Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans.

PURPOSE: Previous work has shown nitric oxide (NO) contributes to ~15% of the hyperemic response to dynamic exercise in healthy humans. This NO-mediated vasodilation occurs, in part, via increases in intracellular cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase. We sought to examine the effect of phosphodiesterase-5 (PDE-5) inhibition on forearm blood flow (FBF) responses to dynamic handgrip exercise in healthy humans and the role of NO. We hypothesized exercise hyperemia would be augmented by sildenafil citrate (SDF, PDE-5 inhibitor). We further hypothesized any effect of SDF on exercise hyperemia would be abolished with intra-arterial infusion of the NO synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA). METHODS: FBF (Doppler ultrasound) was assessed at rest and during 5 min of dynamic forearm handgrip exercise at 15% of maximal voluntary contraction under control (saline) conditions and during 3 experimental protocols: (1) oral SDF (n = 10), (2) intra-arterial L-NMMA (n = 20), (3) SDF and L-NMMA (n = 10). FBF responses to intra-arterial sodium nitroprusside (NTP, NO donor) were also assessed. RESULTS: FBF increased with exercise (p < 0.01). Intra-arterial infusion of L-NMMA resulted in a reduction in exercise hyperemia (17 ± 1 to 15 ± 1 mL/dL/min, p < 0.01). Although the hyperemic response to NTP was augmented by SDF (area under the curve: 41 ± 7 vs 61 ± 11 AU, p < 0.01), there was no effect of SDF on exercise hyperemia (p = 0.33). CONCLUSIONS: Despite improving NTP-mediated vasodilation, oral SDF failed to augment exercise hyperemia in young, healthy adults. These observations reflect a minor contribution of NO and the cGMP pathway during exercise hyperemia in healthy young humans.

Interactions between beta-2 adrenoceptor gene variation, cardiovascular control and dietary sodium in healthy young adults.

Dietary sodium affects function of the beta-2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2-mediated forearm vasodilation in the high sodium condition. Seventy-one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross-over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg(-1) protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6  fmol mg(-1) protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell-based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans.

Influence of locomotor muscle afferent inhibition on the ventilatory response to exercise in heart failure.

NEW FINDINGS: What is the central question of this study? Patients with heart failure often develop ventilatory abnormalities at rest and during exercise, but the mechanisms underlying these abnormalities remain unclear. This study investigated the influence of inhibiting afferent neural feedback from locomotor muscles on the ventilatory response during exercise in heart failure patients. What is the main finding and its importance? Our results suggest that inhibiting afferent feedback from locomotor muscle via intrathecal opioid administration significantly reduces the ventilatory response to exercise in heart failure patients. Patients with heart failure (HF) develop ventilatory abnormalities at rest and during exercise, but the mechanism(s) underlying these abnormalities remain unclear. We examined whether the inhibition of afferent neural feedback from locomotor muscles during exercise reduces exercise ventilation in HF patients. In a randomized, placebo-controlled design, nine HF patients (age, 60 ± 2 years; ejection fraction, 27 ± 2%; New York Heart Association class 2 ± 1) and nine control subjects (age, 63 ± 2 years) underwent constant-work submaximal cycling (65% peak power) with intrathecal fentanyl (impairing the cephalad projection of opioid receptor-sensitive afferents) or sham injection. The hypercapnic ventilatory response was measured to determine whether cephalad migration of fentanyl occurred. There were no differences in hypercapnic ventilatory response within or between groups in either condition. Despite a lack of change in ventilation, tidal volume or respiratory rate, HF patients had a mild increase in arterial carbon dioxide (P(aCO(2)) and a decrease in oxygen (P(aO(2)); P < 0.05 for both) at rest. The control subjects demonstrated no change in P(aCO(2)), P(aO(2)), ventilation, tidal volume or respiratory rate at rest. In response to fentanyl during exercise, HF patients had a reduction in ventilation (63 ± 6 versus 44 ± 3 l min(-1), P < 0.05) due to a lower respiratory rate (30 ± 1 versus 26 ± 2 breaths min(-1), P < 0.05). The reduced ventilation resulted in lower P aO 2 (97.6 ± 2.5 versus 79.5 ± 3.0 mmHg, P < 0.05) and increased P(aCO(2)) (37.3 ± 0.9 versus 43.5 ± 1.1 mmHg, P < 0.05), with significant improvement in ventilatory efficiency (reduction in the ventilatory equivalent for carbon dioxide; P < 0.05 for all). The control subjects had no change in ventilation or measures of arterial blood gases. These data suggest that inhibition of afferent feedback from locomotor muscle significantly reduces the ventilatory response to exercise in HF patients.

