Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Naturally menstruating women exhibit lower cardiovagal baroreflex sensitivity than oral contraceptive users during the lower hormone phase.

The present study evaluated cardiovagal baroreflex sensitivity (BRS) across the menstrual/pill cycle in naturally menstruating women (NAT women) and women using oral hormonal contraceptives (OCP women). In 21 NAT women (23 ± 4 years old) and 22 OCP women (23 ± 3 years old), cardiovagal BRS and circulating concentrations of estradiol and progesterone were evaluated during the lower hormone (early follicular/placebo pill) and higher hormone (late follicular to early luteal/active pill) phases. During the lower hormone phase, cardiovagal BRS up, down and mean gain were lower in NAT women (15.6 ± 8.3, 15.2 ± 6.1 and 15.1 ± 7.1 ms/mmHg) compared with OCP women (24.7 ± 9.4, 22.9 ± 8.0 and 23.0 ± 8.0 ms/mmHg) (P = 0.003, P = 0.002 and P = 0.003, respectively), and higher oestrogen (R2  = 0.15, P = 0.024), but not progesterone (R2  = 0.06, P = 0.18), concentrations were predictive of lower BRS mean gain. During the higher hormone phase, higher progesterone concentrations were predictive of lower BRS mean gain (R2  = 0.12, P = 0.024). A multivariate regression model revealed group (NAT or OCP) to be a significant predictor of cardiovagal BRS mean gain in the lower hormone phase when hormone concentrations were adjusted for (R2  = 0.36, P = 0.0044). The multivariate regression model was not significant during the higher hormone phase (P > 0.05). In summary, cardiovagal BRS is lower in NAT compared with OCP women during the lower hormone phase of the menstrual/pill cycle and might be associated with higher oestrogen concentrations. In contrast, during the higher hormone phase of the menstrual/OCP cycle, higher progesterone concentrations were predictive of lower cardiovagal BRS. NEW FINDINGS: What is the central question of this study? Does cardiovagal baroreflex sensitivity (BRS) differ between naturally menstruating women (NAT women) and women using oral contraceptives (OCP women)? What is the main finding and its importance? The main findings are as follows: (1) NAT women exhibit lower cardiovagal BRS than OCP women during the lower hormone phase of the menstrual or pill cycle; and (2) circulating oestrogen concentrations are significant predictors of cardiovagal BRS during the lower hormone phase, with higher oestrogen concentrations predicting lower BRS. The present data advance our understanding of the effect of endogenous ovarian hormones and OCP use on cardiovascular control mechanisms.

The forearm vascular response to sympathetic activation is attenuated in female, but not male, participants following acute intermittent hypoxia.

Acute exposure to hypoxia promotes both an increase in sympathetic nervous system activity (SNA) and local vasodilation. In rodents, intermittent hypoxia (IH)-mediated increases in SNA are associated with an increase in blood pressure in males but not females; notably, the protective effect of female sex is lost following ovariectomy. These data suggest the vascular response to hypoxia and/or SNA following IH may be sex- and/or hormone specific-although mechanisms are unclear. We hypothesized that hypoxia-mediated vasodilation and SNA-mediated vasoconstriction would be unchanged following acute IH in male adults. We further hypothesized that hypoxic vasodilation would be augmented and SNA-mediated vasoconstriction would be attenuated in female adults following acute IH, with the greatest effect when endogenous estradiol was high. Twelve male (25 ± 1 yr) and 10 female (25 ± 1 yr) participants underwent 30 min of IH. Females were studied in a low (early follicular) and high (late follicular) estradiol state. Preceding and following IH, participants completed two trials [steady-state hypoxia and cold pressor test (CPT)], where forearm blood flow and blood pressure were measured and used to determine forearm vascular conductance (FVC). The FVC response to hypoxia (P = 0.67) and sympathetic activation (P = 0.73) were unchanged following IH in males. There was no effect of IH on hypoxic vasodilation in females, regardless of estradiol state (P = 0.75). In contrast, the vascular response to sympathetic activation was attenuated in females following IH (P = 0.02), independent of estradiol state (P = 0.65). Present data highlight sex-related differences in neurovascular responsiveness following acute IH.NEW & NOTEWORTHY We examined the effects of acute intermittent hypoxia (AIH) on the vascular response to sympathetic activation and acute hypoxia. Present findings show, despite no effect of AIH on the vascular response to hypoxia, the forearm vasoconstrictor response to acute sympathetic activation is attenuated in females following AIH, independent of estradiol state. These data provide mechanistic understanding of potential benefits of AIH, as well as the impact of biological sex.

