Joyner, Michael J.

Microvascular blood flow regulation involves multiple mechanisms designed to maintain adequate perfusion under conditions of varying metabolic demand. The impact of various regulatory factors on metabolism‐perfusion matching was assessed using a heterogeneous microvascular network model that accounted for myogenic, shear, and metabolic flow regulation. Estimates of oxygen extraction under control conditions were compared to an increase in tissue oxygen consumption in combination with a reduction in perfusion. For the values of parameters used, overall oxygen extraction was increased by a factor of 7.19 with a tenfold increase in consumption and a factor of 1.47 when perfusion was reduced by 50%. Combining increased consumption with decreased flow resulted in an increase in extraction by a factor of 9.20 compared to control, suggesting that network regulatory capacity remained intact under these conditions. This has significant implications for the optimization of metabolism‐perfusion matching, since impairment of flow regulation under conditions of increased consumption and decreased perfusion can lead to microvascular perfusion heterogeneity and cause organ failure in critically ill patients.

We examined the reproducibility of the hyperemic response to ischemic exercise (IE) in the forearm and compared the magnitude of this response to ischemia alone (reactive hyperemia, RH). Eight subjects (6M/2F; 26 ±1 yrs) performed 3 trials of IE and 2 of RH. IE consisted of 5 min of forearm ischemia with rhythmic forearm exercise (20% of max) during the final 2 min. RH consisted of 5 min of forearm ischemia. Peak and total (area under the curve) forearm blood flow (FBF; venous occlusion plethysmography) and blood pressure (MAP; Finometer) were measured for 3 min after each stimulus. Forearm vascular conductance (FVC; ml/100ml/min/mmHg) was calculated from FBF (ml/100ml/min) and MAP (mmHg). The mean intra‐individual coefficient of variation (CV) across the 3 IE trials was 13.0±1.4% and 16.3±1.2% for baseline‐adjusted peak FBF and FVC, respectively. The CVs for total FBF and FVC were 10.4±1.0% and 14.9±1.0%, respectively. Mean peak FBF was greater for IE compared to RH (37.3±2.7 and 30.0±1.3, P < 0.002), however mean peak FVC was not different (35.1±2.6 and 34.5±1.1, P = 0.80). Mean total FBF (67.6±3.9 and 18.0±2.5, P < 0.001) and mean total FVC (64.7±2.7 and 20.8±3.2, P < 0.001) were greater for IE compared to RH, respectively. Thus, our data suggest that the hyperemic response to IE is reproducible, and that the magnitude of this response is greater than that of ischemia alone. NIH HL‐46493 (MJJ), CTSA RR‐024150 and RR‐024152

Nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to hypoperfusion during exercise. We tested the potential for adenosine/NO interaction in the compensatory dilation. Eight males (25 ± 2 yrs) performed forearm exercise (20% of max) during intra‐arterial balloon inflation. Each trial included; exercise, exercise with balloon inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and brachial artery catheter pressure (BAP) were measured. Exercise was repeated during NO synthase inhibition (L‐NMMA) alone and with the combination of L‐NMMA/aminophylline (adenosine receptor blockade). Forearm vascular conductance (FVC; ml/min/100mmHg) was calculated from BF (ml/min) and BAP (mmHg). The % recovery in FVC during inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir]. FVC fell acutely with balloon inflation during all trials (P < 0.01). During the control trial, the % recovery in FVC was 111 ± 8%. The % recovery in FVC was attenuated with NOS inhibition alone (80 ± 9%; P < 0.001 vs. control) and attenuated further with combined inhibition of NO/adenosine (63 ± 9%; P < 0.05 vs. L‐NMMA). Thus, adenosine has an NO independent role in the compensatory vasodilatation during exercise with acute hypoperfusion. NIH HL46493 (MJJ), AR55819 (DPC) and RR‐024150.

β 2 ‐adrenergic receptor (ADRB2) gene polymorphisms influence vasodilation, but studies investigating regional or systemic responses conflict, possibly due to counter‐regulatory baroreflex action during systemic β 2 ‐agonist infusion. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (TERB) during baroreflex inhibition. 40 healthy young adults were recruited according to the double homozygous haplotypes: Arg16+Gln27 (n=13), Gly16+Gln27 (n=6), and Gly16+Glu27 (n=21). Arterial pressure was measured by brachial arterial catheter, 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), phenylephrine was titrated to restore blood pressure to baseline. TERB was infused i.v. at 33 and 67 ng/kg/min 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 vs Arg16 ( P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs Arg16 ( P = 0.05). During baroreflex inhibition, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16+Glu27 homozygotes, with greater influence from Gly16. Supported from NIH and DFG.

