Eisenach, John H.

We previously reported that augmented skeletal muscle vasodilation during mild hypoxic forearm exercise includes beta‐adrenergic mechanisms. Furthermore, hypoxic vasodilation at rest is known to include beta‐adrenergic mediated nitric oxide (NO) production. Therefore, we tested the hypothesis that NO contributes to augmented vasodilation with hypoxic exercise. Twelve subjects (6M/6F; 26 ± 2 years) breathed hypoxic gas to titrate arterial O 2 saturation to 80% while remaining normocapnic via a rebreath system. Subjects performed incremental forearm exercise (10% and 20% of maximum) during saline infusion (control) and NO synthase inhibition ( N G ‐monomethyl‐L‐arginine; L‐NMMA) under normoxic and hypoxic conditions. Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from blood flow (ml/min) and blood pressure (mmHg). During the control condition, the rise in FVC (Δfrom normoxic baseline) due to hypoxic exercise was 211 ± 23 and 367 ± 34 (10% and 20% respectively). Infusion of L‐NMMA during hypoxic exercise attenuated ΔFVC at 10% (174 ± 20; P < 0.001) and 20% (317 ± 32; P < 0.01) compared to control condition. Our data indicate that NO contributes to the augmented vasodilation observed during hypoxic exercise. Supported by NIH HL‐46493 (MJJ) and AR‐55819 (DPC) and by CTSA RR‐024150.

The sensitivity of the baroreflex control of muscle sympathetic nerve activity (MSNA) represents the responsiveness of MSNA to changes in blood pressure, whereas the baroreflex threshold diagram evaluates the likelihood of a burst occurrence over a range of resting blood pressure values. We hypothesized that the slope of the threshold diagram would show a significant positive correlation with sympathetic baroreflex sensitivity (BRS). We compared BRS calculated by the Modified Oxford technique (ModOx) with the slope and midpoint (T50) values from threshold analysis (threshold) in 10 participants (9M, age 26 yrs ± 3[mean ± SEM]). MSNA (peroneal microneurography) and blood pressure (brachial catheter) were measured at rest and during vasoactive drug boluses (ModOx). A threshold diagram was created for each subject during rest by associating DBP to the % occurrence of a burst over a 4 min period prior to the ModOx drugs. The midpoint (T50) of this diagram was defined as the DBP at which 50% of the diastoles were associated with a burst. ModOx‐derived BRS positively correlated with the slope of the threshold diagram (r = 0.64, P<0.05), but not with the T50 (r =0.11, P > 0.2). Our results suggest that the slope of the threshold diagram may be a better index of ModOx‐derived BRS values compared to more commonly used "spontaneous" baroreflex techniques. NIH HL‐083947

Dehydration in humans decreases orthostatic tolerance and alters sympathetic neural control of the circulation, but the mechanisms involved are unclear. Our goal was to evaluate the role of angiotensin II (AngII) in altering the sympathetic control mechanisms in dehydration. We hypothesized that dehydration would increase resting muscle sympathetic nerve activity (MSNA) and increase sensitivity of baroreflex control of MSNA and that these changes are mediated in part by AngII via AT1 receptors. We measured resting MSNA and baroreflex control of MSNA in healthy young adults under two conditions: euhydration and dehydration after 24 hr fluid restriction. We continuously measured heart rate (ECG), beat‐to‐beat blood pressure (Finometer), central venous pressure (peripherally inserted central catheter) and MSNA (peroneal microneurography) in both conditions. In each condition, measurements were taken before and after 50 mg losartan (AT1 antagonist). Dehydration was associated with a ~52 % increase in resting MSNA, but losartan did not consistently influence resting MSNA. Contrary to our hypothesis, baroreflex sensitivity increased ~39 % following losartan administration during dehydration. Our results confirm the sympathoexcitatory influence of dehydration, but the role of AngII in this process requires further evaluation. Supported by AHA 0750036Z and NIH CTSA UL1‐RR24150.

