James P. Fisher

Autonomic nervous system influence on arterial baroreflex control of heart rate during exercise in humans

A combination of sympathoexcitation and vagal withdrawal increases heart rate (HR) during exercise, however, their specific contribution to arterial baroreflex sensitivity remains unclear. Eight subjects performed 25 min bouts of exercise at a HR of 90, 120, and 150 beats min−1, respectively, with and without metoprolol (0.16 ± 0.01 mg kg−1; mean ±s.e.m.) or glycopyrrolate (12.6 ± 1.6 μg kg−1). Carotid baroreflex (CBR) function was determined using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr, while transfer function gain (GTF) was calculated to assess the linear dynamic relationship between mean arterial pressure and HR. Spontaneous baroreflex sensitivity (SBR) was evaluated as the slope of sequences of three consecutive beats in which systolic blood pressure and the R–R interval of the ECG either increased or decreased, in a linear fashion. The β‐1 adrenergic blockade decreased and vagal cardiac blockade increased HR both at rest and during exercise (P < 0.05). The gain at the operating point of the modelled reflex function curve (GOP) obtained using NP and NS decreased with workload independent of β‐1 adrenergic blockade. In contrast, vagal blockade decreased GOP from −0.40 ± 0.04 to −0.06 ± 0.01 beats min−1 mmHg−1 at rest (P < 0.05). Furthermore, as workload increased both GOP and SBR, and GOP and GTF were correlated (P < 0.001), suggesting that the two dynamic methods applied to evaluate arterial baroreflex (ABR) function provide the same information as the modelled GOP. These findings suggest that during exercise the reduction of arterial baroreceptor reflex sensitivity at the operating point was a result of vagal withdrawal rather than an increase in sympathetic activity.

The sympathetic nervous system and blood pressure in humans: implications for hypertension

A neurogenic component to primary hypertension (hypertension) is now well established. Along with raised vasomotor tone and increased cardiac output, the chronic activation of the sympathetic nervous system in hypertension has a diverse range of pathophysiological consequences independent of any increase in blood pressure. This review provides a perspective on the actions and interactions of angiotensin II, inflammation and vascular dysfunction/brain hypoperfusion in the pathogenesis and progression of neurogenic hypertension. The optimisation of current treatment strategies and the exciting recent developments in the therapeutic targeting of the sympathetic nervous system to control hypertension (for example, catheter-based renal denervation and carotid baroreceptor stimulation) will be outlined.

Central sympathetic overactivity: Maladies and mechanisms

There is growing evidence to suggest that many disease states are accompanied by chronic elevations in sympathetic nerve activity. The present review will specifically focus on central sympathetic overactivity and highlight three main areas of interest: 1) the pathological consequences of excessive sympathetic nerve activity; 2) the potential role of centrally derived nitric oxide in the genesis of neural dysregulation in disease; and 3) the promise of several novel therapeutic strategies targeting central sympathetic overactivity. The findings from both animal and human studies will be discussed and integrated in an attempt to provide a concise update on current work and ideas in these important areas.

Sprint interval and endurance training are equally effective in increasing muscle microvascular density and eNOS content in sedentary males

Optimal vascular function is critical for health, and endurance training (ET) has previously been shown to be an effective method of improving this. Sprint interval training (SIT) has been proposed as a time efficient alternative to ET but its effect on skeletal muscle microvasculature has not been studied and no direct comparison with ET has been made. ET and SIT in this study were equally effective at decreasing arterial stiffness and increasing skeletal muscle capillarisation and eNOS content. The main results suggest that both training modes improve skeletal muscle microvascular and macrovascular function, with SIT being a time efficient alternative.

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.

Muscle afferent contributions to the cardiovascular response to isometric exercise

The cardiovascular response to isometric exercise is governed by both central and peripheral mechanisms. Both metabolic and mechanical stresses on the exercising skeletal muscle produce cardiovascular change, yet it is often overlooked that the afferent signal arising from the muscle can be modified by factors other than exercise intensity. This review discusses research revealing that muscle fibre type, muscle mass and training status are important factors in modifying this peripheral feedback from the active muscles. Studies in both animals and humans have shown that the pressor response resulting from exercise of muscle with a faster contractile character and isomyosin content is greater than that from a muscle of slower contractile character. Athletic groups participating in training programmes that place a high anaerobic load on skeletal muscle groups show attenuated muscle afferent feedback. Similarly, longitudinal studies have shown that specific local muscle training also blunts the pressor response to isometric exercise. Thus it appears that training may decrease the metabolic stimulation of muscle afferents and in some instances chronic exposure to the products of anaerobic metabolism may blunt the sensitivity of the muscle metaboreflex. There may be surprising parallels between the local muscle conditions induced in athletes training for longer sprint events (e.g. 400 m) and by the low‐flow conditions in, for example, the muscles of chronic heart failure patients. Whether their similar attenuations in muscle afferent feedback during exercise are due to decreased metabolite accumulation or to a desensitization of the muscle afferents is not yet known.

