Joyner, Michael J.

Microvascular blood flow regulation has important implications for optimization of metabolism‐perfusion matching in physiological and pathophysiological conditions such as exercise and sepsis. The purpose of this theoretical study is to assess the impact of various regulatory factors on metabolism‐perfusion matching. A microvascular network model including myogenic, shear, and metabolic flow regulation was developed and utilized to obtain estimates of oxygen extraction under control conditions as compared to a 20% global increase in blood flow accompanied by a 50% increase in oxygen consumption. The exercise state was simulated with preserved flow regulation and sepsis was simulated with impaired metabolic flow regulation. For the values of parameters used, overall oxygen extraction was found to be 28% higher in exercise compared to control values as opposed to only 23% higher in sepsis. This study demonstrates the impact of impaired flow regulation on oxygen delivery and highlights microvascular perfusion abnormalities as a putative mechanism for organ failure in critically ill patients.

Sympathetic neural control has a central role in the regulation of blood pressure. In humans, muscle sympathetic nerve activity (MSNA) is strongly controlled by the arterial baroreflex. Our goal was to evaluate a calculation of blood pressure "error signal" for MSNA burst occurrence and test if there was a gender difference in the relationship between this signal and resting blood pressure. Baseline MSNA was measured in healthy young men (n=49) and women (n=23). T50 (the DBP at which there is a 50% likelihood of an MSNA burst) was calculated. Mean DBP was subtracted from the T50 as an approximate "error signal" for burst activation. We found a positive relationship between this "error signal" and MSNA (bursts/100 heartbeats; BI) in both young men (slope=0.19, r 2 =0.67, p<0.001) and women (slope=0.32, r 2 =0.78, p<0.001). Thus, if DBP was lower than T50, there was an increased likelihood of MSNA bursts and vice versa. Women had a greater average "error signal" (i.e., mean T50 ‐ DBP = ‐5 ± 1 in women and ‐2 ± 0.4 in men), a 59 % steeper slope of the error signal:MSNA relationship, and lower mean BI (31 ± 2 vs 42 ± 4, p<0.05), suggesting that mechanisms exist in women to counteract the larger "driving force" for generation of a MSNA burst. These apparent gender differences in control of MSNA may contribute to differences in prevalence of cardiovascular diseases such as hypertension. NIH HL83947, UL1‐RR24150, Swedish Research Council 12170.

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.

Physical activity (PA) is inversely related with body fat, insulin resistance (IR), and leptin. However, these associations are not clear in patients after gastric bypass surgery (GBS). We hypothesized an inverse relation between PA, BMI, IR, and leptin; and a positive relation between leptin, BMI, and IR in a group of 9 patients after GBS, 8 obese (Ob), and 7 non‐obese (N‐Ob) controls (age=39.0±5.7, 27.7±6.9, 28.0±10.2 yr, respectively). Subjects wore an accelerometer from 6‐7 days, and underwent measurements of height, weight, DEXA, blood glucose, insulin and leptin. IR was estimated using HOMA. Between group differences in PA, BMI, IR, and leptin were determined with ANOVA; and the relation between these variables was determined with simple linear regressions. Between group differences were observed for BMI (Ob=38.7±1.6, GBS=30.4±1.5, N‐Ob=23.8±1.7 kg/m2), IR (Ob=3.0±0.5, GBS=1.1±0.5, N‐Ob=0.7±0.5), and leptin (Ob=55.9, GBS=28.7±4.5, N‐Ob=5.1±5.6 ng/ml). PA was not different between groups. Inverse associations were observed between PA and BMI (r= ‐ 0.55), and leptin (r= ‐ 0.56); and positive associations were observed between leptin and BMI (r= 0.92), and IR (r= 0.63). PA appears to be associated with the control of obesity and IR possibly via reductions in leptin, a mechanism that requires further study. Funded by NIH CTSA UL1‐RR24150, NIH CTSA KL2‐ RR024151