The psychological and physiological effects of acute occupational stress in new anesthesiology residents: a pilot trial.

BACKGROUND: Occupational stress in resident physicians has profound implications for wellness, professionalism, and patient care. This observational pilot trial measured psychological and physiological stress biomarkers before, during, and after the start of anesthesia residency. METHODS: Eighteen physician interns scheduled to begin anesthesia residency were recruited for evaluation at three time points: baseline (collected remotely before residency in June 2013); first-month visit 1 (July); and follow-up visit 2 (residency months 3 to 5, September-November). Validated scales were used to measure stress, anxiety, resilience, and wellness at all three time points. During visits 1 and 2, the authors measured resting heart-rate variability, responses to laboratory mental stress (hemodynamic, catecholamine, cortisol, and interleukin-6), and chronic stress indices (C-reactive protein, 24-h ambulatory heart rate and blood pressure, 24-h urinary cortisol and catecholamines, overnight heart-rate variability). RESULTS: Thirteen interns agreed to participate (72% enrollment). There were seven men and six women, aged 27 to 33 yr. The mean ± SD of all study variables are reported. CONCLUSION: The novelty of this report is the prospective design in a defined cohort of residents newly exposed to the similar occupational stress of the operating environment. Because of the paucity of literature specific to the measures and stress conditions in this investigation, no data were available to generate a priori definition of primary outcomes and a data analytic plan. These findings will allow power analysis for future design of trials examining occupational stress and stress-reducing interventions. Given the importance of physician burnout in our country, the impact of chronic stress on resident wellness requires further study.

Cyclo-oxygenase-2 inhibition and endothelium-dependent vasodilation in younger vs. older healthy adults.

AIM: A major feature of endothelial dysfunction is reduced endothelium-dependent vasodilation, which in ageing may be due to decreased production of endothelial prostacyclin, or nitric oxide (NO), or both. METHOD: We tested this hypothesis in 12 younger (age 18-38 years, six women) and 12 older healthy adults (age 55-73 years, six post-menopausal women). Endothelium-dependent vasodilation was assessed by the forearm vascular conductance (FVC) response to intra-arterial acetylcholine (ACh) (0.5, 1.0, 2.0, 4.0 µg dl(-1) forearm tissue min(-1) ) before and 90 min after inhibition of the enzyme cyclo-oxygenase-2 (COX-2) with oral celecoxib (400 mg), followed by the addition of endothelial NO synthase inhibition with intra-arterial N(G) -monomethyl-l arginine acetate (L-NMMA). RESULTS: Ageing was associated with a significantly reduced FVC response to ACh (P = 0.009, age-by-dose interaction; highest dose FVC ± SEM in ageing: 11.2 ± 1.4 vs. younger: 17.7 ± 2.4 units, P = 0.02). Celecoxib did not reduce resting FVC or the responses to ACh in any group. L-NMMA significantly reduced resting FVC and the responses to ACh in all groups, and absolute FVC values following L-NMMA were similar between groups. CONCLUSION: In healthy normotensive younger and older adults, there is minimal contribution of prostacyclin to ACh-mediated vasodilation, yet the NO component of vasodilation is reduced with ageing. In the clinical context, these findings suggest that acute administration of medications that inhibit prostacyclin (i.e. COX-2 inhibitors) evoke modest vascular consequences in healthy persons. Additional studies are necessary to test whether chronic use of COX-2 medications reduces endothelium dependent vasodilation in older persons with or without cardiovascular risk factors.

