004) and hyperoxia (area under the curve −93 ± 108 to −27 ± 66 AU, p = 0.018) were attenuated following bosentan. Acute ET receptor inhibition attenuates the rise in BP during chemoreflex excitation as well as the fall in BP during chemoreflex inhibition in healthy young men. These data support a role for ET‐1 in control of resting BP, possibly through a chemoreceptor‐mediated mechanism.

Objectives: Upregulation of endothelin-1 (ET-1) and its receptors have been linked to increases in hypoxic sensitivity of the carotid chemoreceptors and the development of hypertension. As such, chemoreflex sensitization has been shown in pre-clinical models to be attenuated by ET-1 receptor blockade. Herein, we sought to assess a role for ET-1 in the maintenance of resting blood pressure (BP) in healthy young men and determine whether chemoreflex control of BP could be altered by ET-1 blockade. We hypothesized endothelin receptor antagonism with oral bosentan would lower resting BP in healthy young men as well as the acute BP response to hypoxia. Methods: Twenty-four healthy young men (31±5 yrs, 26±3 kg/m2) completed two study visits (control, bosentan) separated by a minimum of 1 week. The nonspecific endothelin receptor antagonist bosentan (62.5 mg) was taken by mouth twice daily for 3 days prior to the second study visit. On each visit, beat-by-beat BP was assessed under 3 inspiratory air conditions: 1) steady-state normoxia (FiO2 0.21), 2) chemoreflex excitation produced by acute, graded hypoxia (FiO2 0.05 – 0.21), 3) chemoreflex inhibition elicited by transient hyperoxia (FiO2 1.00). Results: Oral bosentan treatment resulted in an increase in plasma ET-1 (0.9±0.9 to 1.3±0.6 pg/mL, p=0.004), supporting receptor blockade. Resting diastolic and mean BP were reduced following 3 days of bosentan treatment compared to control (diastolic: 73±5 to 69±7 mmHg, p=0.007; mean: 93±7 to 88±7 mmHg, p=0.005) with no change in systolic BP (p=0.507). Notably, the BP response to both acute hypoxia (-0.48±0.38 to -0.25±0.31 mmHg/%, p=0.004) and hyperoxia (main effect of bosentan, p=0.025) were attenuated following bosentan. Conclusions: Acute oral bosentan treatment resulted in a reduction in resting BP in healthy young men. The effect of endothelin receptor inhibition with bosentan further attenuated the rise in BP during chemoreflex excitation via acute, graded hypoxia as well as the fall in BP during chemoreflex inhibition (transient hyperoxia). Together these data support a role for ET-1 in control of resting BP in healthy young men, possibly through a chemoreceptor-mediated mechanism. NIH HL130339 (JL), Mayo Clinic Center for Biomedical Discovery (JL, SB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET-1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ET-receptors in healthy young men.

Objective Hyperinsulinemia elicits an increase sympathetic nervous system activity directed toward skeletal muscle (muscle sympathetic nerve activity, MSNA). The insulin‐mediated increase in MSNA is primarily attributed to its effect within the central nervous system. In addition to direct central effects, insulin also elicits peripheral vasodilation, which may further increase MSNA via arterial baroreflex‐mediated mechanisms in order to maintain blood pressure (BP). Herein we examined the contribution of insulin‐induced peripheral vasodilation and role for the arterial baroreflex in the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with co‐infusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized the insulin‐mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). Methods In 33 healthy adults (28M/5F, 28±1 yrs, BMI 25.0±0.5 kg/m 2 ) MSNA (microneurography) and BP (Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) was calculated at rest and during intravenous insulin (n=20) or SNP (n=13) infusion. A subset of participants receiving insulin (n=7) were co‐infused with phenylephrine. Spontaneous arterial baroreflex sensitivity was determined over 5‐min at baseline and during pharmacological intervention(s). Results Insulin infusion increased MSNA (p=0.05) and decreased TPR (p<0.05), with no effects on arterial baroreflex sensitivity or BP (p>0.05). Co‐infusion with phenylephrine returned MSNA and TPR to baseline, with no effect on baroreflex sensitivity (p>0.05). Similar to insulin, SNP increased MSNA (p<0.01) and decreased TPR (p<0.05), with no effect on baroreflex sensitivity (p>0.05). Conclusions Present findings reveal that acute hyperinsulinemia increases MSNA without a change in arterial baroreflex sensitivity in healthy men and women. Insulin‐mediated increases in MSNA are lost with co‐infusion of phenylephrine and can be recapitulated with infusion of SNP. Results support a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase MSNA and maintain BP.

