Doreen Hartwich

Autonomic control of heart rate by metabolically sensitive skeletal muscle afferents in humans.

Isolated activation of metabolically sensitive skeletal muscle afferents (muscle metaboreflex) using post‐exercise ischaemia (PEI) following handgrip partially maintains exercise‐induced increases in arterial blood pressure (BP) and muscle sympathetic nerve activity (SNA), while heart rate (HR) declines towards resting values. Although masking of metaboreflex‐mediated increases in cardiac SNA by parasympathetic reactivation during PEI has been suggested, this has not been directly tested in humans. In nine male subjects (23 ± 5 years) the muscle metaboreflex was activated by PEI following moderate (PEI‐M) and high (PEI‐H) intensity isometric handgrip performed at 25% and 40% maximum voluntary contraction, under control (no drug), parasympathetic blockade (glycopyrrolate) and β‐adrenergic blockade (metoprolol or propranalol) conditions, while beat‐to‐beat HR and BP were continuously measured. During control PEI‐M, HR was slightly elevated from rest (+3 ± 2 beats min−1); however, this HR elevation was abolished with β‐adrenergic blockade (P < 0.05 vs. control) but augmented with parasympathetic blockade (+8 ± 2 beats min−1, P < 0.05 vs. control and β‐adrenergic blockade). The HR elevation during control PEI‐H (+9 ± 3 beats min−1) was greater than with PEI‐M (P < 0.05), and was also attenuated with β‐adrenergic blockade (+4 ± 2 beats min−1, P < 0.05 vs. control), but was unchanged with parasympathetic blockade (+9 ± 2 beats min−1, P > 0.05 vs. control). BP was similarly increased from rest during PEI‐M and further elevated during PEI‐H (P < 0.05) in all conditions. Collectively, these findings suggest that the muscle metaboreflex increases cardiac SNA during PEI in humans; however, it requires a robust muscle metaboreflex activation to offset the influence of cardiac parasympathetic reactivation on heart rate.

Cerebral perfusion, oxygenation and metabolism during exercise in young and elderly individuals

•  The influence of normative ageing on cerebral perfusion, oxygenation and metabolism during exercise is not well known. •  This study assessed cerebral perfusion and concentration differences for oxygen, glucose and lactate across the brain, in young and elderly individuals at rest and during incremental exercise to exhaustion. •  We observed that during submaximal exercise (at matched relative intensities) and during maximal exercise, cerebral perfusion was reduced in older individuals compared with young individuals, while the cerebral metabolic rate for oxygen and uptake of glucose and lactate were similar. •  The results indicate that the age‐related reduction in cerebral perfusion during exercise does not affect brain uptake of lactate and glucose.

Sex differences in carotid baroreflex control of arterial blood pressure in humans: relative contribution of cardiac output and total vascular conductance

It is presently unknown whether there are sex differences in the magnitude of blood pressure (BP) responses to baroreceptor perturbation or if the relative contribution of cardiac output (CO) and total vascular conductance (TVC) to baroreflex-mediated changes in BP differs in young women and men. Since sympathetic vasoconstrictor tone is attenuated in women, we hypothesized that carotid baroreflex-mediated BP responses would be attenuated in women by virtue of a blunted vascular response (i.e., an attenuated TVC response). BP, heart rate (HR), and stroke volume were continuously recorded during the application of 5-s pulses of neck pressure (NP; carotid hypotension) and neck suction (NS; carotid hypertension) ranging from +40 to -80 Torr in women (n = 20, 21 ± 0.5 yr) and men (n = 20, 21 ± 0.4 yr). CO and TVC were calculated on a beat-to-beat basis. Women demonstrated greater depressor responses to NS (e.g., -60 Torr, -17 ± 1%baseline in women vs. -11 ± 1%baseline in men, P < 0.05), which were driven by augmented decreases in HR that, in turn, contributed to larger reductions in CO (-60 Torr, -15 ± 2%baseline in women vs. -6 ± 2%baseline in men, P < 0.05). In contrast, pressor responses to NP were similar in women and men (e.g., +40 Torr, +14 ± 2%baseline in women vs. +10 ± 1%baseline in men, P > 0.05), with TVC being the primary mediating factor in both groups. Our findings indicate that sex differences in the baroreflex control of BP are evident during carotid hypertension but not carotid hypotension. Furthermore, in contrast to our hypothesis, young women exhibited greater BP responses to carotid hypertension by virtue of a greater cardiac responsiveness.

Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans.

Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise‐induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O2, glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA Vmean; transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n= 9) and the MCA Vmean during ergometer cycling (n= 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from ∼60 to ∼110 beats min−1 (P < 0.01) and cardiac output by ∼40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA Vmean (∼16%; P < 0.01) and CBF (∼12%; P < 0.01) during static handgrip, as well as the increase in MCA Vmean during cycling (∼15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise‐induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.

Experimental Physiology –Research Paper: Glycopyrrolate abolishes the exercise‐induced increase in cerebral perfusion in humans

Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise‐induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O2, glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA Vmean; transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n= 9) and the MCA Vmean during ergometer cycling (n= 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from ∼60 to ∼110 beats min−1 (P < 0.01) and cardiac output by ∼40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA Vmean (∼16%; P < 0.01) and CBF (∼12%; P < 0.01) during static handgrip, as well as the increase in MCA Vmean during cycling (∼15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise‐induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.

Differential responses to sympathetic stimulation in the cerebral and brachial circulations during rhythmic handgrip exercise in humans.

The sympathetic neural regulation of the cerebral circulation remains controversial. The purpose of the present study was to determine how exercise modulates the simultaneous responsiveness of the cerebral and brachial circulations to ‘endogenous’ sympathetic activation (cold pressor test). In nine healthy subjects, heart rate (HR) and mean arterial blood pressure (MAP) were continuously measured during cold pressor tests (4°C water) conducted at rest and during randomized bouts of rhythmic handgrip of 10, 25 and 40% of maximal voluntary contraction. Doppler ultrasound was used to examine brachial artery blood flow (FBF) and middle cerebral artery (MCA) mean blood velocity (Vmean), and indices of vascular conductance were calculated for the brachial artery (forearm vascular conductance, FVC) and MCA (cerebral vascular conductance index, CVCi). End‐tidal   was evaluated on a breath‐by‐breath basis. Handgrip evoked increases in HR, FBF, FVC and MCA Vmean (P < 0.05 versus rest), while MAP and CVCi were unchanged and fell slightly (P < 0.05 versus rest). Increases in MAP and HR during the cold pressor test were similar at rest and during all handgrip trials. Forearm vascular conductance was markedly reduced with the cold pressor test at rest (−45 ± 8%), but this vasoconstrictor effect was progressively attenuated with increasing exercise intensity (FVC −17 ± 3% during exercise at 40% of maximal voluntary contraction; P < 0.05). In contrast, the small reduction in CVCi with cold pressor test was similar at rest and during handgrip (approximately −5%). Our data indicate that while the marked vasoconstrictor responses to sympathetic activation in the skeletal muscle vasculature are blunted by handgrip exercise, the modest cerebrovascular responses to a cold pressor test remain unchanged.

Effect of muscle metaboreflex activation on spontaneous cardiac baroreflex sensitivity during exercise in humans

Non‐technical summary  The ‘arterial baroreflex’ plays an important role in the moment‐to‐moment regulation of blood pressure. It does this partly by eliciting changes in heart rate, but its ability to do this (i.e. sensitivity) during exercise is reduced from rest. During exercise, chemicals accumulate in the muscles (i.e. metabolites) that stimulate sensory nerves within the muscle (i.e. muscle metaboreflex). We show for the first time in humans that the stimulation of metabolically sensitive nerves within the muscles during leg cycling exercise decreases arterial baroreflex sensitivity. This new knowledge increases our understanding of the control of the human heart during exercise.

Influence of menstrual cycle phase on muscle metaboreflex control of cardiac baroreflex sensitivity, heart rate and blood pressure in humans

•  What is the central question of this study? Oestrogen has been reported to modify exercise‐induced autonomic responses and to impact on exercising skeletal muscle blood flow. Together, these oestrogenic influences might attenuate metabolite accumulation and muscle metaboreflex activation during exercise. Moreover, in dogs and in humans, the muscle metaboreflex has been reported to decrease cardiac baroreflex sensitivity during dynamic exercise. •  What is the main finding and its importance? Endogenous fluctuations in oestrogen between the early and late follicular phases of the menstrual cycle in healthy women, do not modify either the increase in heart rate and blood pressure or the reduction in spontaneous cardiac baroreflex sensitivity evoked by muscle metaboreflex activation.