Endothelin-1 receptor blockade does not alter the sympathetic and hemodynamic response to acute intermittent hypoxia in men.

Repeat exposures to low oxygen (intermittent hypoxia, IH), like that observed in sleep apnea, 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 are unclear. We hypothesized that ET-receptor antagonism would ameliorate any rise in MSNA and BP following acute IH in humans. Twelve healthy men (31 ± 1 yr) completed two visits (control, bosentan) separated by at least 1 wk. MSNA, BP, and baroreflex sensitivity (modified Oxford) were assessed during normoxic rest before and following 30 min of IH. The midpoint (T50) for each individual's baroreflex curve was calculated. Acute IH increased plasma ET-1 (P < 0.01), MSNA burst frequency (P = 0.03), and mean BP (P < 0.01). There was no effect of IH on baroreflex sensitivity (P = 0.46), although an increase in T50 was observed (P < 0.01). MSNA burst frequency was higher (P = 0.04) and mean BP (P < 0.01) was lower following bosentan treatment compared with control. There was no effect of bosentan on baroreflex sensitivity (P = 0.53), although a lower T50 was observed on the bosentan visit (P < 0.01). There was no effect of bosentan on increases in MSNA (P = 0.81) or mean BP (P = 0.12) following acute IH. Acute IH results in an increase in ET-1, MSNA, and BP in healthy young men. The effect of IH on MSNA and BP is not attenuated following ET-receptor inhibition. Present data suggest that acute IH does not increase MSNA or BP through activation of ET-receptors in healthy young men.NEW & NOTEWORTHY 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.

Effect of oral hormonal contraceptive pill use on the hemodynamic response to the cold pressor test.

Acute increases in sympathetic nervous system activity (SNA) often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in SNA. We hypothesized sympathoexcitation via cold pressor test (CPT) would elicit greater peripheral vasoconstriction and increases BP in females with natural menstrual cycles (NC) compared with females taking OC. We further hypothesized that SNA-mediated vasoconstriction would be attenuated during the high estradiol (HE) phase versus the low estradiol (LE) phase of the menstrual/pill cycle. Female NC (n = 11, 25 ± 1 yr) and OC (n = 10, 24 ± 1 yr) participants were studied during the LE (early follicular, placebo pill) and HE (late follicular, active pill) phase of the menstrual/pill cycle. BP (finger photoplethysmography), heart rate (HR, ECG), and forearm blood flow (FBF, venous occlusion plethysmography) were measured during a 5-min baseline and a 2-min CPT. CPT elicited an increase in BP in both groups (time, P < 0.01). During CPT, OC participants exhibited greater and sustained increases in HR compared with NC participants (group × time, P < 0.01). Higher HRs were met with increases in FBF in OC participants during the CPT, which was not observed in NC participants (group × time, P < 0.01). OC participants exhibit greater increases in HR, and paradoxical vasodilation during acute sympathetic activation compared with NC participants. Group differences are unaffected by menstrual/pill phase.NEW & NOTEWORTHY Acute increases in sympathetic nervous system activity often elicit peripheral vasoconstriction and increases in blood pressure (BP). Given sympathetic support of BP is modulated by ovarian sex hormones (e.g., estradiol), we sought to examine the effect of menstrual cycle and oral hormonal contraceptive pill (OC) phase on the hemodynamic response to acute increases in sympathetic nervous system activity via the cold pressor test. We show OC participants exhibit paradoxical vasodilation during acute sympathetic activation compared with participants with natural menstrual cycles; notably, group differences were unaffected by menstrual/pill phase.

Sex differences in the effect of acute intermittent hypoxia on respiratory modulation of sympathetic activity.

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.

