Joyner, Michael J.

Molecular reductionism has so far failed to deliver the broad-based therapeutic insights that were initially hoped for. This form of reductionism is now being replaced by so-called “systems biology.” This is a nebulously defined approach and/or discipline, with some versions of it relying excessively on hypothesis-neutral approaches and only minimally informed by key physiological concepts such as homeostasis and regulation. In this context, physiology is uniquely positioned to continue to provide impressive levels of both biological and therapeutic insight by using hypothesis-driven “classical” approaches and concepts to help frame what might be described as the “pieces of the puzzle” that emerge from molecular reductionism. The strength of physiology as a “bridge” between reductionism and epidemiology, along with its unparalleled ability to generate therapeutic insights and opportunities justifies increased attention and emphasis on our discipline into the future. Arguments relevant to this set of assertions are advanced and this paper, which was based on the 2011 Adolph Lecture, represents an effort to fill the intellectual void left by reductionism and improve scientific progress.

We tested the hypothesis that 1) prostaglandins (PGs) contribute to compensatory vasodilation in contracting human forearm subjected to acute hypoperfusion, and 2) the combined inhibition of PGs and nitric oxide would attenuate the compensatory vasodilation more than PG inhibition alone. In separate protocols, subjects performed forearm exercise (20% of maximum) during hypoperfusion evoked by intra-arterial balloon inflation. Each trial included baseline, exercise before inflation, exercise with inflation, and exercise after deflation. Forearm blood flow (FBF; ultrasound) and local (brachial artery) and systemic arterial pressure [mean arterial pressure (MAP); Finometer] were measured. In protocol 1 ( n = 8), exercise was repeated during cyclooxygenase (COX) inhibition (Ketorolac) alone and during Ketorolac-NOS inhibition [ NG-monomethyl-l-arginine (l-NMMA)]. In protocol 2 ( n = 8), exercise was repeated during l-NMMA alone and during l-NMMA-Ketorolac. Forearm vascular conductance (FVC; ml·min−1·100 mmHg−1) was calculated from FBF (ml/min) and local MAP (mmHg). The percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value − nadir)/[steady-state exercise (control) value − nadir] × 100. In protocol 1, COX inhibition alone did not reduce the %FVC recovery compared with the control (no drug) trial (92 ± 11 vs. 100 ± 10%, P = 0.83). However, combined COX-nitric oxide synthase (NOS) inhibition caused a substantial reduction in %FVC recovery (54 ± 8%, P < 0.05 vs. Ketorolac alone). In protocol 2, the percent recovery in FVC was attenuated with NOS inhibition alone (69 ± 9 vs. 107 ± 10%, P < 0.01) but not attenuated further during combined NOS-COX inhibition (62 ± 10%, P = 0.74 vs. l-NMMA alone). Our data indicate that PGs are not obligatory to the compensatory dilation observed during forearm exercise with hypoperfusion.

Hypoxia during exercise augments blood flow in active muscles to maintain the delivery of O2 at normoxic levels. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is not completely understood. Therefore, we tested the hypothesis that the hyperemic response to forearm exercise during hyperbaric hyperoxia would be blunted compared with exercise during normoxia. Seven subjects (6 men/1 woman; 25 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; in ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; in ml·min−1·100 mmHg−1) was calculated from FBF and blood pressure (in mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 atmospheres absolute (ATA) (sea level) while breathing normoxic gas [21% O2, 1 ATA; inspired Po2 (PiO2) ≈ 150 mmHg] and at 2.82 ATA while breathing hyperbaric normoxic (7.4% O2, 2.82 ATA, PiO2 ≈ 150 mmHg) and hyperoxic (100% O2, 2.82 ATA, PiO2 ≈ 2,100 mmHg) gas. Resting FBF and FVC were less during hyperbaric hyperoxia compared with hyperbaric normoxia ( P < 0.05). The change in FBF and FVC (Δ from rest) during exercise under normoxia (204 ± 29 ml/min and 229 ± 37 ml·min−1·100 mmHg−1, respectively) and hyperbaric normoxia (203 ± 28 ml/min and 217 ± 35 ml·min−1·100 mmHg−1, respectively) did not differ ( P = 0.66–0.99). However, the ΔFBF (166 ± 21 ml/min) and ΔFVC (163 ± 23 ml·min−1·100 mmHg−1) during hyperbaric hyperoxia were substantially attenuated compared with other conditions ( P < 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia.

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.

We hypothesized that individuals who have undergone gastric bypass have greater insulin sensitivity that obese subjects but less compared with lean. We measured free fatty acid (FFA) and glucose kinetics during a two-step, hyperinsulinemic euglycemic clamp in nondiabetic subjects who were 38 ± 5 mo post-gastric bypass surgery (GB; n = 15), in lean subjects (L; n = 15), and in obese subjects (O; n = 16). Fasting FFAa were not significantly different between the three study groups but during both doses of insulin were significantly higher in O than in either GB or L. The effective insulin concentration resulting in half-maximal suppression of FFA was similar in L and GB and significantly less in both groups compared with O. Glucose infusion rates during low-dose insulin were not significantly different in GB compared with either L or O. During high-dose insulin, glucose infusion rates were significantly greater in GB than in O but less than in L. Endogenous glucose production in GB was significantly lower than O only during low dose of insulin. We conclude that gastric bypass is associated with improvements in adipose tissue insulin sensitivity to levels similar to lean, healthy persons and also with improvements in the response of glucose metabolism to insulin. These changes may be due to preferential reduction in visceral fat and decreased FFA availability. However, some differences in insulin sensitivity in GB remain compared with L. Residual insulin resistance may be related to excess total body fat or abnormal lipolysis and requires further study.