Reply from James P. Fisher, Thomas Seifert, Doreen Hartwich, Colin N. Young, Niels H. Secher and Paul J. Fadel

We are grateful to C. F. Notarius and J. S. Floras for their interest in our recent article (Fisher et al. 2010) and for highlighting the previous work they performed in patients with heart failure indicating a potential role for muscle metaboreflex-mediated cardiac sympatho-excitation (Notarius et al. 2001). The alterations in neural cardiovascular regulation that occur during exercise in heart failure have been an intense area of investigation for quite some time, with often inconsistent findings leading to lively debate (Piepoli & Coats, 2007). However, this debate has centred largely on the regulation of sympathetic vasoconstrictor tone, blood pressure or ventilation, rather than on heart rate per se. As such, the significantly elevated heart rate observed during isolated muscle metaboreflex activation with post-exercise muscle ischaemia (PEI) in heart failure patients compared with healthy controls reported by Notarius et al. (2001) is particularly intriguing. These findings concur with our speculations derived from autonomic blockade studies in healthy young subjects. Indeed, the muscle metaboreflex can increase cardiac sympathetic drive and heart rate during PEI in humans, an effect that appears enhanced when reductions in cardiac parasympathetic control are manifest. However, it should be noted that a muscle metaboreflex-mediated increase in heart rate in the setting of heart failure does not seem to be a universal observation (Piepoli et al. 1996; Carrington et al. 2004). The reason for these discrepant findings is unclear but may be explained by heterogeneity in the patient populations and muscle groups studied as well as the intensity of muscle metaboreflex activation achieved. In regards to the latter, an advantage of both our work (Fisher et al. 2010) and the study of Notarius et al. (2001) is that multiple graded intensities of handgrip and PEI were utilized, thus maximizing muscle metaboreflex activation. Indeed, it appears that robust muscle metaboreflex activation may be needed to discern clear reflex-mediated heart rate effects. Interestingly, in the study of Notarius et al. (2001) a sustained heart rate elevation was observed during PEI despite 71% of the heart failure patients taking a β-1 blocker. As such, it may be of interest to specifically examine the heart rate responses of those patients that were not on a β-1 blocker. One might speculate that the greatest heart rate elevation would be seen in this group, perhaps indicating another benefit of β-blockade in heart failure patients. Due to its prognostic significance, the kinetics of heart rate recovery from exercise has received much attention. Indeed, a rapid heart rate recovery following exercise has been attributed to vagal reactivation and a sign of healthy heart rate control (Imai et al. 1994), whilst a delayed heart rate recovery is a powerful independent predictor of mortality even in low risk patients (Cole et al. 1999). However, the precise mechanisms underlying the rate of heart rate recovery from exercise have remained obscure in humans (i.e. central command, metaboreflex, mechanoreflex, arterial baroreflex); although we believe our recent data may be somewhat helpful in this regard. We suggest that in humans, as has been previously shown in dogs (O’Leary, 1993), the activation of metabolically sensitive muscle afferents can elicit a sympathetically mediated tachycardia that is ordinarily masked during PEI by the over-riding reactivation of cardiac parasympathetic activity due to arterial baroreflex activation and/or loss of inhibitory central command and muscle mechanoreflex inputs to parasympathetic neurons (Fisher et al. 2010). Although there are obvious differences between exercise recovery under occluded versus free flow conditions, it is plausible that in clinical situations where exaggerated skeletal muscle afferent activity is coupled with impairments in cardiac parasympathetic reactivation, sustained elevations in heart rate and a more sluggish heart rate recovery would be evident in the period immediately following exercise. The data of Notarius et al. (2001) add weight to this contention. Overall, these collective studies in animals (O’Leary, 1993), healthy humans (Fisher et al. 2010) and heart failure patients (Notarius et al. 2001) tend to corroborate one another, which is encouraging in light of the present emphasis on clinical translational science.

Experimental Physiology -Research Paper: Glycopyrrolate abolishes the exercise-induced increase in cerebral perfusion in humans: Glycopyrrolate and cerebral blood flow during exercise

Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise‐induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O2, glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA Vmean; transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n= 9) and the MCA Vmean during ergometer cycling (n= 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from ∼60 to ∼110 beats min−1 (P < 0.01) and cardiac output by ∼40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA Vmean (∼16%; P < 0.01) and CBF (∼12%; P < 0.01) during static handgrip, as well as the increase in MCA Vmean during cycling (∼15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise‐induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.