Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

Hypoxia increases the heart rate response to exercise, but the mechanism(s) remains unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate, but not combined, inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise to exhaustion in normoxia and hypoxia (fraction of inspired O2 = 12%) after intravenous administration of 1) no drugs (Cont), 2) propranolol (Prop), 3) glycopyrrolate (Glyc), or 4) Prop + Glyc. HR increased with exercise in all drug conditions ( P < 0.001) but was always higher at a given workload in hypoxia than normoxia ( P < 0.001). Averaged over all workloads, the difference between hypoxia and normoxia was 19.8 ± 13.8 beats/min during Cont and similar (17.2 ± 7.7 beats/min, P = 0.95) during Prop but smaller ( P < 0.001) during Glyc and Prop + Glyc (9.8 ± 9.6 and 8.1 ± 7.6 beats/min, respectively). Cardiac output was enhanced by hypoxia ( P < 0.002) to an extent that was similar between Cont, Glyc, and Prop + Glyc (2.3 ± 1.9, 1.7 ± 1.8, and 2.3 ± 1.2 l/min, respectively, P > 0.4) but larger during Prop (3.4 ± 1.6 l/min, P = 0.004). Our results demonstrate that the tachycardic effect of hypoxia during exercise partially relies on vagal withdrawal. Conversely, sympathoexcitation either does not contribute or increases heart rate through mechanisms other than β-adrenergic transmission. A potential candidate is α-adrenergic transmission, which could also explain why a tachycardic effect of hypoxia persists during combined β-adrenergic and muscarinic receptor inhibition.

Abstract 432: Up-regulation of Calcyon Increases Arterial Pressure via Enhancement of Adrenergic Transmission

Recent studies suggest a link between blood pressure (BP) and executive functions including working memory, response inhibition, and attention. Older adults and children with hypertension exhibit deficits in working memory and attention; however, it is not clear whether a common mechanism could link the elevation in BP and the cognitive abnormalities. The expression of the Calcyon (Caly), a protein which regulates receptor endocytosis, is increased in the brain of the spontaneously hypertensive rat (SHR), a widely accepted animal model of essential hypertension and attention deficit hyperactivity disorder. We hypothesize that Caly up-regulation in forebrain elevates BP under normal physiological response by altering adrenergic transmission. Radio-telemetry transmitters were implanted in CalOE transgenic mice in which Caly is up-regulated, and in tTA littermate controls. Mean arterial pressure was significantly higher in CalOE mice compared to tTA control (121± 1 vs. 108±1 mmHg, P<0.05). Consistent with deficits in executive functions, CalOE mice were also more active and less able to extinguish a learned behavior than tTA controls. Silencing the transgene with doxycycline treatment improved learning deficits and prevented the elevation in BP in CalOE mice. Plasma nor-epinephrine levels were higher in CalOE vs. tTA control mice (20±2 vs. 13±4 ng/ml). In the brain, dopamine levels were significantly lower in CalOE mice vs. control (0.2 ± 0.02 vs. 0.5±0.08 ng/mg) together with decreased dopamine D1 receptor expression whereas urinary dopamine excretion levels were higher in CalOE vs. control (0.5± 0.1 vs. 0.1± .04 μg/day, P<0.05). These data suggest that up-regulation of Caly in brain could increase BP and compromise inhibitory control mechanisms under normal physiological condition via the differential regulation of adrenergic transmission.

Contrasting effects of phentolamine and nitroprusside on neural and cardiovascular variability

The relative contributions of a central neural oscillator and of the delay in α-adrenergic transmission within the baroreflex loop in the predominance of low-frequency (LF) cardiovascular variability during sympathetic activation in humans are unclear. We measured R-R interval (RR), muscle sympathetic nerve activity (MSNA), blood pressure (BP), and their variability in 10 normal subjects during sympathetic activation achieved by BP lowering with sodium nitroprusside (SNP) and α-adrenergic blockade using phentolamine. SNP and phentolamine induced comparable reductions in BP ( P > 0.25). Despite tachycardia and sympathetic activation with both SNP and phentolamine, LF variability in RR, MSNA, and BP increased during SNP and decreased during phentolamine (SNP: RR +20 ± 6%, MSNA +3 ± 5%, systolic BP +9 ± 6%, diastolic BP +7 ± 5%; phentolamine: RR −2 ± 7%, MSNA −34 ± 6%, systolic BP −16 ± 8%, diastolic BP −13 ± 4%, P< 0.05 except systolic BP, where P = 0.09). Thus LF variability is reduced when sympathetic activation is induced by α-adrenergic blockade. This suggests that α-adrenergic transmission within the baroreflex loop may contribute importantly to the predominance of LF cardiovascular variability associated with sympathetic excitation in humans.