Although drug treatment of human hypertension has greatly improved, there is renewed interest in non-drug methods of blood pressure reduction. Animal experiments have now shown that arterial baroreflexes do control long-term blood pressure levels, particularly by nervously mediated renal excretion of sodium and water. This Paton Lecture provides a review of the historical development of knowledge of peripheral circulatory control in order to supplement prior Paton Lectures concerned with cerebral cortical and other areas of influence. I also discuss how improved understanding of nervous control of the circulation has led to current methods of non-drug blood pressure control in man by implanted carotid baroreceptor pacemakers or by renal denervation. Finally, the role of other therapy, particularly listening to music, is reviewed.
Tonic arterial chemoreceptor activity contributes to cardiac sympathetic activation in mild ovine heart failure
Heart failure (HF) is associated with a large increase in cardiac sympathetic nerve activity (CSNA), which has detrimental effects on the heart and promotes arrhythmias and sudden death. There is increasing evidence that arterial chemoreceptor activation plays an important role in stimulating renal sympathetic nerve activity (RSNA) and muscle sympathetic nerve activity in HF. Given that sympathetic nerve activity to individual organs is differentially controlled, we investigated whether tonic arterial chemoreceptor activation contributes to the increased CSNA in HF. We recorded CSNA and RSNA in conscious normal sheep and in sheep with mild HF induced by rapid ventricular pacing (ejection fraction <40%). Tonic arterial chemoreceptor function was evaluated by supplementing room air with 100% intranasal oxygen (2–3 l min–1) for 20 min, thereby deactivating chemoreceptors. The effects of hyperoxia on resting levels and baroreflex control of heart rate, CSNA and RSNA were determined. In HF, chemoreceptor deactivation induced by hyperoxia significantly reduced CSNA [90 ± 2 versus 75 ± 5 bursts (100 heart beats)–1, P < 0.05, n = 10; room air versus hyperoxia] and heart rate (96 ± 4 versus 85 ± 4 beats min–1, P < 0.001, n = 12). There was no change in RSNA burst incidence [93 ± 4 versus 92 ± 4 bursts (100 heart beats)–1, n = 7], although due to the bradycardia the RSNA burst frequency was decreased (90 ± 8 versus 77 ± 7 bursts min–1, P < 0.001). In normal sheep, chemoreceptor deactivation reduced heart rate without a significant effect on CSNA or RSNA. In summary, deactivation of peripheral chemoreceptors during HF reduced the elevated levels of CSNA, indicating that tonic arterial chemoreceptor activation plays a critical role in stimulating the elevated CSNA in HF.
AGTR2 gene polymorphism is associated with muscle fibre composition, athletic status and aerobic performance
Muscle fibre type is a heritable trait and can partly predict athletic success. It has been proposed that polymorphisms of genes involved in the regulation of muscle fibre characteristics may predispose the muscle precursor cells of a given individual to be predominantly fast or slow. In the present study, we examined the association between 15 candidate gene polymorphisms and muscle fibre type composition of the vastus lateralis muscle in 55 physically active, healthy men. We found that rs11091046 C allele carriers of the angiotensin II type 2 receptor gene (AGTR2; involved in skeletal muscle development, metabolism and circulatory homeostasis) had a significantly higher percentage of slow-twitch fibres than A allele carriers [54.2 (11.1) versus 45.2 (10.2)%; P = 0.003]. These data indicate that 15.2% of the variation in muscle fibre composition of the vastus lateralis muscle can be explained by the AGTR2 genotype. Next, we investigated the frequencies of the AGTR2 alleles in 2178 Caucasian athletes and 1220 control subjects. The frequency of the AGTR2 C allele was significantly higher in male and female endurance athletes compared with power athletes (males, 62.7 versus 51.7%, P = 0.0038; females, 56.6 versus 48.1%, P = 0.0169) and control subjects (males, 62.7 versus 51.0%, P = 0.0006; elite female athletes, 65.1 versus 55.2%, P = 0.0488). Furthermore, the frequency of the AGTR2 A allele was significantly over-represented in female power athletes (51.9%) in comparison to control subjects (44.8%, P = 0.0069). We also found that relative maximal oxygen consumption was significantly greater in male endurance athletes with the AGTR2 C allele compared with AGTR2 A allele carriers [n = 28; 62.3 (4.4) versus 57.4 (6.0) ml min–1 kg–1; P = 0.0197]. Taken together, these results demonstrate that the AGTR2 gene C allele is associated with an increased proportion of slow-twitch muscle fibres, endurance athlete status and aerobic performance, while the A allele is associated with a higher percentage of fast-twitch fibres and power-oriented disciplines.