Outcomes after radical prostatectomy for cancer: a comparison between general anesthesia and epidural anesthesia with fentanyl analgesia: a matched cohort study.

BACKGROUND: The use of regional anesthesia for cancer surgery has been associated with improved oncologic outcomes. One of the proposed mechanisms is a reduction in the use of systemic opioids that may cause immunosuppression. We used a retrospective matched cohort design to compare long-term oncologic outcomes after prostatectomy for cancer performed under general anesthesia with systemic opioids or with epidural anesthesia with epidural fentanyl analgesia. Since epidural fentanyl is quickly reabsorbed systemically, we hypothesized that there would be no difference in long-term oncological outcomes between the 2 groups. METHODS: There were 486 men who underwent prostatectomy performed under epidural anesthesia between January 1, 1991, and January 31, 1996. They were 1:1 matched based on age (±5 years), surgical year (±1 year), and baseline prostate cancer pathology to patients who had general anesthesia with systemic opioids. Long-term cancer outcomes and all-cause mortality were examined. Analyses were performed using stratified proportional hazards regression models, with hazard ratios >1 indicating worse outcome for general anesthesia only compared with epidural anesthesia and fentanyl analgesia. RESULTS: After adjusting for positive surgical margins and adjuvant therapies, patients in the general anesthesia group were found not to be at increased risk of prostate cancer recurrence (hazard ratio [HR] = 0.79, 95% confidence interval [CI], 0.60-1.04], systemic tumor progression (HR = 0.92, 95% CI, 0.46-1.84), cancer-specific mortality (HR = 0.53, 95% CI, 0.18-1.58), or overall mortality (HR = 1.23, 95% CI 0.93-1.63) when compared with patients who received epidural anesthesia. CONCLUSIONS: Compared with general anesthesia with systemic opioids, epidural anesthesia and analgesia with fentanyl were not associated with improvement in oncologic outcomes in patients undergoing radical prostatectomy for cancer.

Autonomic function following endoscopic thoracic sympathotomy for hyperhidrosis.

PURPOSE: Primary palmar-plantar hyperhidrosis is the condition of excessive sweating of the hands and feet. For severe and medically refractory cases, endoscopic thoracic sympathotomy (ETS) is a bilateral ganglion-sparing disconnection between the stellate and T2 ganglion in an effort to minimize compensatory hyperhidrosis. The purpose of this study was to determine the effect of ETS on cardiac autonomic function. METHODS: Participants in this study were 22 otherwise healthy hyperhidrosis patients with 17 returning 1-12 months after surgery. Heart rate (HR) and blood pressure were collected at rest and during sequential nitroprusside/phenylephrine infusion (modified Oxford). To determine change in cardiac autonomic function, heart rate variability indices of RMSSD, LF and HF (log, nu) power were calculated. Sequential baroreflex sensitivity was also calculated. RESULTS: After surgery, resting HR on standardized ECG tended to be lower and reached significance during the modified Oxford baseline (p < 0.001). HRV changed significantly between assessments with an increase in HF (nu) and decrease in LF (nu) and LF (log) spectral ranges (p < 0.05), while the increase in RMSSD was marginally significant (p < 0.06). Compared with matched controls, HRV indices were significantly different before surgery, but similar after surgery. No change was detected in resting sequential baroreflex sensitivity, baroslope obtained by modified Oxford or QTc interval. CONCLUSIONS: We conclude that ETS changes cardiac autonomic modulation of HR to levels similar to controls. Despite the minimally destructive nature of ETS, effects on HRV are consistent with previously reported post-sympathectomy blunting of exaggerated sympathetic control associated with hyperhidrosis. No significant changes in the baroreflex indices suggest that ETS did not significantly affect blood pressure regulation.

Hemodynamics following endoscopic thoracic sympathotomy for palmar hyperhidrosis.

