Mozer, Michael T.

Objective Insulin has known sympathoexcitatory effects that have been historically attributed to primarily central mechanisms. Although controversy exists, recent evidence from rodents suggests the carotid chemoreceptors may play a role in the sympathoexcitatory response to hyperinsulinemia. Therefore, we sought to examine the contribution of the carotid chemoreceptors to insulin‐mediated increases in sympathetic nervous system activity in humans. We hypothesized reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia in humans – thus supporting a role for the carotid chemoreceptors in insulin‐mediated sympathoexcitation. Methods Young, healthy adults (n=15, 8M/7F, 27±1 yrs, 24±1 kg/m 2 ) completed a 30‐min euglycemic baseline followed by a 90‐min hyperinsulinemic (1 mU/kg FFM/min), euglycemic (90–100 mg/dL) clamp. Heart rate (electrocardiography) and muscle sympathetic nerve activity (MSNA, microneurography of the peroneal nerve) were continuously measured. The role of the carotid chemoreceptors was assessed using the following protocols: 1) acute (1‐min) hyperoxia (n=13), 2) low‐dose dopamine (1–4 μg/kg/min; n=7), 3) acute hyperoxia + low‐dose dopamine (n=8). The nadir 15‐s value for MSNA within each hyperoxic condition was determined and the nadir at baseline was compared to the nadir during hyperinsulinemia. Results MSNA increased from baseline during the hyperinsulinemic, euglycemic clamp [12±2 to 18±2 bursts/min (p<0.01)]. In protocol 1, MSNA was reduced during acute hyperoxia at baseline (12±1 to 6±1 bursts/min, p<0.01) and during the hyperinsulinemic clamp (17±2 to 12±2 bursts/min, p=0.02); however, the fall in MSNA during hyperoxia did not differ between baseline and hyperinsulinemia (p=0.82). In protocol 2, when low‐dose dopamine was given prior to the hyperinsulinemic clamp, MSNA did not increase from baseline (19±2 to 22±5 bursts/min, p=0.51); this is in contrast to increases observed under saline conditions (14±3 to 22±4 bursts/min, p=0.03). In protocol 3, in the presence of low‐dose dopamine, MSNA was reduced during acute hyperoxia at baseline (16±3 to 9±2 bursts/min, p=0.048) and during the hyperinsulinemic clamp (16±4 to 9±3 bursts/min, p=0.02); however, the fall in MSNA with hyperoxia did not differ between baseline and hyperinsulinemia (p=0.97). Conclusions Low‐dose dopamine given prior to the onset of a hyperinsulinemic, euglycemic clamp attenuates the sympathoexcitatory response to hyperinsulinemia. In contrast, acute carotid chemoreceptor desensitization (1‐min hyperoxia) during steady‐state hyperinsulinemia does not augment the fall in MSNA observed at baseline. Our data suggest the carotid chemoreceptors do not contribute acutely to insulin‐mediated increases in sympathetic nervous system activity in healthy humans; however, they may play a role during longer‐term exposure. Support or Funding Information Support: DK090541 (MJJ); HL83947 (MJJ); HL130339 (JKL); AHA15SDG25080095 (JKL)

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)

Slow‐paced breathing is a simple strategy to reduce psychological stress. We tested the hypothesis that slow paced breathing would decrease muscle sympathetic nerve activity (MSNA). Ten young, healthy males were studied. The subjects were instructed to rest supine and breathe normally (baseline) or at six breaths per minute, each for 20 minutes. MSNA was measured (peroneal microneurography) and analyzed 5 minutes into each stage for a steady state measurement. Statistical analysis was completed using one way RM ANOVA and Tukey’s posthoc analysis (reported mean±SEM). Average respiratory rate was 11.9 ± 1.1 breaths/min during baseline and 5.8 ± 0.7 breaths/min during slow‐paced breathing. There was no significant difference from baseline compared to slow paced breathing in MSNA burst frequency (18±2.0 vs 18±2.40 bursts/min), burst incidence (31.2±4.01 vs. 30.4±3.80 bursts/100 heartbeats) or burst area (12.70±2.18 vs 13.02±1.98%). However, there was a change in the pattern of burst firing with a significant increase in quiescent periods between burst clusters during slow paced breathing compared to baseline (6.50±0.61 vs. 3.59±0.41 seconds), which was accompanied by a significant decrease in the number of bursts/cluster (2.9±0.38 vs. 5.6±0.8 bursts). This has physiological relevance since there was a significant decrease in plasma norepinephrine, increase in blood flow, and a reduction in mean arterial pressure during these same periods. These findings indicate that despite no change in burst incidence, slow paced breathing alters the pattern of MSNA firing, which may contribute to favorable cardiovascular changes. Grant Funding Source : Supported by NIH HL‐083947

Objective: Given recent evidence from rodents supporting a novel role for the carotid bodies in insulin‐mediated sympathoexcitation, we sought to determine whether carotid chemoreceptor desensitization would reduce muscle sympathetic nerve activity (MSNA) during hyperinsulinemia in humans. Methods: Young, healthy subjects (n=4, 30±2 yrs) breathed hyperoxic gas (End‐tidal O2 = 100%, PaO2 505±13 mmHg) for 15 min at baseline and during steady‐state hyperinsulinemia (5±1 vs 53±1 µU/mL). Hyperinsulinemia was achieved using a 90‐min hyperinsulinemic (1 mU/kg FFM/min), euglycemic (108±4 mg/dL) clamp. CO2 was maintained at resting levels (PaCO2 41±1 mmHg). Changes in heart rate, blood pressure, minute ventilation, and MSNA (microneurography of the peroneal nerve) were assessed. Results: Hyperinsulinemia increased MSNA [burst frequency (p<0.01), burst incidence (p=0.02), total activity (p=0.02)]. Hyperoxia decreased heart rate (p=0.01) and minute ventilation (p=0.11), and increased mean blood pressure (p=0.04). Consistent with our hypothesis, the effect of hyperoxia on MSNA (Δ) was different between baseline and hyperinsulinemia (burst frequency, p=0.03; burst incidence, p=0.10). Conclusion: These data are the first to suggest the carotid chemoreceptors may contribute to insulin‐mediated sympathoexcitation in humans. Grant Funding Source : Supported by: NIH R01 DK090541 (MJJ), NIH T32 DK07352 (JKL)

