Sympathetically mediated increases in cardiac output, not restraint of peripheral vasodilation, contribute to blood pressure maintenance during hyperinsulinemia.

Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin.NEW & NOTEWORTHY 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.

Role of the carotid chemoreceptors in insulin-mediated sympathoexcitation in humans.

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.

Reductions in carotid chemoreceptor activity with low-dose dopamine improves baroreflex control of heart rate during hypoxia in humans.

The purpose of the present investigation was to examine the contribution of the carotid body chemoreceptors to changes in baroreflex control of heart rate with exposure to hypoxia. We hypothesized spontaneous cardiac baroreflex sensitivity (scBRS) would be reduced with hypoxia and this effect would be blunted when carotid chemoreceptor activity was reduced with low-dose dopamine. Fifteen healthy adults (11 M/4 F) completed two visits randomized to intravenous dopamine or placebo (saline). On each visit, subjects were exposed to 5-min normoxia (~99% SpO2), followed by 5-min hypoxia (~84% SpO2). Blood pressure (intra-arterial catheter) and heart rate (ECG) were measured continuously and scBRS was assessed by spectrum and sequence methodologies. scBRS was reduced with hypoxia (P < 0.01). Using the spectrum analysis approach, the fall in scBRS with hypoxia was attenuated with infusion of low-dose dopamine (P < 0.01). The decrease in baroreflex sensitivity to rising pressures (scBRS "up-up") was also attenuated with low-dose dopamine (P < 0.05). However, dopamine did not attenuate the decrease in baroreflex sensitivity to falling pressures (scBRS "down-down"; P > 0.05). Present findings are consistent with a reduction in scBRS with systemic hypoxia. Furthermore, we show this effect is partially mediated by the carotid body chemoreceptors, given the fall in scBRS is attenuated when activity of the chemoreceptors is reduced with low-dose dopamine. However, the improvement in scBRS with dopamine appears to be specific to rising blood pressures. These results may have important implications for impairments in baroreflex function common in disease states of acute and/or chronic hypoxemia, as well as the experimental use of dopamine to assess such changes.

Interindividual variability in the dose-specific effect of dopamine on carotid chemoreceptor sensitivity to hypoxia.

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.

Effect of bilateral carotid body resection on cardiac baroreflex control of blood pressure during hypoglycemia.

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.