We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Sex-related differences in respiratory modulation of sympathetic activity have been observed in rodent models of sleep apnea [intermittent hypoxia (IH)]. In light of sex disparities in the respiratory response to acute IH in humans as well as changes in respiratory modulation of muscle sympathetic nerve activity (MSNA) in clinical sleep apnea, we examined sex-related differences in respiratory modulation of MSNA following acute IH. We hypothesized that respiratory modulation of MSNA would be altered in both male and female participants after IH; however, the respiratory patterning of MSNA following IH would be sex specific. Heart rate, MSNA, and respiration were evaluated in healthy male ( n = 21, 30 ± 5 yr) and female ( n = 10, 28 ± 5 yr) participants during normoxic rest before and after 30 min of IH. Respiratory modulation of MSNA was assessed by fitting polynomials to cross-correlation histograms constructed between sympathetic spikes and respiration. MSNA was elevated after IH in male (20 ± 6 to 24 ± 8 bursts/min) and female (19 ± 8 to 22 ± 10 bursts/min) participants ( P < 0.01). Both male and female participants exhibited respiratory modulation of MSNA ( P < 0.01); however, the pattern differed by sex. After IH, modulation of MSNA within the breath was reduced in male participants ( P = 0.03) but increased in female participants ( P = 0.02). Both male and female adults exhibit changes in respiratory patterning of MSNA after acute IH; however, this pattern differs by sex. These data support sex disparities in respiratory modulation of MSNA and may have implications for conditions such as sleep apnea.

