Treatment with 75 U/kg rhAT is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation in the majority of heparin-resistant patients. Treating heparin-resistant patients with rhAT may decrease the requirement for heparin and fresh frozen plasma.

Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.

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.

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 µg·kg·min, n = 13) or PE (0.2-1.0 µg·kg·min, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Repetitive hypoxic apneas, similar to that 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 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. Herein we examined sex-related differences in the effect of IH on sympathetic control of BP in humans. We hypothesized following acute IH, we would observe a rise in muscle sympathetic nerve activity (MSNA) and arterial BP in young men (n=30) which would be absent in young women (n=19). BP and MSNA were measured during normoxic rest prior to and following 30-minutes 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 following 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 any BP-raising effects of IH are absent in young women. These data enhance our understanding of sex-specific mechanisms which may contribute to BP changes in sleep apnea.

PURPOSE Sympathetic nervous system responses to voluntary apnea are increased by hypoxia and attenuated by hyperoxia. However, whether neural firing and recruitment strategies in response to apnea can be modified by hypoxia and/or hyperoxia were previously unknown. We examined the influence of chemoreceptor stimuli on sympathetic neural firing and recruitment strategies during voluntary end‐expiratory apnea. We hypothesized increases in the firing frequency and probability of low‐threshold axons during apnea would be exaggerated during hypoxia and attenuated during hyperoxia. METHODS Multi‐unit muscle sympathetic nerve activity (MSNA, microneurography) was measured in 10 young, healthy men (31±2 yrs, 25±1 kg/m2). Data were collected at baseline and during maximal voluntary end‐expiratory apnea under normoxic (SpO2: 98±1%), hypoxic (FiO2: 0.17±0.01; SpO2: 82±1%), and hyperoxic (FiO2: 0.92±0.03; SpO2: 100±0%) conditions. Condition order was randomized and trials were separated by a minimum of 15‐min quiet normoxic rest. Action potential (AP) patterns were studied from the filtered raw signal using wavelet‐based methodology. Data are reported from the last 2‐min of baseline and during the second half of apnea, reflecting the time of highest MSNA. RESULTS There was an increase in multi‐unit MSNA (24±3 to 35±3 bursts/min, p=0.04) during normoxic apnea, which was due to an increase in the frequency and incidence of AP spikes (243±75 to 519±134 AP/min, p=0.048; 412±133 to 773±185 AP/100 heart beats, p=0.04). An increase in the probability of AP firing more than once per burst was also observed (p=0.01). There was an increase in multi‐unit MSNA (20±4 to 46±7 bursts/min, p<0.01) during hypoxic apnea that was due to an increase in the frequency and incidence of AP spikes (192±59 to 952±266 AP/min, p<0.01; 326±89 to 1212±327 AP/100 heart beats, p<0.01). Hypoxic apnea also resulted in an increase in the probability of AP firing more than once per burst (p<0.01). Hyperoxia attenuated any increase in MSNA with apnea, such that no changes in multi‐unit MSNA (24±4 to 28±5 bursts/min, p=0.14) nor frequency or incidence of AP spikes (155±35 to 253±71 AP/min, p=0.12; 249±61 to 502±188 AP/100 heart beats, p=0.28) were observed. Hyperoxia also attenuated any increase in the probability of AP firing more than once per burst (p=0.47). CONCLUSION These data are the first to show neural firing and recruitment strategies in response to voluntary end‐expiratory apnea are modified by hypoxia and hyperoxia. Our results demonstrate that hypoxic apnea increases the frequency and incidence of action potential spikes, as well as the probability of multiple within‐burst firing; whereas this response was suppressed when individuals were hyperoxic. These data may have important implications for neural control of the circulation in recreational activities (i.e. diving) and/or clinical conditions prone to apnea (i.e. sleep apnea). Support or Funding Information FUNDING: AHA #15SDG25080095, NIH HL130339, Natural Sciences and Engineering Research Counc...

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.

Background: Sex-related differences in respiratory modulation of sympathetic activity have been observed in rodent models of sleep apnea (intermittent hypoxia, IH). Based on 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 respiratory modulation of MSNA would be altered in both male and female participants following IH; however, the respiratory patterning of MSNA following IH would be sex-specific. Methods: Heart rate, MSNA and respiration were evaluated in healthy male (n=21, 30±5 yrs) and female (n=10, 28±5 yrs) participants during normoxic rest prior to and following 30-min of IH. 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 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. Following IH, modulation of MSNA within the breath was reduced in male participants (p=0.03), but increased in females (p=0.02). Conclusion: Both male and female adults exhibit changes in respiratory patterning of MSNA following 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.