We examined the effects of acute β‐adrenergic blockade on central artery hemodynamics and wave reflection characteristics in young healthy humans. High‐fidelity radial artery waveforms were recorded non‐invasively by applanation tonometry before and after intravenous propranolol (0.25 mg/kg bolus for 5 min followed by a maintenance infusion of 0.004/mg/kg/min for 20–30 min) in fourteen subjects (9 F/5M; 27 ± 2 years). Radial blood pressure (BP) was calibrated from the brachial BP (arterial catheter). Aortic augmentation index (AI a ; a measure of amplitude and timing of arterial pressure wave reflection) and roundtrip travel time of the reflected wave to and from the periphery (Δt p ; inverse of pulse wave velocity) were calculated from the generated aortic pressure waveform and are indices of central arterial stiffness. Systemic β‐blockade reduced heart rate (HR; 60 ± 2 vs. 53 ± 2 bpm, P < 0.001) and increased AI a (9.9 ± 4.3% vs. 4.3 ± 4.4%, P < 0.05), but did not alter Δt p (156 ± 4 msec vs. 152 ± 2 msec, P = 0.34). The AI a normalized to a HR of 75bpm (AI a @75) was not increased following β‐blockade (P = 0.67). Taken together, our data indicate that the increase in AI a following systemic β‐blockade is a result of a slower HR and not due to changes in β‐ mediated vascular tone. Supported by NIH K23 DK‐082424 (TBC), AHA 2170087(ECH) and CTSA RR‐024150

The purpose of this study was to evaluate the relationship between the cardiac and sympathetic baroreflex sensitivities within healthy, young individuals. The gains in cardiac (as measured by changes in R‐R interval, RRI, and heart rate, HR) and sympathetic (as measured by changes in muscle sympathetic nerve activity, MSNA) baroreflex during rapid changes in arterial blood pressure were compared in 27 normotensive individuals (18 men and 9 women; age 24 yrs ±1.24; body mass index 24 ±0.51 cm/kg 2 , mean ±SEM). Heart rate, arterial blood pressure (brachial artery catheter), and peroneal MSNA were recorded under resting conditions (HR 58 ±1.6 bpm; SBP 124 ±2.7 mmHg; DBP 71 ±1.7 mmHg; MAP 87 ±1.7 mmHg; MSNA BF 17 ±1.6 bursts/min) as well as during rapid changes in arterial blood pressure induced by sequential boluses of nitroprusside and phenylephrine (Modified Oxford technique). Integrated baroreflex sensitivities for MSNA and HR were analyzed using the slopes of the linear portions of the MSNA‐diastolic blood pressure and RRI‐systolic blood pressure relationships, respectively. When individual cardiac baroreflex sensitivity was compared to sympathetic baroreflex sensitivity, no correlation (R 2 =0.0003) was found. These results indicate that although both cardiac and sympathetic efferents function in baroreflex control of the autonomic system, there does not appear to be a direct correlation in their function within healthy normotensive individuals. Research Support: NIH HL083947 and Swedish Medical Council grant 12170

We examined the relationship between flow restoration and vascular resistance in the exercising forearm during hypoperfusion caused by balloon inflation in the brachial artery. 75 trials (with and without nitric oxide synthase (NOS) inhibition) were analyzed. Each included forearm exercise (10% or 20% of max), exercise with inflation, and exercise after deflation (3 min each). FBF (ultrasound), local (brachial artery; BAP), and systemic arterial pressure (SAP) were measured. FBF restoration during balloon inflation was calculated as (steady state inflation plus exercise value – nadir)/[steady state exercise (control) value‐nadir] and expressed as % recovery of FBF. Balloon resistance [(SAP‐BAP)/flow] and vascular resistance (BAP/flow) were expressed as the % change from onset of inflation to end inflation. The % recovery of FBF was strongly related to the drop in vascular resistance for all trials (r = 0.664, P <0.001). This relationship was unaffected by NOS inhibition (n= 27; r = 0.623, P < 0.001 vs. control n = 48; r = 0.685, P < 0.001). The relationship was also stronger with increasing exercise intensity (r = 0.57 vs. 0.704). The % recovery of FBF was unrelated to changes in balloon resistance under any condition. Thus, flow restoration is determined primarily by the fall in local vascular resistance during forearm exercise with hypoperfusion. Supported by NIH HL‐46493 (MJJ), AR‐55819 (DPC) and RR‐024150.