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

The key vascular signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults, leg blood flow (LBF) during exercise would be reduced independently by pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX). In 13 young adults, we measured heart rate (ECG), blood pressure (femoral artery and vein), blood gases, and venous oxygen saturation (indwelling oximeter) during steady‐state dynamic (60/min) knee extension exercise. LBF was determined by Doppler ultrasound of the femoral artery. Exercise (20W) increased leg vascular conductance (LVC) from 4± 1 to 33± 3 ml/min/100mmHg. The NOS inhibitor L‐NAME reduced LVC by ∼10% to 30± 1. Infusion of the COX inhibitor, ketoralac (n=9), increased LVC from 30± 1 to 34± 2. L‐NAME infusion reduced venous oxygen saturation from 48 to 38%, suggesting greater extraction to maintain oxygen consumption. Control intra‐arterial infusions of acetylcholine (ACH) and nitroprusside (NTP) tested inhibitor efficacy. The change in LVC to two doses of ACh was blunted 53 and 15%, by L‐NAME+ketorolac infusion. In contrast, the LVC responses to NTP were unaltered. These data implicate a modest role for NO‐mediated leg exercise hyperemia in adults and a potentially modest LBF restraint by vasoconstrictor prostaglandins. Funded by the NIH HL‐46493 and the Minnesota Obesity Center.

Functional renal oxygen consumption, V r O 2 is due to tubular reabsorption of sodium (T Na ) in the proximal and distal nephrons, resulting in compartments (cortex/medulla) with distinct V r O 2 /T Na relationships. Compartmental divisions promote non‐invasive imaging strategies like MRI, to indirectly assess tissue oxygenation, (P t O 2 ). However, the extent to which these regional P t O 2 differences are affected by successive T Na are not fully understood. The objective is to determine V r O 2 and intra‐renal regional alterations in P t O 2 directly and indirectly during successive T Na inhibition. It is hypothesized successive T Na inhibition is accompanied by intra‐renal regional changes in P t O 2 . Pigs (n=6) underwent MRI scans at baseline, furosemide and acetazolamide. Five days later, the right kidney was instrumented with P t O 2 sensors (cortex/medulla). P t O 2 was measured during drug infusions (identical to MRI exam). There was a decrease in V r O 2 , and a 40% and 30% increase in medullary and cortical P t O 2 following drug infusions. There was ~25% medullary and ~20–30% cortical decrease in BOLD signal with furosemide and acetazolamide administration, respectively. This study suggests successive inhibition of T Na is accompanied by intra‐renal regional P t O 2 changes and these changes are detectable with BOLD‐MRI, a non‐invasive imaging modality. Funding provided by NIH Grant (HL16496‐32), 2007 APS Porter Physiology Fellowship and the Mayo Foundation.

Inter‐individual variability in hemodynamic variables appears to be important in human blood pressure regulation. It is not known whether the rat, often used for studies of cardiovascular regulation, exhibits similar inter‐individual variability. In the present study, we evaluated whether inter‐individual variability in cardiac output (CO) and total peripheral resistance (TPR) is similar in humans and in rats, and whether a balance between these variables is similar in the two species. We assessed the relationship between CO and TPR during control conditions in humans (N = 40) and in Sprague‐Dawley rats (N = 16). We further assessed whether the relationship between CO and TPR was altered during acute increases in blood pressure, which were accomplished in humans with acute systemic L‐NMMA (N = 17), and in rats with a DOCA‐salt model (N = 16). Both humans and rats showed marked inter‐individual variability in CO and TPR but low variability in blood pressure. In both species, CO and TPR showed strong inverse correlations during normotension (r 2 = 0.88 (humans) and 0.89 (rats)) and during blood pressure increases (r 2 = 0.91 (humans) and 0.58 (rats)). We conclude that inter‐individual variability CO and TPR, and the balance between these variables, are important aspects of blood pressure regulation in both humans and rats. Supported by NIH HL32352, HL83947, HL64176, UL1‐RR24150 and Swedish Research Council 12170.

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.