Joyner, Michael J.

The Gly allele of the Arg16/Gly β 2 ‐adrenergic receptor polymorphism has been associated with hypertension in a linkage analysis in Rochester, MN. Gly homozygotes have greater forearm β 2 ‐receptor mediated vasodilation than Arg after a normal Na + diet (150 mmol/day), and the difference is mediated by endothelial NO. To test the hypothesis that dietary Na + restriction affects β 2 ‐mediated dilation in these groups, we measured forearm blood flow (FBF, plethysmography) during brachial arterial infusion of isoproterenol (ISO) after 5 days of low dietary Na + (10 mmol/day), in healthy subjects homozygous for Arg (n=15, 8 women, 29 ± 8 yrs, mean ± SD) vs. Gly (n=17, 7 women, 31 ± 7 yrs). Baseline FBF did not differ between groups. ISO caused a significant increase in FBF that was not different based on genotype (P = 0.51, main effect of genotype; P = 0.72, genotype‐by‐ISO‐interaction). For example, the highest response to ISO was 10.3 ± 5.5 in Arg and 12.0 ± 4.4 ml/100 ml forearm vol/min in Gly (P t‐test = 0.33). NO inhibition with L‐NMMA decreased baseline FBF, and significantly blunted the response to ISO, but there was no evidence to suggest the responses were influenced by genotype (P = 0.89, genotype‐by‐ISO‐by‐L‐NMMA interaction). We conclude that greater NO‐mediated β 2 ‐receptor vasodilation in Gly homozygotes is no longer apparent following dietary Na + restriction, suggesting that greater dilator function in Gly homozygotes during normal Na + intake may be a protective vascular mechanism in a population where the Gly allele is associated with hypertension. Support: HL‐63328, GCRC RR‐00585, NCRR K23‐17520.

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol . 22:249–262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen–hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO 2 ) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (F I O 2 : 0.125) and normoxia (F I O 2 : 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort ( n = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p < 0.05). Throughout incremental exercise in hypoxia, SaO 2 was systematically higher after drug (peak exercise SaO 2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p < 0.001), whereas oxygen extraction (Ca-vO 2 diff) and consumption (VO 2 ) were similar (peak exercise Ca-vO 2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p = 0.417; peak VO 2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p = 0.127). Throughout incremental exercise in normoxia, SaO 2 was systematically higher after drug, whereas peak VO 2 was reduced (peak exercise SaO 2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p = 0.008; peak VO 2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO 2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

Patients with sleep apnea exhibit ventilatory instability and increased carotid chemoreceptor activity. Whether ventilatory instability is directly related to altered chemoreceptor activity has not been examined in humans. Therefore we tested the hypothesis that acute activation of the carotid chemoreflex with hypoxia (10% O 2 ) would increase breathing variability (assessed by coefficient of variation of tidal volume {%CV}) and blunting the peripheral chemoreflex with IV dopamine would attenuate the response. To test this hypothesis, nine healthy subjects (3 M/6 F) were studied on two separate study days: 1) saline or 2) low‐dose dopamine infusion. Individualized dopamine dose (1‐4 mg/kg/min), that maximally blunted chemoreflex sensitivity, was identified during a separate screening visit. Respiratory rate (RR), tidal volume (TV), end tidal CO 2 (ETCO 2 )and O 2 (ETO 2 ) were measured. Baseline measures were similar between days. Saline infusion did not affect RR, TV, end tidal gases, or %CV. However, dopamine infusion significantly increased %CV (25 ± 5 to 32 ± 6 %; p<0.05) and ETCO 2 (0.3 ± 0.1 %; p<0.0001) without affecting RR, or TV. Hypoxia increased %CV during saline infusion (18 ± 3 to 29 ± 3%; p<0.05), and this effect was blunted during dopamine infusion (31 ± 6 to 38 ± 6%; p>0.05). These data indicate hypoxia increases respiratory variability and this effect is mediated by the carotid chemoreceptors. Furthermore, the effect of increased chemoreceptor drive on ventilatory instability, such as that seen in sleep apnea, may be blunted by low‐dose dopamine in humans. These data provide a potential therapeutic target for improving ventilatory instability in human disease. Funding:NIH DK090541