PURPOSE: We studied patients with palmar hyperhidrosis before and after endoscopic thoracic sympathotomy (ETS) to determine the effect of chronic sympathetic denervation on (1) forearm blood flow (FBF) response to mental stress and (2) exercise tolerance. METHODS AND RESULTS: Twenty-two healthy patients were evaluated before ETS, and 17 returned after surgery (11 F; 19-32 years). We measured heart rate (HR; 12 lead), blood pressure, and FBF (plethysmography, ml dl(-1) min(-1)). Supine HR tended to decrease after ETS (69 ± 10 vs. 66 ± 6, p = 0.2). Mental stress FBF was recorded during baseline, 3-min Stroop color word test, and 2-min recovery. Mental stress responses were unaffected by ETS. However, during post-mental stress recovery period, ETS resulted in a significant elevation in FBF (2 ± 1 vs. 3 ± 1), FVC (3 ± 1 vs. 4 ± 2), and a decrease in FVR (52 ± 22 vs. 32 ± 16, p < 0.01 for all). ETS resulted in a reduction in pre-exercise seated baseline HR (94 ± 2.5 beats/min preoperatively vs. 84 ± 4.3 beats/min postoperatively, p < 0.05), maximal HR response to cycle exercise, and exercise systolic blood pressure (172 ± 5.2 mmHg pre-op vs. 158 ± 5.9 mmHg post-op, p < 0.05) but not mean or diastolic pressure. VO(2)max and exercise duration determined by cycle ergometry was unchanged. CONCLUSIONS: Functional evidence of upper limb denervation is observed during the FBF recovery period from mental stress and hemodynamic alterations associated with upright cycle exercise. However, the sustained exercise capacity suggests modest clinical consequences.

What we talk about when we talk with medical students.

In this article, we review how we interact with medical students in our efforts to teach blood pressure regulation and systemic cardiovascular control along with related elements of respiratory and exercise physiology. Rather than provide a detailed lecture with key facts, we attempted to outline our approach to teaching integrative cardiovascular physiology to medical students, which includes five major themes. First, focus on questions versus answers and facts. We believe that this offers both the learner and teacher a number of advantages. Second, avoid teaching dogma in the name of clarity (i.e., heavy focus on teaching "facts" that have not yet been fully investigated). This is especially important because of the way knowledge evolves over time. Third, include laboratory-based experiences in human integrative physiology. Fourth, provide students with intellectual frameworks versus a list of "facts" to serve as a platform for question generation. Finally, focus on the role of integration and regulatory redundancy in physiology and the idea that physiology is a narrative that can help. In this article, we discuss the philosophy behind the themes outlined above and argue that questions, and not answers, are where the action is for both research and education.

Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise.

We tested the hypotheses that (1) nitric oxide (NO) contributes to augmented skeletal muscle vasodilatation during hypoxic exercise and (2) the combined inhibition of NO production and adenosine receptor activation would attenuate the augmented vasodilatation during hypoxic exercise more than NO inhibition alone. In separate protocols subjects performed forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O(2) saturation). In protocol 1 (n = 12), subjects received intra-arterial administration of saline (control) and the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA). In protocol 2 (n = 10), subjects received intra-arterial saline (control) and combined L-NMMA-aminophylline (adenosine receptor antagonist) administration. Forearm vascular conductance (FVC; ml min(-1) (100 mmHg)(-1)) was calculated from forearm blood flow (ml min(-1)) and blood pressure (mmHg). In protocol 1, the change in FVC (Delta from normoxic baseline) due to hypoxia under resting conditions and during hypoxic exercise was substantially lower with L-NMMA administration compared to saline (control; P < 0.01). In protocol 2, administration of combined L-NMMA-aminophylline reduced the DeltaFVC due to hypoxic exercise compared to saline (control; P < 0.01). However, the relative reduction in DeltaFVC compared to the respective control (saline) conditions was similar between L-NMMA only (protocol 1) and combined L-NMMA-aminophylline (protocol 2) at 10% (-17.5 +/- 3.7 vs. -21.4 +/- 5.2%; P = 0.28) and 20% (-13.4 +/- 3.5 vs. -18.8 +/- 4.5%; P = 0.18) hypoxic exercise. These findings suggest that NO contributes to the augmented vasodilatation observed during hypoxic exercise independent of adenosine.