Background Muscle sympathetic nerve activity (MSNA) is augmented in patients with sleep apnea. This increase in activity is due to increases in firing probability and mean firing rates of individual vasoconstrictor neurons, in addition to multiple within‐burst firing; however, contributing mechanisms and the impact of such firing patterns on peripheral vascular tone are less clear. We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing and recruitment strategies and the relationship between changes in MSNA and neurovascular transduction following acute IH. We hypothesized exposure to acute IH would increase MSNA via an increase in action potential (AP) discharge rates and within‐burst firing. We further hypothesized any change in discharge patterns following acute IH would be positively related to a change in neurovascular transduction. Methods Blood pressure (brachial arterial catheter) and MSNA (microneurography of the peroneal nerve) were assessed in 17 healthy adults (11M/6F; 31 ± 1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic (0.05 F i O 2 ) exposures alternating with 90‐s room air breathing]. AP patterns were studied from the filtered raw MSNA signal using wavelet‐based methodology. The slope of the relationship between diastolic blood pressure (DBP) and the preceding MSNA burst area at a fixed cardiac cycle lag was used to quantify neurovascular transduction. Results IH resulted in 15 events where oxygen saturation was reduced (S p O 2 : 99 ± 1% vs 92 ± 1%, P <0.01). Compared to baseline, multi‐unit MSNA burst incidence (33 ± 4 to 43 ± 5 bursts/100 heart beats), AP incidence (272 ± 50 to 501 ± 112 AP/100 heart beats) and AP content per integrated burst (7 ± 1 to 10 ± 1 AP/burst; 4 ± 1 to 5 ± 1 clusters/burst) were increased following IH (all P< 0.05). Neurovascular transduction was not altered following IH ( P =0.34); however, there was a positive relationship between the change (Δ) in neurovascular transduction (mmHg/%/s) and changes in AP discharge rate (AP/100 heart beats; R=0.52, P= 0.03) and within‐burst firing (AP/burst; R=0.38, P= 0.14) following IH. Conclusions Acute IH increases sympathetic neuronal discharge by increasing within‐burst firing of low‐threshold axons. A positive relationship exists between increases in the neural discharge rates and neurovascular transduction following acute IH, such that those individuals with the greatest increase in AP firing exhibited the greatest increase in transduction of sympathetic activity into blood pressure. These data may have important implications for mechanistic understanding of sympathetic activation in sleep apnea and its down‐stream effects, including the development of hypertension and cardiovascular disease. Support or Funding Information Funding: NIH HL130339, Mayo Clinic Center for Biomedical Discovery, Mizzou HES PURE, APS UGSRF. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background Sex‐related differences in respiratory‐sympathetic coupling have been described in preclinical models of intermittent hypoxia (IH) and have been implicated in the development of neurogenic hypertension. Based on sex disparities in the respiratory and blood pressure response to acute IH in humans as well as changes in respiratory‐sympathetic coupling in clinical sleep apnea, we examined sex‐related differences in respiratory modulation of muscle sympathetic nerve activity (MSNA) following acute IH in healthy humans. We hypothesized the magnitude of respiratory‐sympathetic coupling would increase in both men and women following IH; however, the respiratory patterning of MSNA following IH would be sex‐specific. Methods Heart rate, MSNA, and respiration were assessed in 21 healthy young men (30±1 yrs) and 10 healthy young women (28±1 yrs) during normoxic rest prior to and following IH. IH was achieved by alternating between a hypercapnic hypoxic (3% carbon dioxide, 5% oxygen) gas cylinder and room air (21% oxygen) to target 15 hypoxic events over 30‐min. Respiratory modulation of MSNA was assessed by fitting polynomials to cross‐correlation histograms constructed between sympathetic spikes and respiration. Results MSNA was elevated following IH in both men (34±2 to 41±3 bursts/100 heart beats) and women (30±4 to 35±5 bursts/100 heart beats) (p<0.01). When examining the normalized temporal profile of MSNA, both men and women exhibited changes in respiratory patterning of MSNA following IH; however, the pattern of MSNA differed by sex. Following IH, women exhibited more sympathetic activity during late expiration and less during post‐inspiration (interaction of IH and time, p<0.01). In contrast, men exhibited greater sympathetic activity during post‐inspiration following IH (interaction of IH and time, p<0.01). Conclusions Both men and women exhibit changes in respiratory patterning of MSNA following acute IH; however, this pattern differs by sex. These data support sex disparities in respiratory‐sympathetic coupling and advance our understanding of sex‐specific changes in sympathetic activation following IH which may have important implications for the development of neurogenic hypertension.

Repetitive hypoxic apneas, similar to those observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP). This baroreflex resetting is associated with hypertension in preclinical models of sleep apnea (intermittent hypoxia, IH); however, the majority of understanding comes from males. There are data to suggest that female rats exposed to IH do not develop high BP. Clinical data further support sex differences in the development of hypertension in sleep apnea, but mechanistic data are lacking. Here we examined sex-related differences in the effect of IH on sympathetic control of BP in humans. We hypothesized that after acute IH we would observe a rise in muscle sympathetic nerve activity (MSNA) and arterial BP in young men ( n = 30) that would be absent in young women ( n = 19). BP and MSNA were measured during normoxic rest before and after 30 min of IH. Baroreflex sensitivity (modified Oxford) was evaluated before and after IH. A rise in mean BP following IH was observed in men (+2.0 ± 0.7 mmHg, P = 0.03), whereas no change was observed in women (−2.7 ± 1.2 mmHg, P = 0.11). The elevation in MSNA following IH was not different between groups (4.7 ± 1.1 vs. 3.8 ± 1.2 bursts/min, P = 0.65). Sympathetic baroreflex sensitivity did not change after IH in either group ( P > 0.05). Our results support sex-related differences in the effect of IH on neurovascular control of BP and show that any BP-raising effects of IH are absent in young women. These data enhance our understanding of sex-specific mechanisms that may contribute to BP changes in sleep apnea.

We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.