Hypertensive pregnancy (HP) is considered a risk factor for cardiovascular disease. Blood pressure (BP) response to physical stressor is an independent marker of cardiovascular risk. However, there is limited data regarding the pressor response to acute physical stress in women with a history of HP. Hence, the aim of the study was to compare BP responses in women with a history of HP to age and parity matched controls. Beat to beat BP was recorded in postmenopausal women (age = 59 ± 1 yrs, BMI = 31 ± 2 kg/m2) with and without a history of HP at baseline and during isometric handgrip (HG) exercise (30% of MVC) to fatigue. Isometric handgrip exercise was followed by 90 seconds of supra‐systolic cuff occlusion on the exercising arm. In both groups combined (N=31), systolic blood pressure (SBP) increased significantly from baseline to HG to cuff inflation (143 ± 3 to 161 ± 3 to 167 ± 4 mmHg). Similarly, mean arterial pressure (MAP) increased significantly from baseline to HG to cuff inflation (106 ± 2 to 119 ± 2 to 122 ± 2 mmHg). Diastolic pressure (DBP) increased significantly only from baseline to HG (80 ± 1 to 88 ± 1 mmHg) and baseline to cuff inflation (89 ± 2 mmHg). However, there were no significant differences in SBP, DBP and MAP between women with and without a history of HP (p>0.05). Even though both groups had an increase in BP variables in response to HG and cuff occlusion, there was no difference in the BP response to acute physical stressors in women with a history of HP as compared to control participants. Funding: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154 (JNB)

Background Hypoglycemia results in a reduction in spontaneous cardiac baroreflex sensitivity (scBRS) and a shift in the baroreflex working range to higher heart rates; this effect may be mediated by the carotid chemoreceptors. We hypothesized changes in baroreflex control of heart rate with hypoglycemia would be blunted in carotid body resected patients when compared with healthy controls. Methods Five patients (3M/2F) with bilateral carotid body resection for glomus tumors and ten healthy controls (7M/3F) completed a 180‐min hyperinsulinemic, hypoglycemic (~3.3 µmol/mL) clamp. Changes in heart rate, blood pressure, and scBRS were assessed. Results scBRS was reduced from baseline during hypoglycemia (p<0.01) and was lower in carotid body resected patients when compared with controls (p=0.01). Hypoglycemia‐mediated reductions in systolic and mean blood pressure were significantly greater in patients when compared with controls (p<0.05). Despite lower blood pressures, increases in heart rate with hypoglycemia were blunted in patients (p<0.01). Conclusion Reductions in scBRS with hypoglycemia cannot be exclusively attributed to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range to higher heart rates during hypoglycemia such that a rise in heart rate is not observed in carotid body resected patients. These data support a contribution of the carotid chemoreceptors to baroreflex control of blood pressure during hypoglycemia and highlight potential widespread effects of carotid body resection in humans. Funding DK090541, HL120570

Evidence suggests that increased sympathetic tone but no change of blood pressure (BP) via lower body negative pressure (LBNP) reduces indices of aortic wave reflection in young adults. The aim of this study was to examine whether aging affects central artery hemodynamics and indices of wave reflection during LBNP. In 12 young (27 ± 2 years, 5F/7M) and 10 older (70 ± 2 years 5F/5M) subjects, noninvasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms via applanation tonometry before and during 10 minutes of LBNP (‐20mmHg). Aortic BP and indices of aortic wave reflection (i.e. Augmentation index; AIx) were calculated from the generated aortic pressure waveform. Aortic systolic BP decreased during LBNP in the young (110 ± 3 vs. 106 ± 3 mmHg, P<0.05), but not the older adults (139 ± 3 vs. 136 ± 3 mmHg, P=0.15). Aortic diastolic BP did not change in either group (P=0.56). Since heart rate (HR) changed in the young (P<0.05) but not in the older adults (P=0.33) during LBNP, we used the AIx normalized to a HR of 75bpm as an index of wave reflection. AIx@75bpm decreased in young adults (‐6 ± 3 vs. ‐13 ± 3%, P<0.001), whereas no change was observed in older adults (26 ± 3 vs. 25 ± 3%, P=0.39). Our data suggest that reductions in aortic systolic blood pressure and wave reflection during lower body negative pressure are attenuated in older compared to young adults. Funded by NIH HL‐105467

Activation or inhibition of the carotid body chemoreceptors (CBCs) may impact cardiac baroreflex sensitivity (cBRS). The purpose of this study was to test the hypothesis that inhibition of the CBCs will elicit a change in cBRS when compared to normal resting conditions. Young, healthy subjects (n=16, 31±2, 6 women) were given IV saline and a range of IV dopamine (DA) (1‐4 µg/kg/min) for 15 minutes prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects were initially infused with IV saline. After each HVR, the DA infusion rate was increased by 1 µg/kg/min. A 3‐lead EKG and beat‐by‐beat blood pressure (NexFin) were used to determine cBRS. Data were analyzed from the 5 minutes prior to the HVR associated with the DA dose that elicited the greatest attenuation of the HVR when compared to saline. Heart rate was not significantly different during saline vs. DA (62±3 vs. 65±3, p=0.25). Diastolic blood pressure (77±2 vs. 72±1 mmHg), mean arterial pressure (98±2 vs. 92±2 mmHg), and cBRS “up” sequence (38±7 vs. 21±3 ms/mmHg) were significantly lower during saline vs. DA (p<0.05 for all). cBRS values from the RRI spectrum were not statistically distinguishable between saline and DA (26±4 vs. 21.1±3, p=0.06). In summary, inhibiting the CBCs via DA infusion in young, healthy subjects results in a fall in blood pressure and a reduction in cBRS in response to a rise in blood pressure. These data suggest the CBCs contribute to cBRS and play an important role in modulating parasympathetic control of blood pressure. Funding: NIH R01DK090541

