Limb neurovascular control during altered otolithic input in humans

Head-down rotation (HDR), which activates the vestibulosympathetic reflex, increases leg muscle sympathetic nerve activity (MSNA) and produces calf vasoconstriction with no change in either cardiac output or arterial blood pressure. Based on animal studies, it was hypothesized that differential control of arm and leg MSNA explains why HDR does not alter arterial blood pressure. Fifteen healthy subjects were studied. Heart rate, arterial blood pressure, forearm and calf blood flow, and leg MSNA responses were measured during HDR in these subjects. Simultaneous recordings of arm and leg MSNA were obtained from five of the subjects. Forearm and calf blood flow, vascular conductances, and vascular resistances were similar before HDR, as were arm and leg MSNA. HDR elicited similar significant increases in leg (Δ6 ± 1 bursts min⁻¹; 59 ± 16 % from baseline) and arm MSNA (Δ5 ± 1 bursts min⁻¹; 80 ± 28 % from baseline). HDR significantly decreased calf (−19 ± 2 %) and forearm vascular conductance (−12 ± 2 %) and significantly increased calf (25 ± 4 %) and forearm vascular resistance (15 ± 2 %), with ∼60 % greater vasoconstriction in the calf than in the forearm. Arterial blood pressure and heart rate were not altered by HDR. These results indicate that there is no differential control of MSNA in the arm and leg during altered feedback from the otolith organs in humans, but that greater vasoconstriction occurs in the calf than in the forearm. These findings indicate that vasodilatation occurs in other vascular bed(s) to account for the lack of increase in arterial blood pressure during HDR.     

Carotid chemoreceptor modulation of sympathetic vasoconstrictor outflow during exercise in healthy humans

Recently, we have shown that specific, transient carotid chemoreceptor (CC) inhibition in exercising dogs causes vasodilatation in limb muscle. The purpose of the present investigation was to determine if CC suppression reduces muscle sympathetic nerve activity (MSNA) in exercising humans. Healthy subjects ( N = 7) breathed hyperoxic gas ( F _IO2∼1.0) for 60 s at rest and during rhythmic handgrip exercise (50% maximal voluntary contraction, 20 r.p.m.). Microneurography was used to record MSNA in the peroneal nerve. End-tidal P _CO2 was maintained at resting eupnoeic levels throughout and breathing rate was voluntarily fixed. Exercise increased heart rate (67 versus 77 beats min⁻¹), mean blood pressure (81 versus 97 mmHg), MSNA burst frequency (28 versus 37 bursts min⁻¹) and MSNA total minute activity (5.7 versus 9.3 units), but did not change blood lactate (0.7 versus 0.7 m m ). Transient hyperoxia had no significant effect on MSNA at rest. In contrast, during exercise both MSNA burst frequency and total minute activity were significantly reduced with hyperoxia. MSNA burst frequency was reduced within 9–23 s of end-tidal P _O2 exceeding 250 mmHg. The average nadir in MSNA burst frequency and total minute activity was −28 ± 2% and −39 ± 7%, respectively, below steady state normoxic values. Blood pressure was unchanged with hyperoxia at rest or during exercise. CC stimulation with transient hypoxia increased MSNA with a similar time delay to that obtained with CC inhibition via hyperoxia. Consistent with previous animal work, these data indicate that the CC contributes to exercise-induced increases in sympathetic vasoconstrictor outflow.     

Sympathetic responses during saline infusion into the veins of an occluded limb

Animal studies have shown that the increased intravenous pressure stimulates the group III and IV muscle afferent fibres, and in turn induce cardiovascular responses. However, this pathway of autonomic regulation has not been examined in humans. The aim of this study was to examine the hypothesis that infusion of saline into the venous circulation of an arterially occluded vascular bed evokes sympathetic activation in healthy individuals. Blood pressure, heart rate, and muscle sympathetic nerve activity (MSNA) responses were assessed in 19 young healthy subjects during local infusion of 40 ml saline into a forearm vein in the circulatory arrested condition. From baseline (11.8 ± 1.2 bursts min⁻¹), MSNA increased significantly during the saline infusion (22.5 ± 2.6 bursts min⁻¹, P < 0.001). Blood pressure also increased significantly during the saline infusion. Three control trials were performed during separate visits. The results from the control trial show that the observed MSNA and blood pressure responses were not due to muscle ischaemia. The present data show that saline infusion into the venous circulation of an arterially occluded vascular bed induces sympathetic activation and an increase in blood pressure. We speculate that the infusion under such conditions stimulates the afferent endings near the vessels, and evokes the sympathetic activation.     