We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

We examined the contribution of the carotid chemoreceptors to insulin-mediated increases in muscle sympathetic nerve activity (MSNA) in healthy humans. We hypothesized that reductions in carotid chemoreceptor activity would attenuate the sympathoexcitatory response to hyperinsulinemia. Young, healthy adults (9 male/9 female, 28 ± 1 yr, 24 ± 1 kg/m2) completed a 30-min euglycemic baseline followed by a 90-min hyperinsulinemic (1 mU·kg fat-free mass−1·min−1), euglycemic infusion. MSNA (microneurography of the peroneal nerve) was continuously measured. The role of the carotid chemoreceptors was assessed at baseline and during hyperinsulinemia via 1) acute hyperoxia, 2) low-dose dopamine (1–4 µg·kg−1·min−1), and 3) acute hyperoxia + low-dose dopamine. MSNA burst frequency increased from baseline during hyperinsulinemia ( P < 0.01). Acute hyperoxia had no effect on MSNA burst frequency at rest ( P = 0.74) or during hyperinsulinemia ( P = 0.83). The insulin-mediated increase in MSNA burst frequency ( P = 0.02) was unaffected by low-dose dopamine ( P = 0.60). When combined with low-dose dopamine, acute hyperoxia had no effect on MSNA burst frequency at rest ( P = 0.17) or during hyperinsulinemia ( P = 0.85). Carotid chemoreceptor desensitization in young, healthy men and women does not attenuate the sympathoexcitatory response to hyperinsulinemia. Our data suggest that the carotid chemoreceptors do not contribute to acute insulin-mediated increases in MSNA in young, healthy adults.

Human studies use varying levels of low-dose (1-4 μg·kg −1 ·min −1 ) dopamine to examine peripheral chemosensitivity, based on its known ability to blunt carotid body responsiveness to hypoxia. However, the effect of dopamine on the ventilatory responses to hypoxia is highly variable between individuals. Thus we sought to determine 1) the dose response relationship between dopamine and peripheral chemosensitivity as assessed by the ventilatory response to hypoxia in a cohort of healthy adults, and 2) potential confounding cardiovascular responses at variable low doses of dopamine. Young, healthy adults ( n = 30, age = 32 ± 1, 24 male/6 female) were given intravenous (iv) saline and a range of iv dopamine doses (1–4 μg·kg −1 ·min −1 ) prior to and throughout five hypoxic ventilatory response (HVR) tests. Subjects initially received iv saline, and after each HVR the dopamine infusion rate was increased by 1 μg·kg −1 ·min −1 . Tidal volume, respiratory rate, heart rate, blood pressure, and oxygen saturation were continuously measured. Dopamine significantly reduced HVR at all doses ( P < 0.05). When subjects were divided into high ( n = 13) and low ( n = 17) baseline chemosensitivity, dopamine infusion (when assessed by dose) reduced HVR in the high group only ( P < 0.01), with no effect of dopamine on HVR in the low group ( P > 0.05). Dopamine infusion also resulted in a reduction in blood pressure (3 μg·kg −1 ·min −1 ) and total peripheral resistance (1–4 μg·kg −1 ·min −1 ), driven primarily by subjects with low baseline chemosensitivity. In conclusion, we did not find a single dose of dopamine that elicited a nadir HVR in all subjects. Additionally, potential confounding cardiovascular responses occur with dopamine infusion, which may limit its usage.

Hypoglycemia results in a reduction in cardiac baroreflex sensitivity and a shift in the baroreflex working range to higher heart rates. This effect is mediated, in part, by the carotid chemoreceptors. Therefore, we hypothesized hypoglycemia-mediated changes in baroreflex control of heart rate would be blunted in carotid body–resected patients when compared with healthy controls. Five patients with bilateral carotid body resection for glomus tumors and 10 healthy controls completed a 180-minute hyperinsulinemic, hypoglycemic (≈3.3 mmol/L) clamp. Changes in heart rate, blood pressure, and spontaneous cardiac baroreflex sensitivity were assessed. Baseline baroreflex sensitivity was not different between groups ( P >0.05). Hypoglycemia resulted in a reduction in baroreflex sensitivity in both the groups (main effect of time, P <0.01) and responses were lower in resected patients when compared with controls (main effect of group, P <0.05). Hypoglycemia resulted in large reductions in systolic (−17±7 mm Hg) and mean (−14±5 mm Hg) blood pressure in resected patients that were not observed in controls (interaction of group and time, P <0.05). Despite lower blood pressures, increases in heart rate with hypoglycemia were blunted in resected patients (interaction of group and time, P <0.01). Major novel findings from this study demonstrate that intact carotid chemoreceptors are essential for increasing heart rate and maintaining arterial blood pressure during hypoglycemia in humans. These data support a contribution of the carotid chemoreceptors to blood pressure control and highlight the potential widespread effects of carotid body resection in humans.