There are known interactions between the chemoreflex and baroreflex. The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of blood pressure with exposure to hypoxia. Low‐dose dopamine blunts carotid body afferent activity and can thus be used to examine the contribution of the carotid chemoreceptors to reflex responses during hypoxia. Hypothesis Spontaneous cardiac baroreflex sensitivity (scBRS) will be reduced with hypoxia and this effect will be blunted when the carotid chemoreceptors are desensitized with low‐dose dopamine. Methods Seven subjects (4M/3F) completed 2 visits randomized to IV dopamine (individualized dose shown to result in a nadir hypoxic ventilatory response, 1‐4 μg/kg/min) or placebo (saline). Subjects were exposed to 5‐min normoxia (99±0% SpO2), followed by 5‐min hypoxia (83±2%SpO2). Blood pressure (intra‐arterial catheter) and heart rate (ECG) were measured continuously and sCBRS was assessed by spectrum analysis. The relative (%) change in sCBRS with hypoxia [(Hypoxia‐Normoxia)/Normoxia x 100)] was compared between dopamine and placebo. Results scBRS was reduced with hypoxia (saline p<0.01; dopamine p<0.01). The fall in scBRS with hypoxia was blunted with dopamine (saline: ‐58±7 %, dopamine: ‐42±9 %, p=0.02). Conclusion These data are consistent with a reduction in scBRS with chemoreceptor activation. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when the chemoreceptors are desensitized with low‐dose dopamine. Funding NIH DK090541 (Joyner)

Background In models of congestive heart failure, carotid body denervation decreases ventilatory oscillations, thereby increasing ventilatory stability. Low‐dose dopamine can acutely blunt carotid body chemosensitivity assessed by a reduction of the hypoxic ventilatory response (HVR), but whether it affects ventilatory stability was previously unknown. We hypothesized ventilatory oscillations [as assessed by coefficient of variation of tidal volume (%CV V t ) and breathing frequency (%CV F b )] would be reduced when the carotid chemoreceptors were desensitized by low‐dose dopamine. Methods Healthy adults (n=20, 6F/14M, 31±2 years) rested quietly for 5‐min and breath‐by‐breath ventilation was measured during normoxia under 2 IV infusion conditions: 1) saline, 2) an individualized dose of dopamine (1‐4 ug/kg/min) shown to result in a nadir HVR. Results Dopamine infusion increased breathing frequency (13±1 to 14±1 breaths/min, p=0.03) with no change in mean tidal volume (740±65 to 700±68 mL, p=0.18). Infusion of dopamine in young healthy adults increased ventilatory oscillations (%CV V t : saline = 21±2, dopamine = 30±4, p=0.01; %CV F b : saline = 17±1, dopamine = 21±2, p=0.07). There was no relationship between the decrease in HVR and the increase in ventilatory oscillations (V t : r=0.15, p=0.54; F b : r=0.33, p=0.16). Conclusion Contrary to our hypothesis, IV dopamine (at an individualized dose that attenuates HVR) significantly increases ventilatory oscillations in healthy subjects. These data suggest the effect of low‐dose dopamine on ventilatory oscillations in healthy adults is in contrast to that seen with carotid body denervation in disease. Funding : NIH DK090541

BACKGROUND Increased activation of Group III/IV skeletal muscle afferents is suggested to play a role in exercise intolerance in heart failure (HF). PURPOSE The purpose of this study was to examine if skeletal muscle afferent feedback inhibition improves exercise tolerance in HF. METHODS 8 HF patients [59±8 yr, mean±SD] participated in two randomized incremental recumbent cycling exercise sessions to peak capacity (peak oxygen consumption, VO 2 ). Session 1: The synthetic opioid fentanyl (50 mcg), known to block afferent feedback, was injected intrathecally (INJ) in the lumbar spine (L3‐L4 intervertebral space) prior to exercise. Session 2: Participants were prepared similarly with a sham injection (placebo, PLA). Gas exchange, dyspnea and RPE were measured. RESULTS HF patients exercised for a longer duration (Δ3±3 min, p=0.02) and reached a higher power output (PLA:109±30 vs. INJ:128±34 W, p=0.02) with locomotor afferent inhibition. Additionally, peak VO 2 was non‐significantly greater (PLA:18.7±3.3 vs. INJ:21.8±4.4 ml/kg/min, p=0.10). With INJ workload matched to peak PLA workload, RPE was reduced (PLA:18±2 vs. INJ:15±2, respectively, p=0.005) and dyspnea was lower (PLA:7.5±2 vs. INJ:4.2±1, p=0.003) with no difference in VO 2 (p>0.05). CONCLUSION Inhibition of group III/IV locomotor muscle afferent feedback contributes to improved exercise tolerance and exertional symptoms in HF patients.