The augmented skeletal muscle vasodilation during hypoxic exercise is due, in part, to an intensity dependent contribution of beta‐receptor activation. We tested the hypothesis that an adenosine mediated vasodilation increases with hypoxic exercise intensity. Subjects (N=10) breathed hypoxic gas to titrate arterial O 2 saturation to 80% while remaining normocapnic (re‐breath system). Consecutive bouts of forearm exercise (10% and 20% of maximum) were performed under normoxia and hypoxia during phentolamine (alpha‐receptor antagonist) alone and the combination of phentolamine / aminophyline (adenosine receptor antagonist). Exogenous adenosine administered before and after aminophyline established effective receptor blockade. Forearm vascular conductance (FVC; ml/100mmHg/min) was calculated from blood flow (ml/min) and blood pressure (mmHg). During hypoxic exercise, the rise in FVC (Δ from baseline) during phentolamine was 314±30 and 470±37 (10% and 20% respectively). ΔFVC was similar at both 10% (349±45; P=0.3) and 20% (536±47; P=0.2) exercise during hypoxia with combined phentolamine / aminophyline. This occurred despite significant reduction in ΔFVC to exogenous adenosine following phentolamine / aminophyline (P<0.03). Our data suggests that in the absence of overlying vasoconstriction, adenosine does not contribute to the augmented hypoxic exercise hyperemia in humans.

The physiological changes that occur after gastric bypass surgery (GBS) are not well understood but changes in activation of the sympathetic nervous system may be involved. We hypothesized that GBS would be associated with greater sympathetically mediated resting energy expenditure as measured by a greater decrease in REE after beta‐blockade (beta‐REE). Subjects who had undergone GBS (average reduction in BMI of 31.6% from peak, N=7) along with lean (BMI<25 kg/m 2 , N=5) and obese (BMI=35–45 kg/m 2 , N=4) subjects underwent measurements of REE before and after IV propranolol (0.25 mg/kg bolus followed by an infusion of 0.004 mg/kg/min). The decrease in REE (mean±SD) after beta‐blockade tended to be greater in lean (102±58 kcal) compared with obese (−22±100 kcal) and GBS (26±55 kcal) subjects (P=0.06). The decrease in REE after beta‐blockade negatively correlated with the % body fat (r=0.54, P<0.05) and VO 2max (r=0.67, P=0.01) of the subjects, but not with resting catecholamine or leptin levels. We did not find that subjects who had undergone GBS had a significant difference in the amount of their REE that is dependent on sympathetic stimulation. Beta‐REE appears to be related to fitness and also to fatness and the fact that GBS subjects had high body fat even after significant weight loss may explain our results. Support: NIH HL46493, NIH CTSA UL1‐RR24150, Department of Anesthesiology.

Orthostatic stress such as head‐up tilt (HUT) elicits a wide range of HR and BP responses among healthy individuals. In this study, we evaluated cardiovascular dynamics of subjects with different HR responses to HUT but without autonomic dysfunction. We measured BP (brachial artery) and HR (ECG) during 5 min of 60° HUT in 76 healthy young individuals, while norepinephrine (NE) was assayed during the final 30 s. We then chose 30 individuals based on the extremes of HR responses to HUT: 15 with the highest (ΔHR≥ 20 bpm) and 15 with the lowest response (ΔHR ≤10 bpm). Age and BMI were not different between groups; however, gender distribution was different (high: 5F, 10 M; low: 10F, 5M). Peak HR during HUT was 87.2±10.4 bpm in the high and 69.1±14.1 bpm in the low group (P< 0.05). Baseline HR was not different between groups. High HR responders had lower SBP at baseline (120.9±9.4 vs. 129.4±11.0 mmHg) and during HUT (119.9±9.7 vs. 131.4±13.1 mmHg). High HR responders also had higher plasma NE response to HUT (ΔNE: 156.9±82.1 vs. 89.0±48.0 pg/ml; P< 0.05). Higher HR with lower BP during HUT is consistent with normal baroreflex mechanisms of integration. Although inter‐individual variability appears to be a fundamental part of cardiovascular regulation, the mechanisms of these differences and the gender discrepancy requires further investigation. Supported by K23 RR17520, HL46493, NS32352, KL2 RR024151 ‐01.