Young men display a positive association between breathing rate and muscle sympathetic nerve activity (MSNA). We compared breathing rate, peroneal MSNA and cardiovascular variables at rest in 17 men (age 27 ± 2 yrs) and 15 women (age 25 ± 1 yrs). Breathing rates and MSNA were similar in men and women but women had significantly lower systolic and mean blood pressures, cardiac output and stroke volume. In men breathing rate correlated positively to MSNA (r = 0.58, p<0.05) but not in women (r = 0.12, p> 0.05).. In men respiratory rate correlated positively to total peripheral resistance (r = 0.65, p<0.05) and inversely to cardiac output (r = − 0.84, p<0.05) and heart rate (r = − 0.60, p<0.05) but there were no such relationships in women (p> 0.05 for all). In another group of subjects, linear regression was performed on respiratory rate and brachial arterial plasma norepinephrine. There was no relationship in men (r=0.0847, n=38) or women (r=0.0367, n=74). Importantly, MSNA does not always predict plasma NE levels at rest. The positive relationship between breathing and MSNA in men, and the inverse coupling of breathing to cardiac output and heart rate suggest that influences of respiration may be important, not only for dynamic, but also for “tonic” cardiovascular function. The lack of relationships among these variables in women shows that there are fundamental differences in basic blood pressure regulation between the sexes.

We tested the hypothesis that dietary Na + intake alters the hemodynamic response to mental stress (MS) in normotensive subjects, which could be mediated by β‐adrenergic receptors (ADRB). As part of an ongoing ADRB2 phenotyping protocol, 12 subjects (age 23±5 year) completed 5 days of low (10 mmol day −1 ), normal (150) and high (400) dietary Na + intake. We measured heart rate (ECG), mean arterial pressure (MAP, Finometer), and calculated stroke volume (SV), cardiac output (CO) and systemic vascular resistance (SVR) responses to arithmetic MS, before and after administration of propranolol. The high Na + diet decreased CO (6.3±0.3 vs. 5.7±0.3 l min −1 , p<0.01) and increased SVR (1187±47 vs. 1311±68 dynes s −1 cm −1 , p<0.01) at rest, but MAP was unchanged (92±2 vs. 93±3 mmHg, p=0.37). During MS, the increase in HR, CO, and MAP was not affected by diet, nor was the decrease in SVR. However, on the high Na + diet β‐blockade increased resting MAP (93±3 vs. 97±2 mmHg, p<0.01), while the absolute MAP response to MS was unchanged, the ΔMAP was blunted (7.3 vs. 4.3 %, p=0.03) and ΔSV was decreased (1.7±3.5 vs. −5.3±2.0 %, p=0.03). In conclusion, reactivity to MS was not influenced by dietary Na + , but systemic β‐blockade after high Na + blunted the SV response during MS. This may be suggestive of augmented ADRB function or blunted non‐ADRB mechanisms of ventricular function during MS after high Na + . Support: R‐01 HL‐089331 and CTSA RR‐024150.

We tested the hypothesis that administering low‐dose dopamine (2 mcg/kg/min) to desensitize the carotid body chemoreceptors would alter metrics of heart rate variability (HRV). Electrocardiogram (ECG) recordings were obtained from 18 healthy adults (age = 31 ± 2 years; BMI = 24.6 ± 0.6 kg/m 2 ) during two randomized study days where they received an IV infusion of saline (S) or dopamine (DA). HRV was analyzed during five minute segments at baseline and during infusions of S and DA. Time‐domain analysis of the root mean square of the successive differences (RMSSD) along with spectral domain analysis of low (LF) and high frequency (HF) were obtained. There were no differences (P > 0.05) in respiration rate or blood pressure at any time point. Heart rate increased from baseline during DA (60 ± 2 vs. 63 ± 2 bpm; P < 0.01) and during infusion it was greater in DA vs. S (63 ± 2 vs. 58 ± 2 bpm; P < 0.01). RMSSD decreased from baseline to infusion during DA (68.2 ± 7.6 vs. 51.6 ± 6.0 ms; P < 0.01) and during infusion it was lower in DA vs. S (78.3 ± 10.3 vs. 51.6 ± 6.0 ms; P < 0.01). HF was reduced during DA vs. baseline (1733± 301 vs. 870 ± 171 ms 2 ; P < 0.01), and during infusion DA was also lower than S (1936 ± 471 vs. 870 ± 171 ms 2 ; P = 0.02). There were no changes (P > 0.05) in LF, LF/HF or normalized HF and LF values. These data indicate that during resting conditions the carotid body chemoreceptors likely modulate parasympathetic components of HRV in healthy adults. Grant Funding Source : Supported by NIH R01DK090541 and RO1HL61388