Effects of respiratory muscle work on blood flow distribution during exercise in heart failure.

Heart failure (HF) patients have a reduced cardiac reserve and increased work of breathing. Increased locomotor muscle blood flow demand may result in competition between respiratory and locomotor vascular beds. We hypothesized that HF patients would demonstrate improved locomotor blood flow with respiratory muscle unloading during activity. Ten patients (ejection fraction = 31 +/- 3%) and 10 controls (CTL) underwent two cycling sessions (60% peak work). Session 1 (S1): 5 min of normal breathing (NB), 5 min respiratory muscle unloading with a ventilator, and 5 min of NB. Session 2 (S2): 5 min NB, 5 min of respiratory muscle loading with inspiratory resistance, and 5 min of NB. Measurements included: leg blood flow (LBF, thermodilution), cardiac output (Q), and oesophageal pressure (P(pl), index of pleural pressure). S1: P(pl) was reduced in both groups (HF: 73 +/- 8%; CTL: 60 +/- 13%, P < 0.01). HF: Q increased (9.6 +/- 0.4 vs. 11.3 +/- 0.8 l min(-1), P < 0.05) and LBF increased (4.8 +/- 0.8 vs. 7.3 +/- 1.1 l min(-1), P < 0.01); CTL: no changes in Q (14.7 +/- 1.0 vs. 14.8 +/- 1.6 l min(-1)) or LBF (10.9 +/- 1.8 vs. 10.3 +/- 1.7 l min(-1)). S2: P(pl) increased in both groups (HF: 172 +/- 16%, CTL: 220 +/- 40%, P < 0.01). HF: no change was observed in Q(10.0 +/- 0.4 vs. 10.3 +/- 0.8 l min(-1)) or LBF (5.0 +/- 0.6 vs. 4.7 +/- 0.5 l min(-1)); CTL: increased (15.4 +/- 1.4 vs. 16.9 +/- 1.5 l min(-1), P < 0.01) and LBF remained unchanged (10.7 +/- 1.5 vs. 10.3 +/- 1.8 l min(-1)). These data suggest HF patients preferentially steal blood flow from locomotor muscles to accommodate the work of breathing during activity. Further, HF patients are unable to vasoconstrict locomotor vascular beds beyond NB when presented with a respiratory load.

beta2-Adrenoceptor gene variation and systemic vasodilatation during ganglionic blockade.

Regional infusions of beta(2)-adrenoceptor (ADRB2) agonist have generally shown that individuals homozygous for Gly16 produces greater vasodilatation than those homozygous for Arg16. Systemic infusions have shown an opposite effect on systemic vascular resistance (SVR), possibly confounded by baroreflexes or interactions between single nucleotide polymorphism (SNP) positions 16 and 27. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (Terb) during ganglionic blockade. Forty healthy young adults were recruited according to the double homozygous haplotypes: Arg16 + Gln27 (n = 13), the rare Gly16 + Gln27 (n = 6), and Gly16 + Glu27 (n = 21). Arterial pressure was measured by brachial arterial catheter, and cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3-7 mg min(1)), continuous phenylephrine was titrated to restore blood pressure to baseline. Terb was infused i.v. at 33 and 67 ng kg(1) min(1) for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR (P = 0.06). For SNP position 16, the highest dose of Terb produced lower SVR in Gly16 (mean +/- s.e.m.: 7.5 +/- 0.4) vs. Arg16 (8.9 +/- 0.7 units; P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs. Arg16 (P = 0.05). We conclude that during ganglionic blockade, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16 + Glu27 homozygotes, with greater influence from Gly16, providing further evidence that ADRB2 gene variation influences vasodilatation.