Sex differences in the vascular response to sympathetic activation during acute hypoxaemia.

NEW FINDINGS: What is the central question of this study? Sympathetically mediated vasoconstriction is preserved during hypoxaemia in humans, but our understanding of vascular control comes from predominantly male cohorts. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not? What is the main finding and its importance? Sympathetically mediated vasoconstriction is preserved or even enhanced during steady-state hypoxia in young men, and the peripheral vascular response to sympathetic activation during hypoxaemia is attenuated in young women. These data advance our understanding of sex-related differences in hypoxic vascular control. ABSTRACT: Activation of the sympathetic nervous system causes vasoconstriction and a reduction in peripheral blood flow. Sympathetically mediated vasoconstriction may be attenuated during systemic hypoxia to maintain oxygen delivery; however, in predominantly male participants sympathetically mediated vasoconstriction is preserved or even enhanced during hypoxaemia. Given the potential for sex-specific differences in hypoxic vascular control, prior results are limited in application. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not. Healthy young men (n = 13, 25 ± 4 years) and women (n = 11, 24 ± 4 years) completed two trials consisting of a 2-min cold pressor test (CPT, a well-established sympathoexcitatory stimulus) during baseline normoxia and steady-state hypoxaemia. Beat-to-beat blood pressure (finger photoplethysmography) and forearm blood flow (venous occlusion plethysmography) were measured continuously. Total and forearm vascular conductance (TVC and FVC, respectfully) were calculated. A change (Δ) in TVC and FVC from steady-state during the last 1 min of CPT was calculated and differences between normoxia and systemic hypoxia were assessed. In men, the reduction in TVC during CPT was greater during hypoxia compared to normoxia (ΔTVC, P = 0.02), whereas ΔTVC did not differ between conditions in women (P = 0.49). In men, ΔFVC did not differ between normoxia and hypoxia (P = 0.92). In women, the reduction in FVC during CPT was attenuated during hypoxia (ΔFVC, P < 0.01). We confirm sympathetically mediated vasoconstriction is preserved or enhanced during hypoxaemia in young men, whereas peripheral vascular responsiveness to sympathetic activation during hypoxaemia is attenuated in young women. The results advance our understanding of sex-related differences in hypoxic vascular control.

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of ß-adrenergic activation.

Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following ß-adrenergic receptor blockade. In accordance, we also reveal that insulin augments ß-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of ß-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.

Sex differences in integrated neurocardiovascular control of blood pressure following acute intermittent hypercapnic hypoxia.

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.

Sympathetically mediated increases in cardiac output, not restraint of peripheral vasodilation, contribute to blood pressure maintenance during hyperinsulinemia.

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY 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.

Sympathetic neural recruitment strategies following acute intermittent hypoxia in humans.

We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing patterns and the role of the carotid chemoreceptors. We hypothesized exposure to acute IH would increase muscle sympathetic nerve activity (MSNA) via an increase in action potential (AP) discharge rates and within-burst firing. We further hypothesized any change in discharge patterns would be attenuated during acute chemoreceptor deactivation (hyperoxia). MSNA (microneurography) was assessed in 17 healthy adults (11 male/6 female; 31 ± 1 yr) during normoxic rest before and after 30 min of experimental IH. Prior to and following IH, participants were exposed to 2 min of 100% oxygen (hyperoxia). AP patterns were studied from the filtered raw MSNA signal using wavelet-based methodology. Compared with baseline, multiunit MSNA burst incidence (P < 0.01), AP incidence (P = 0.01), and AP content per burst (P = 0.01) were increased following IH. There was an increase in the probability of a particular AP cluster firing once (P < 0.01) and more than once (P = 0.03) per burst following IH. There was no effect of hyperoxia on multiunit MSNA at baseline or following IH (P > 0.05); however, hyperoxia following IH attenuated the probability of particular AP clusters firing more than once per burst (P < 0.01). Acute IH increases MSNA by increasing AP discharge rates and within-burst firing. A portion of the increase in within-burst firing following IH can be attributed to the carotid chemoreceptors. These data advance the mechanistic understanding of sympathetic activation following acute IH in humans.