We previously demonstrated that nitric oxide (NO) contributes to compensatory vasodilation in the contracting human forearm subjected to acute hypoperfusion. We examined the potential role of an adenosine-NO interaction to this response in 17 male subjects (25 ± 2 yr). In separate protocols subjects performed rhythmic forearm exercise (20% of maximum) while hypoperfusion was evoked by balloon inflation in the brachial artery above the elbow. Each trial included exercise before inflation, exercise with inflation, and exercise after deflation (3 min each). Forearm blood flow (FBF; ultrasound) and local [brachial artery catheter pressure (BAP)] and systemic [mean arterial pressure (MAP); Finometer] arterial pressure were measured. In protocol 1 ( n = 10), exercise was repeated during nitric oxide synthase inhibition [ NG-monomethyl-l-arginine (l-NMMA)] alone and during l-NMMA-aminophylline (adenosine receptor blockade) administration. In protocol 2, exercise was repeated during aminophylline alone and during aminophylline-l-NMMA. Forearm vascular conductance (FVC; ml·min−1·100 mmHg−1) was calculated from blood flow (ml/min) and BAP (mmHg). Percent recovery in FVC during inflation was calculated as (steady-state inflation + exercise value − nadir)/[steady-state exercise (control) value − nadir]. In protocol 1, percent recovery in FVC was 108 ± 8% during the control (no drug) trial. Percent recovery in FVC was attenuated with inhibition of NO formation alone (78 ± 9%; P < 0.01 vs. control) and was attenuated further with combined inhibition of NO and adenosine (58 ± 9%; P < 0.01 vs. l-NMMA). In protocol 2, percent recovery was reduced with adenosine receptor blockade (74 ± 11% vs. 113 ± 6%, P < 0.01) compared with control drug trials. Percent recovery in FVC was attenuated further with combined inhibition of adenosine and NO (48 ± 11%; P < 0.05 vs. aminophylline). Our data indicate that adenosine contributes to compensatory vasodilation in an NO-independent manner during exercise with acute hypoperfusion.

Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries, a hemodynamic environment that favors a proatherogenic endothelial cell phenotype. We evaluated whether nitric oxide (NO) bioavailability in resistance vessels contributes to age-related differences in shear rate patterns in upstream conduit arteries at rest and during rhythmic muscle contraction. Younger (n=11, age 26±2 years) and older (n=11, age 61±2 years) healthy subjects received intra-arterial saline (control) and the NO synthase inhibitor N G -Monomethyl- l -arginine. Brachial artery diameter and velocities were measured via Doppler ultrasound at rest and during a 5-minute bout of rhythmic forearm exercise. At rest, older subjects exhibited greater brachial artery retrograde and oscillatory shear (−13.2±3.0 s −1 and 0.11±.0.02 arbitrary units, respectively) compared with young subjects (−4.8±2.3 s −1 and 0.04±0.02 arbitrary units, respectively; both P <0.05). NO synthase inhibition in the forearm circulation of young, but not of older, subjects increased retrograde and oscillatory shear (both P <0.05), such that differences between young and old at rest were abolished (both P >0.05). From rest to steady-state exercise, older subjects decreased retrograde and oscillatory shear (both P <0.05) to the extent that no exercise-related differences were found between groups (both P >0.05). Inhibition of NO synthase in the forearm circulation did not affect retrograde and oscillatory shear during exercise in either group (all P >0.05). These data demonstrate for the first time that reduced NO bioavailability in the resistance vessels contributes, in part, to age-related discrepancies in resting shear patterns, thus identifying a potential mechanism for increased risk of atherosclerotic disease in conduit arteries.

Increased arterial stiffness is associated with higher levels of aortic wave reflection and aortic blood pressure. Recent evidence suggests a link between muscle sympathetic nerve activity and indices of arterial stiffness. Therefore, the aims of this study were to examine the relationship between resting muscle sympathetic nerve activity and characteristics of aortic pressure wave reflection and the influence of sex on these relationships. In 44 subjects (23 females and 21 males; 25±1 years of age), we measured muscle sympathetic nerve activity via peroneal microneurography. In addition, noninvasive aortic pressure waveforms were synthesized from radial pressure waveforms obtained from applanation tonometry. Aortic blood pressure, augmentation index, wave reflection amplitude, and wasted left ventricular energy were calculated. Resting sympathetic activity (bursts/100 heart beats) was not associated with any of the aortic pressure wave reflection characteristics for all patients. However, there was a positive relationship between sympathetic activity and augmentation index ( r =0.46; P =0.05) in men. Further, sympathetic activity in men was related to wave reflection amplitude ( r =0.53; P <0.05) and wasted left ventricular energy ( r =0.57; P <0.01). In contrast to men, women demonstrated strong inverse relationships between sympathetic activity and augmentation index ( r =−0.63), wave reflection amplitude ( r =−0.59), and wasted left ventricular energy ( r =−0.58; P <0.01 for all). Our results suggest another possible mechanism by which young women are protected against the development of cardiovascular disease.