{beta}-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype.

Intermediate physiological phenotype is the genetic and environmental influence on functional physiological characteristics with direct prognostic relevance to distant, more complex phenotypes, such as cardiovascular and metabolic disease. Increasingly available and affordable genotyping techniques have created an explosion of information on candidate gene variation and its relationship to intermediate physiological traits. Variation in beta-adrenoceptor genes is an intense focus of investigation because beta-adrenoceptors are: (1) ubiquitous in organ system distribution; (2) integral to a multitude of physiological processes; (3) well described in cardiovascular and metabolic disease; and (4) major pharmacological treatment targets. Furthermore, knowledge of functional gene variants in these receptors predates the description of the human genome. This review highlights the influence of common gene variation in the three beta-adrenoceptor subtypes on intermediate physiological phenotype predictive of cardiovascular disease and obesity. Although further information is needed to replicate this information across populations, this review condenses and summarizes growing trends in specific pleiotropic effects of beta-adrenoceptor polymorphisms and suggests which variants may be predictive of distant phenotype.

Forearm vascular conductance during mental stress is related to the heart rate response.

The forearm vasodilator response to mental stress is multifactorial and widely variable among individuals. We evaluated the association between the heart rate and forearm vascular conductance (FVC) responses to a color word test in 101 healthy adults. We found a striking correlation between heart rate and FVC (r = 0.66, P < 0.001), which remained significant when controlling for subject characteristics, blood pressure, and catecholamines. This suggests that the mechanical stimulation is one of the key factors that contribute to the increase in FVC during mental stress.

Cardiovascular dynamics in healthy subjects with differing heart rate responses to tilt.

Orthostatic stress such as head-up tilt (HUT) elicits a wide range of heart rate (HR) and arterial pressure (AP) responses among healthy individuals. In this study, we evaluated cardiovascular dynamics in healthy subjects with different HR responses to HUT, but without autonomic dysfunction. We measured AP (brachial artery) and HR (ECG) during 5 min of 60 degrees HUT in 76 healthy normotensive individuals. We then chose individuals on the basis of the extremes of HR responses to HUT (high = DeltaHR > or = 20 beats/min, and low = DeltaHR < or = 10 beats/min; n = 15 per group). Peak HR during HUT was 87 +/- 10 beats/min in the high and 69 +/- 14 beats/min in the low group (P < 0.05). High HR responders had lower systolic pressure at baseline (121 +/- 9 vs. 129 +/- 11 mmHg, P < 0.05) and during HUT (120 +/- 10 vs. 131 +/- 13 mmHg, P < 0.05), and higher plasma norepinephrine (NE) response to HUT (DeltaNE: 156.9 +/- 17.8 vs. 89.0 +/- 17.2 pg/ml; P < 0.05). DeltaNE during HUT was also significantly correlated with DeltaHR when all 76 subjects were included in a regression analysis (r = 0.39; P < 0.001). Pulse pressure was lower during HUT in high HR responders compared with low HR responders (45 +/- 1 vs. 55 +/- 2 mmHg, P < 0.05). High HR responders also had larger fluctuations in systolic and pulse pressure during HUT (coefficient of variation = 10.7 +/- 0.7 vs. 5.7 +/- 0.3%; 7.9 +/- 0.5 vs. 4.1 +/- 0.4%, respectively, P < 0.05). Sex distribution was different between groups (high: 5 women, 10 men; low: 10 women, 5 men). Higher HR with lower AP during HUT is consistent with normal baroreflex mechanisms of integration. Although interindividual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the sex discrepancy requires further investigation.