Glucose clearance is higher in arm than leg muscle in type 2 diabetes

Insulin-mediated glucose clearance (GC) is diminished in type 2 diabetes. Skeletal muscle has been estimated to account for essentially all of the impairment. Such estimations were based on leg muscle and extrapolated to whole body muscle mass. However, skeletal muscle is not a uniform tissue and insulin resistance may not be evenly distributed. We measured basal and insulin-mediated (1 pmol min⁻¹ kg⁻¹) GC simultaneously in the arm and leg in type 2 diabetes patients (TYPE 2) and controls (CON) ( n = 6 for both). During the clamp arterio-venous glucose extraction was higher in CON versus TYPE 2 in the arm (6.9 ± 1.0 versus 4.7 ± 0.8%; mean ± s.e.m. ; P = 0.029), but not in the leg (4.2 ± 0.8 versus 3.1 ± 0.6%). Blood flow was not different between CON and TYPE 2 but was higher ( P < 0.05) in arm versus leg (CON: 74 ± 8 versus 56 ± 5; TYPE 2: 87 ± 9 versus 43 ± 6 ml min⁻¹ kg⁻¹ muscle, respectively). At basal, CON had 84% higher arm GC ( P = 0.012) and 87% higher leg GC ( P = 0.016) compared with TYPE 2. During clamp, the difference between CON and TYPE 2 in arm GC was diminished to 54% but maintained at 80% in the leg. In conclusion, this study shows that glucose clearance is higher in arm than leg muscles, regardless of insulin resistance, which may indicate better preserved insulin sensitivity in arm than leg muscle in type 2 diabetes.     

Arm Blood Flow and Oxygenation on the Transition from Arm to Combined Arm and Leg Exercise in Humans

The cardiovascular response to exercise with several groups of skeletal muscle implies that work with the legs may reduce arm blood flow. This study followed arm blood flow ( _arm) and oxygenation on the transition from arm cranking (A) to combined arm and leg exercise (A+L). Seven healthy male subjects performed A at ∼80 % of maximum work rate ( W _max) and A at ∼80 % W _max combined with L at ∼60 % W _max. A transition trial to volitional exhaustion was performed where L was added after 2 min of A. The _arm was determined by constant infusion thermodilution in the axillary vein and changes in biceps muscle oxygenation were measured with near-infrared spectroscopy. During A+L _arm was lowered by 0.38 ± 0.06 l min⁻¹ (10.4 ± 3.3 %,   P < 0.05  ) from 2.96 ± 1.54 l min⁻¹ during A. Total (HbT) and oxygenated haemoglobin (HbO₂) concentrations were also lower. During the transition from A to A+L _arm decreased by 0.22 ± 0.03 l min⁻¹ (7.9 ± 1.8 %,   P < 0.05  ) within 9.6 ± 0.2 s, while HbT and HbO₂ decreased similarly within 30 ± 2 s. At the same time mean arterial pressure and arm vascular conductance also decreased. The data demonstrate reduction in blood flow to active skeletal muscle during maximal whole body exercise to a degree that arm oxygen uptake and muscle tissue oxygenation are compromised.     

Reduced α-adrenoceptor responsiveness and enhanced baroreflex sensitivity in Cry-deficient mice lacking a biological clock

To reveal the role of clock genes in generating the circadian rhythm of baroreflexes, we continuously measured mean arterial pressure and baroreflex sensitivity in free-moving normal wild-type mice, and in Cry -deficient mice which lack a circadian rhythm, in constant darkness for 24 h. In wild-type mice the mean arterial pressure was higher at night than during the day, and was accompanied by a significantly enhanced baroreflex sensitivity of −13.6 ± 0.8 at night compared with −9.7 ± 0.7 beats min⁻¹ mmHg⁻¹ during the day ( P < 0.001). On the other hand, diurnal changes in arterial pressure disappeared in Cry -deficient mice with remarkably enhanced baroreflex sensitivity compared with wild-type mice ( P < 0.001): −21.9 ± 1.6 at night and −23.1 ± 2.1 beats min⁻¹ mmHg⁻¹ during the day. Moreover, the mean arterial pressure response to 10 μg kg⁻¹ of phenylephrine, an α₁-adrenoceptor agonist, was severely suppressed in Cry -deficient mice regardless of time, while that for the wild-type mice was 10.1 ± 1.9 mmHg in the night, significantly lower than 22.0 ± 3.5 mmHg in the day ( P < 0.01). These results suggest that CRY genes are involved in generating the circadian rhythm of baroreflex sensitivity, partially by regulating α₁-adrenoceptor-mediated vasoconstriction in peripheral vessels.     