Blood flow in internal carotid and vertebral arteries during orthostatic stress

It remains unclear whether orthostatic stress evokes regional differences in cerebral blood flow. The present study compared blood flow in the internal carotid (ICA) and vertebral arteries (VA) during orthostatic stress (60 deg head‐up tilt; HUT) in six healthy young men. The ICA and VA blood flow were measured using Doppler ultrasonography. Dynamic cerebral autoregulation was also determined during supine (Supine) and HUT conditions, from the rate of regulation (RoR) in cerebrovascular conductance of the ICA and VA during acute hypotension induced by the release of bilateral thigh‐cuffs. The HUT decreased ICA blood flow by −9.4 ± 1.7% (P < 0.01 versus Supine), leaving ICA conductance unchanged. In contrast, there was no significant difference in VA blood flow between Supine and HUT, and VA conductance increased (+12.9 ± 0.8%, P < 0.01). In addition, dynamic cerebral autoregulation in both the ICA and VA was attenuated during HUT, and the magnitude of the attenuation in RoR was greater in the VA [0.25 ± 0.03 s−1 Supine versus 0.16 ± 0.02 s−1 HUT (−33.9 ± 5.8%); P < 0.05] compared with the ICA [0.23 ± 0.02 s−1 Supine versus 0.20 ± 0.03 s−1 HUT (−10.6 ± 13.4%); P > 0.05]. These data indicate that orthostatic stress evokes regional differences in cerebral blood flow and possible differences in dynamic cerebral autoregulation between two main brain vascular areas in response to an acute change in blood pressure during orthostatic stress.

The effect of phenylephrine on arterial and venous cerebral blood flow in healthy subjects

Aim:  Sympathetic regulation of the cerebral circulation remains controversial. Although intravenous phenylephrine (PE) infusion reduces the near‐infrared spectroscopy (NIRS)‐determined measure of frontal lobe oxygenation (ScO2) and increases middle cerebral artery mean blood velocity (MCA Vmean), suggesting α‐adrenergic‐mediated cerebral vasoconstriction, this remains unconfirmed by evaluation of arterial and venous cerebral blood flow.

Cardiovascular responses to human calf muscle stretch during varying levels of muscle metaboreflex activation.

The purpose of the present study was to investigate the cardiovascular responses to muscle metaboreflex‐ and concurrent muscle stretch‐induced mechanoreflex activation. Eight subjects (7 males, 1 female) performed 90 s of isometric calf plantarflexion at 0, 30, 50 and 70% of maximum voluntary contraction. During exercise and for 3.5 min postexercise, circulatory occlusion (PECO) was ensured by inflation of a thigh cuff. After 90 s of PECO the calf muscle was stretched for 60 s (Stretch). Heart rate (HR; assessed from ECG), blood pressure (BP; Finapres) and phase of respiratory cycle were recorded. Exercise increased diastolic BP (DBP) from rest by 1 ± 0.8, 14 ± 2.5, 29 ± 3.9 and 35 ± 3.6 mmHg, during the 0, 30, 50 and 70% conditions, respectively (ANOVA rest versus exercise, P < 0.05). During PECO DBP remained elevated, by 2 ± 0.4, 8 ± 0.3, 12 ± 0.3 and 13 ± 0.9 mmHg, respectively. Stretch produced a further increase in DBP that was not different between conditions (3 ± 1.4, 2 ± 0.8, 3 ± 1.0 and 3 ± 0.9 mmHg, for the 0, 30, 50 and 70%, respectively). HR increased during exercise but returned to baseline during PECO. HR increased at Stretch onset in all conditions. No EMG was detected from the gastrocnemius and soleus during Stretch. Our data show that the cardiovascular responses to human calf Stretch are independent of the level of concurrent muscle metaboreflex activation.

Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension

The pathogenesis of hypertension and its mode of progression are complex, multifactoral and incompletely understood. However, there is accumulating evidence from humans and animal models of hypertension indicating that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in triggering and sustaining the essential hypertensive state (the so‐called ‘neuroadrenergic hypothesis’). Importantly, augmented central sympathetic outflow has also been implicated in the initiation and progression of a plethora of pathophysiological processes independent of any increase in blood pressure, such as left ventricular hypertrophy and cardiac arrhythmias. Thus, the sympathetic nervous system constitutes an important putative drug target in hypertension. However, traditional pharmacological approaches for the management of essential hypertension appear ineffective in reducing central sympathetic outflow. Recently, several new and promising therapeutic strategies targeting neurogenic hypertension have been developed. The present report will provide a brief update of this topic with a particular emphasis on human studies examining the efficacy of novel pharmacological approaches (central sympatholytics and statins), lifestyle modification (aerobic exercise training, weight loss and stress reduction) and surgical intervention (renal denervation, chronic carotid baroreflex stimulation and deep brain stimulation) in reducing excessive central sympathetic activation in hypertension.