Reduced stroke volume during exercise in postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is characterized by excessive tachycardia without hypotension during orthostasis. Most POTS patients also report exercise intolerance. To assess cardiovascular regulation during exercise in POTS, patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter), heart rate (HR; measured by ECG), and cardiac output (open-circuit acetylene breathing) were measured. In both positions, mean arterial pressure, cardiac output, and total peripheral resistance at rest and during exercise were similar in patients and controls (P > 0.05). However, supine stroke volume (SV) tended to be lower in the patients than controls at rest (99 +/- 5 vs. 110 +/- 9 ml) and during 75-W exercise (97 +/- 5 vs. 111 +/- 7 ml) (P = 0.07), and HR was higher in the patients than controls at rest (76 +/- 3 vs. 62 +/- 4 beats/min) and during 75-W exercise (127 +/- 3 vs. 114 +/- 5 beats/min) (both P < 0.01). Upright SV was significantly lower in the patients than controls at rest (57 +/- 3 vs. 81 +/- 6 ml) and during 75-W exercise (70 +/- 4 vs. 94 +/- 6 ml) (both P < 0.01), and HR was much higher in the patients than controls at rest (103 +/- 3 vs. 81 +/- 4 beats/min) and during 75-W exercise (164 +/- 3 vs. 131 +/- 7 beats/min) (both P < 0.001). The change (upright - supine) in SV was inversely correlated with the change in HR for all participants at rest (R(2) = 0.32), at 25 W (R(2) = 0.49), 50 W (R(2) = 0.60), and 75 W (R(2) = 0.32) (P < 0.01). These results suggest that greater elevation in HR in POTS patients during exercise, especially while upright, was secondary to reduced SV and associated with exercise intolerance.

Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety.

Postural tachycardia syndrome (POTS) is characterized by excessive increases in heart rate (HR) without hypotension during orthostasis. The relationship between the tachycardia and anxiety is uncertain. Therefore, we tested whether the HR response to orthostatic stress in POTS is primarily related to psychological factors. POTS patients (n = 14) and healthy controls (n = 10) underwent graded venous pooling with lower body negative pressure (LBNP) to -40 mmHg while wearing deflated antishock trousers. "Sham" venous pooling was performed by 1) trouser inflation to 5 mmHg during LBNP and 2) vacuum pump activation without LBNP. HR responses to mental stress were also measured in both groups, and a questionnaire was used to measure psychological parameters. During LBNP, HR in POTS patients increased 39 +/- 5 beats/min vs. 19 +/- 3 beats/min in control subjects at -40 mmHg (P < 0.01). LBNP with trouser inflation markedly blunted the HR responses in the patients (9 +/- 2 beats/min) and controls (2 +/- 1 beats/min), and there was no HR increase during vacuum application without LBNP in either group. HR responses during mental stress were not different in the patients and controls (18 +/- 2 vs. 19 +/- 1 beats/min; P > 0.6). Anxiety, somatic vigilance, and catastrophic cognitions were significantly higher in the patients (P < 0.05), but they were not related to the HR responses during LBNP or mental stress (P > 0.1). These results suggest that the HR response to orthostatic stress in POTS patients is not caused by anxiety but that it is a physiological response that maintains arterial pressure during venous pooling.

Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome.

Patients with postural tachycardia syndrome (POTS) have excessive tachycardia without hypotension during orthostasis as well as exercise. We tested the hypothesis that excessive tachycardia during exercise in POTS is not related to abnormal baroreflex control of heart rate (HR). Patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter) and HR (ECG) were measured. Baroreflex sensitivity of HR was assessed by bolus intravenous infusion of phenylephrine at each workload. In both positions, HR was higher in the patients than the controls during exercise. Supine baroreflex sensitivity (HR/systolic pressure) in POTS patients was -1.3 +/- 0.1 beats.min(-1).mmHg(-1) at rest and decreased to -0.6 +/- 0.1 beats.min(-1).mmHg(-1) during 75-W exercise, neither significantly different from the controls (P > 0.6). In the upright position, baroreflex sensitivity in POTS patients at rest (-1.4 +/- 0.1 beats.min(-1).mmHg(-1)) was higher than the controls (-1.0 +/- 0.1 beats.min(-1).mmHg(-1)) (P < 0.05), and it decreased to -0.1 +/- 0.04 beats.min(-1).mmHg(-1) during 75-W exercise, lower than the controls (-0.3 +/- 0.09 beats.min(-1).mmHg(-1)) (P < 0.05). The reduced arterial baroreflex sensitivity of HR during upright exercise was accompanied by greater fluctuations in systolic and pulse pressure in the patients than in the controls with 56 and 90% higher coefficient of variations, respectively (P < 0.01). However, when baroreflex control of HR was corrected for differences in HR, it was similar between the patients and controls during upright exercise. These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR.