This study tested the hypothesis that during fatiguing quadriceps exercise, supraspinal fatigue develops late, is associated with both increased corticospinal excitability and inhibition and recovers quickly. Eight subjects performed 20 s contractions [15 s at 50% maximal voluntary contraction (MVC) followed by 5 s MVC] separated by a 10 s rest period until task failure. Transcranial magnetic stimulation (TMS) and electrical femoral nerve stimulation (PNS) were delivered ~2 s apart during 50% MVC, during MVC and after MVC in relaxed muscle. Voluntary activation was assessed by TMS (VATMS) immediately before and after exercise and then three times over a 6 min recovery period. During exercise, MVC and twitch force evoked by PNS in relaxed muscle decreased progressively to 48 ± 8 and 36 ± 16% of control values, respectively (both P < 0.01). Significant changes in voluntary activation assessed by PNS and twitch evoked by TMS during MVC were observed during the last quarter of exercise only (from 96.4 ± 1.7 to 86 ± 13%, P = 0.03 and from 0.76 ± 0.8 to 4.9 ± 4.7% MVC, P = 0.02, from baseline to task failure, respectively). The TMS-induced silent period increased linearly during both MVC (by ~79 ms) and 50% MVC (by ~63 ms; both P < 0.01). Motor-evoked potential amplitude did not change during the protocol at any force levels. Both silent period and VATMS recovered within 2 min postexercise, whereas MVC and twitch force evoked by PNS in relaxed muscle recovered to only 84 ± 9 and 73 ± 17% of control values 6 min after exercise, respectively. In conclusion, high-intensity single-joint quadriceps exercise induces supraspinal fatigue near task failure, with increased intracortical inhibition and, in contrast to previous upper-limb results, unchanged corticospinal excitability. These changes recover rapidly after task failure, emphasizing the need to measure corticospinal adaptations immediately at task failure to avoid underestimation of exercise-induced corticospinal changes.
Amelioration of capillary regression and atrophy of the soleus muscle in hindlimb-unloaded rats by astaxanthin supplementation and intermittent loading
A chronic decrease in neuromuscular activity (activation and/or loading) results in muscle atrophy and capillary regression that are due, in part, to the overproduction of reactive oxygen species. We have reported that antioxidant treatment with astaxanthin attenuates the overexpression of reactive oxygen species in atrophied muscles that, in turn, ameliorates capillary regression in hindlimb-unloaded rats. Astaxanthin supplementation, however, had little effect on muscle mass and fibre cross-sectional area. In contrast, intermittent loading of the hindlimbs of hindlimb-unloaded rats ameliorates muscle atrophy. Therefore, we hypothesized that the combination of astaxanthin supplementation and intermittent loading would attenuate both muscle atrophy and capillary regression during hindlimb unloading. As expected, 2 weeks of hindlimb unloading resulted in atrophy, a decrease in capillary volume and a shift towards smaller-diameter capillaries in the soleus muscle. Intermittent loading alone (1 h of cage ambulation per day) attenuated atrophy of the soleus, while astaxanthin treatment alone maintained the capillary network to near control levels. The combination of intermittent loading and astaxanthin treatment, however, ameliorated atrophy of the soleus and maintained the capillary volume and luminal diameters and the superoxide dismutase-1 protein levels near control values. These results indicate that intermittent loading combined with astaxanthin supplementation could be an effective therapy for both the muscle atrophy and the capillary regression associated with a chronic decrease in neuromuscular activity.
Ankle dorsiflexor muscle size, composition and force with ageing and chronic obstructive pulmonary disease
Loss of skeletal muscle strength is a well-recognized feature of ageing and chronic obstructive pulmonary disease (COPD). Reductions in muscle size provide only a partial explanation for this loss of strength, and additional contributory factors remain undetermined. We hypothesized that reductions in skeletal muscle strength, as measured in the ankle dorsiflexor muscles, would be reduced with ageing and COPD as a result of changes in both size and composition of the tibialis anterior muscle. Twenty healthy young subjects, 18 healthy elderly subjects and 17 patients with COPD were studied. Ankle dorsiflexor muscle strength was assessed by maximal voluntary contraction (ADMVC) and 100 Hz supramaximal electrical stimulation of the peroneal nerve (100 HzAD). Tibialis anterior cross-sectional area (TACSA) and composition, as assessed by echo intensity (TAEI), were measured using ultrasonography. Despite a lack of differences in TACSA between groups, ADMVC and 100 HzAD were significantly reduced in COPD patients compared with both healthy elderly and healthy young subjects, when expressed as absolute values and when normalized to TACSA (P < 0.01). The TAEI was, however, higher in COPD patients compared with healthy elderly (P = 0.025) and healthy young subjects (P = 0.0008), suggesting increased levels of non-contractile tissue. Across all participants, ADMVC and 100 HzAD correlated positively with TACSA (r = 0.78, P < 0.0001) and negatively with TAEI (r = –0.46, P < 0.0005). The variance in 100 HzAD was best explained with a regression model incorporating TACSA, TAEI, age and COPD status (r2 = 0.822, P = 0.001). These data demonstrate that the loss of skeletal muscle strength in COPD is related to changes in muscle composition, with infiltration of non-contractile tissue beyond that seen during normal ageing.
Studies on experimental animals established that the carotid bodies are sensory organs for detecting arterial blood O2 levels and that the ensuing chemosensory reflex is a major regulator of cardiorespiratory functions during hypoxia. However, little information is available on the human carotid body responses to hypoxia. The present study was performed on human carotid bodies obtained from surgical patients undergoing elective head and neck cancer surgery. Our results show that exposing carotid body slices to hypoxia for a period as brief as 5 min markedly facilitates the release of ACh and ATP. Furthermore, prolonged hypoxia for 1 h induces an increased release of interleukin (IL)-1β, IL-4, IL-6, IL-8 and IL-10. Immunohistochemical analysis revealed that type 1 cells of the human carotid body express an array of cytokine receptors as well as hypoxia-inducible factor-1α and hypoxia-inducible factor-2α. Taken together, these results demonstrate that ACh and ATP are released from the human carotid body in response to hypoxia, suggesting that these neurotransmitters, as in several experimental animal models, play a role in hypoxic signalling also in the human carotid body. The finding that the human carotid body releases cytokines in response to hypoxia adds to the growing body of information suggesting that the carotid body may play a role in detecting inflammation, providing a link between the immune system and the nervous system.