Central modulation of exercise-induced muscle pain in humans

The purpose of the current study was to determine if exercise-induced muscle pain is modulated by central neural mechanisms (i.e. higher brain systems). Ratings of muscle pain perception (MPP) and perceived exertion (RPE), muscle sympathetic nerve activity (MSNA), arterial pressure, and heart rate were measured during fatiguing isometric handgrip (IHG) at 30% maximum voluntary contraction and postexercise muscle ischaemia (PEMI). The exercise trial was performed twice, before and after administration of naloxone (16 mg intravenous; n = 9) and codeine (60 mg oral; n = 7). All measured variables increased with exercise duration. During the control trial in all subjects ( n = 16), MPP significantly increased during PEMI above ratings reported during IHG (6.6 ± 0.8 to 9.5 ± 1.0; P < 0.01). However, MSNA did not significantly change compared with IHG (7 ± 1 to 7 ± 1 bursts (15 s)⁻¹), whereas mean arterial blood pressure was slightly reduced (104 ± 4 to 100 ± 3 mmHg; P < 0.05) and heart rate returned to baseline values during PEMI (83 ± 3 to 67 ± 2 beats min⁻¹; P < 0.01). These responses were not significantly altered by the administration of naloxone or codeine. There was no significant relation between arterial blood pressure and MSNA with MPP during either IHG or PEMI. A second study ( n = 8) compared MPP during ischaemic IHG to MPP during PEMI. MPP was greater during PEMI as compared with ischaemic IHG. These findings suggest that central command modulates the perception of muscle pain during exercise. Furthermore, endogenous opioids, arterial blood pressure and MSNA do not appear to modulate acute exercise-induced muscle pain.     

Inspiratory muscle training attenuates the human respiratory muscle metaboreflex

We hypothesized that inspiratory muscle training (IMT) would attenuate the sympathetically mediated heart rate (HR) and mean arterial pressure (MAP) increases normally observed during fatiguing inspiratory muscle work. An experimental group (Exp, n = 8) performed IMT 6 days per week for 5 weeks at 50% of maximal inspiratory pressure (MIP), while a control group (Sham, n = 8) performed IMT at 10% MIP. Pre- and post-training, subjects underwent a eucapnic resistive breathing task (RBT) (breathing frequency = 15 breaths min⁻¹, duty cycle = 0.70) while HR and MAP were continuously monitored. Following IMT, MIP increased significantly ( P < 0.05) in the Exp group (−125 ± 10 to −146 ± 12 cmH₂O; mean ± s.e.m. ) but not in the Sham group (−141 ± 11 to −148 ± 11 cmH₂O). Prior to IMT, the RBT resulted in significant increases in HR (Sham: 59 ± 2 to 83 ± 4 beats min⁻¹; Exp: 62 ± 3 to 83 ± 4 beats min⁻¹) and MAP (Sham: 88 ± 2 to 106 ± 3 mmHg; Exp: 84 ± 1 to 99 ± 3 mmHg) in both groups relative to rest. Following IMT, the Sham group observed similar HR and MAP responses to the RBT while the Exp group failed to increase HR and MAP to the same extent as before (HR: 59 ± 3 to 74 ± 2 beats min⁻¹; MAP: 84 ± 1 to 89 ± 2 mmHg). This attenuated cardiovascular response suggests a blunted sympatho-excitation to resistive inspiratory work. We attribute our findings to a reduced activity of chemosensitive afferents within the inspiratory muscles and may provide a mechanism for some of the whole-body exercise endurance improvements associated with IMT.     

Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise

We tested the hypotheses that (1) nitric oxide (NO) contributes to augmented skeletal muscle vasodilatation during hypoxic exercise and (2) the combined inhibition of NO production and adenosine receptor activation would attenuate the augmented vasodilatation during hypoxic exercise more than NO inhibition alone. In separate protocols subjects performed forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O₂ saturation). In protocol 1 ( n = 12), subjects received intra-arterial administration of saline (control) and the NO synthase inhibitor N ^G-monomethyl- l -arginine ( l -NMMA). In protocol 2 ( n = 10), subjects received intra-arterial saline (control) and combined l -NMMA–aminophylline (adenosine receptor antagonist) administration. Forearm vascular conductance (FVC; ml min⁻¹ (100 mmHg)⁻¹) was calculated from forearm blood flow (ml min⁻¹) and blood pressure (mmHg). In protocol 1, the change in FVC (Δ from normoxic baseline) due to hypoxia under resting conditions and during hypoxic exercise was substantially lower with l -NMMA administration compared to saline (control; P < 0.01). In protocol 2, administration of combined l -NMMA–aminophylline reduced the ΔFVC due to hypoxic exercise compared to saline (control; P < 0.01). However, the relative reduction in ΔFVC compared to the respective control (saline) conditions was similar between l -NMMA only (protocol 1) and combined l -NMMA–aminophylline (protocol 2) at 10% (−17.5 ± 3.7 vs. −21.4 ± 5.2%; P = 0.28) and 20% (−13.4 ± 3.5 vs. −18.8 ± 4.5%; P = 0.18) hypoxic exercise. These findings suggest that NO contributes to the augmented vasodilatation observed during hypoxic exercise independent of adenosine.     