Reduced forearm alpha1-adrenergic vasoconstriction is associated with enhanced heart rate fluctuations in humans.

In the present study, we assessed whether heart rate (HR) or arterial pressure fluctuations are enhanced in healthy young humans with reduced alpha-adrenergic vasoconstrictor responses and, if so, whether this occurs for both alpha1- and alpha2-adrenergic receptor-mediated vasoconstriction. Arterial pressure (brachial artery catheter) and HR (ECG) were monitored continuously, and alpha1- and alpha2-adrenergic responsiveness was determined by assessing the effects of brachial artery infusions of phenylephrine (alpha1-adrenergic agonist) and dexmedetomidine (alpha2-adrenergic agonist), respectively, on forearm blood flow (strain gauge plethysmography). alpha1-Adrenergic responsiveness varied markedly among the subjects (n=20) and was inversely correlated with coefficient of variation for HR (R2=0.37, P<0.01), whereas the responsiveness was not correlated with the coefficient of variation for either systolic or diastolic arterial pressure. alpha1-Adrenergic responsiveness was inversely and more strongly correlated with baroreflex sensitivity (R2=0.62, P<0.0001), determined from beat-to-beat changes in HR and systolic arterial pressure, than the coefficient of variation for HR. On the other hand, alpha2-adrenergic responsiveness was not correlated with any of the parameters determined above. These results suggest that, in healthy young subjects, the enhanced HR response to changes in systolic pressure helps maintain the stability of arterial blood pressure when alpha1-adrenergic responsiveness is reduced.

Influences of adenosine receptor antagonism on vasodilator responses to adenosine and exercise in adenosine responders and nonresponders.

We previously demonstrated a bimodal distribution of vasodilator responsiveness to adenosine (Ado) infusion in human subjects, despite similar responses to exercise between subgroups [subjects responsive to Ado infusion (Ado responders) and subjects with blunted vasodilator responses to Ado infusion (Ado nonresponders]). (Martin EA, Nicholson WT, Eisenach JH, Charkoudian N, and Joyner MJ. J Appl Physiol 101: 492-499, 2006). A component of this difference was attributed to a larger nitric oxide component of Ado-mediated vasodilation in responders. However, there may also be differences in Ado receptors between these subgroups. We hypothesized that Ado receptor antagonism would reduce vasodilator responsiveness to Ado and exercise only in Ado responders. To test this hypothesis, we compared forearm vasodilation induced by intra-arterial infusion of three doses of Ado to vasodilation during three workloads of forearm handgrip exercise before and after Ado receptor antagonism with aminophylline (Aph) in 19 subjects. In Ado responders, the change in forearm vascular conductance above baseline for the low, medium, and high doses of Ado, respectively, was 93 +/- 16, 140 +/- 14, 194 +/- 18 before Aph and 27 +/- 12, 71 +/- 19, and 134 +/- 34 ml.min(-1).100 mmHg(-1) after Aph (P < 0.05 for low and medium dose before vs. after Aph). For nonresponders, these values were 30 +/- 5, 39 +/- 6, and 78 +/- 9 ml.min(-1).100 mmHg(-1) before Aph (P < 0.05 vs. responders), with no difference after Aph (P > 0.05). We found that Ado receptor blockade significantly inhibited exercise hyperemia only at high workloads in both responders and nonresponders (P < 0.05 before vs. after Aph). We conclude that there may be reduced Ado receptor responsiveness or sensitivity in nonresponders. Furthermore, Ado may play a limited role exercise hyperemia in both subgroups.