We recently reported altered cardiovascular structure and function in heart failure (HF) patients based on the Arg16/Gly and Gln27/Glu beta‐2 adrenergic receptor (ADRB2) polymorphisms. The purpose of this study was to extend the echocardiographic analysis based on haplotype combination of ADRB2 at nucleotides −654, 46 79, 252, 491, 523, in a larger database of HF patients (n=126, age 56±1yr, LV ejection fraction, LVEF 29±1%, BMI 28±0.4kg/m 2 , mean±SEM) and healthy controls (n=100, age 50±2yr, LVEF 63±0.7%, BMI 25±0.3kg/m 2 ). The most common haplotypes in both HF and control were 2, 8, and 12 (2=AACGCC, 8=GGCACA, and 12=GGGGCC, for nucleotides −654, 46, 79, 252, 491, and 523). Cardiac function did not differ according to haplotype pairs in the control subjects. In HF, the widest discrepancies were between haplotype pair 2/2 (which includes the Arg16+Gln27 homozygotes) and haplotype pair 12/12 (which includes the Gly16+Glu27 homozygotes), respectively: 2/2 displayed lower cardiac index (2.3±0.1 v 2.7±0.1 l/min/m 2 ), greater left atrial diameter (53±2 v 47±2 mm), shorter LV decel time (185±11 v 224±14 msec), and greater right ventricular pressure (44±2 v 33±2 mmHg) p<0.05 for all). These data suggest that in HF, haplotype variation of the ADRB2 is associated with differences in cardiac function, and SNP positions 16 and 27 remain major loci of interest. Support: K23RR‐17520, HL‐71478.

The ganglionic blocker trimethaphan (TMP) is no longer produced; alternatives are needed to inhibit baroreflex control of the circulation during systemic hemodynamic studies. We tested the hypothesis that combination anti‐cholinergic glycopyrrolate (Gly) and α2 receptor agonist dexmedetomidine (Dex) would inhibit baroreflex buffering in response to vasodilation to a similar degree as ganglionic blockade with TMP. In 2 separate trials, 5 males received an I.V. bolus and infusion of Gly‐Dex, and 11 males received TMP infusion. To offset the fall in blood pressure with TMP, phenylephrine (PE) was used to raise pressure to pre‐TMP baseline. Terbutaline was then infused for 15 minutes at 2 doses (33 and 67 ng/kg/min). Heart rate (HR), blood pressure (BP, oscillometric cuff for Gly‐Dex, brachial arterial line for TMP+PE), and cardiac output (CO, acetylene breathing) were recorded. Resting HR was higher with Gly‐Dex (mean ± SEM: 93±7mmHg) than TMP+PE (74±3mmHg, p<0.001) but resting BP, CO, stroke volume (SV), and total peripheral resistance (TPR) were similar between Gly‐Dex and TMP+PE. The cardiovascular responses to terbutaline were similar between Gly‐Dex and TMP+PE, except for the increase in CO which was significantly greater in the TMP + PE group. We conclude that Gly‐Dex is a viable pharmacologic alternative to TMP in physiologic measures of BP and TPR during vasodilator infusions.

The vascular effects of prostacyclin and contribution of endothelial derived nitric oxide (NO) to prostacyclin mediated dilation are unknown in aging. A pilot study was performed in healthy older subjects (n=6, 61–73 years old) and younger controls (n=6, 19–45 years old) that were matched for BMI. Subjects underwent brachial artery catheterization and received escalating doses of epoprostenol (PGI 2 2.5, 5, 10 ng/100ml forearm tissue/min) followed by sodium nitroprusside (SNP 0.25, 0.5, 1 mcg/100ml forearm tissue/min) after PGI 2 washout. SNP and PGI 2 were repeated after NO synthase inhibition with N G ‐Monomethyl‐L arginine acetate (L‐NMMA 1mg/min after 50mg load). Using venous occlusion plethysmography, forearm vascular conductance (FVC) was calculated using mean arterial pressure (MAP), as FVC= (FBF/MAP X 100). Percent change in FVC from baseline after PGI 2 was lower in the aging individuals (47, 160, 227 % change FVC) compared to younger controls (85, 218, 327 %change FVC) (p=0.039), L‐NMMA reduced baseline FVC similarly, and the dilator response to PGI 2 was no longer significant between groups. SNP effects were not significant between groups and unaffected by L‐NMMA. This data suggests a reduced effect to prostacyclin in the aging individual may be due to a reduction in the contribution of endothelial derived NO. Support provided by HL‐46493 and UL1‐RR24150.