Long-term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans

We determined the effects of 10 daily exposures of intermittent hypoxia (IH; 1 h day⁻¹; oxyhaemoglobin saturation = 80%) on muscle sympathetic nerve activity (MSNA, peroneal nerve) and the hypoxic ventilatory response (HVR) before, during and after an acute 20 min isocapnic hypoxic exposure. We also assessed the potential parallel modulation of the ventilatory and sympathetic systems following IH. Healthy young men ( n = 11; 25 ± 1 years) served as subjects and pre- and post-IH measures of MSNA were obtained on six subjects. The IH intervention caused HVR to significantly increase  (pre-IH = 0.30 ± 0.03; post-IH = 0.61 ± 0.12 l min⁻¹% S _aO2⁻¹)  . During the 20 min hypoxic exposure sympathetic activity was significantly greater than baseline and remained above baseline after withdrawal of the hypoxic stimulus, even though oxyhaemoglobin saturation had normalized and ventilation and blood pressure had returned to baseline levels. When compared to the pre-IH trial, burst frequency increased ( P < 0.01), total MSNA trended towards higher values ( P = 0.06), and there was no effect on burst amplitude ( P = 0.82) during the post-IH trial. Following IH the rise in MSNA burst frequency was strongly related to the change in HVR ( r = 0.79, P < 0.05) suggesting that these sympathetic and ventilatory responses may have common central control.     

Rapid Report

Sympathetic vasoconstriction is blunted in the vascular beds of contracting skeletal muscles. We sought to determine whether this blunted vasoconstriction is specific for post-junctional α₁- or α₂-adrenergic receptors. We measured forearm blood flow (Doppler ultrasound) and calculated the vascular conductance (FVC) responses to brachial artery infusions of tyramine (which evokes endogenous noradrenaline release), phenylephrine (an α₁ agonist) and clonidine (an α₂ agonist) in 10 healthy men during rhythmic handgrip exercise (10-15 % of maximum) and during a control non-exercise vasodilator condition (intra-arterial adenosine). Steady-state FVC during exercise and adenosine was similar in all trials (range: 243-272 and 234-263 ml min⁻¹ (100 mmHg)⁻¹, respectively; P > 0.5). During exercise the percentage reductions in FVC in response to tyramine (−24 ± 7 vs. −55 ± 6 %), phenylephrine (−12 ± 8 vs. −37 ± 8 %) and clonidine (−17 ± 6 vs. −49 ± 4 %) were significantly less compared with adenosine (all P < 0.05). The magnitude of the blunted vasoconstrictor responses was similar for both receptor subtypes. These findings are in contrast to those from studies in animals demonstrating that α₂-adrenergic receptor-mediated vasoconstrictor responses are much more sensitive to contraction-induced inhibition than α₁-mediated responses. We conclude that vasoconstrictor responses mediated via both post-junctional α₁- and α₂-adrenergic receptors are blunted in contracting human skeletal muscles.     

Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia

Acute exposure to hypoxia causes chemoreflex activation of the sympathetic nervous system. During acclimatization to high altitude hypoxia, arterial oxygen content recovers, but it is unknown to what degree sympathetic activation is maintained or normalized during prolonged exposure to hypoxia. We therefore measured sympathetic nerve activity directly by peroneal microneurography in eight healthy volunteers (24 ± 2 years of age) after 4 weeks at an altitude of 5260 m (Chacaltaya, Bolivian Andes) and at sea level (Copenhagen). The subjects acclimatized well to altitude, but in every subject sympathetic nerve activity was highly elevated at altitude vs. sea level (48 ± 5 vs. 16 ± 3 bursts min⁻¹, respectively,   P < 0.05  ), coinciding with increased mean arterial blood pressure (87 ± 3 vs. 77 ± 2 mmHg, respectively,   P < 0.05  ). To examine the underlying mechanisms, we administered oxygen (to eliminate chemoreflex activation) and saline (to reduce cardiopulmonary baroreflex deactivation). These interventions had minor effects on sympathetic activity (48 ± 5 vs. 38 ± 4 bursts min⁻¹, control vs. oxygen + saline, respectively,   P < 0.05  ). Moreover, sympathetic activity was still markedly elevated (37 ± 5 bursts min⁻¹) when subjects were re-studied under normobaric, normoxic and hypervolaemic conditions 3 days after return to sea level. In conclusion, acclimatization to high altitude hypoxia is accompanied by a striking and long-lasting sympathetic overactivity. Surprisingly, chemoreflex activation by hypoxia and baroreflex deactivation by dehydration together could account for only a small part of this response, leaving the major underlying mechanisms unexplained.     

Organization of the central control of muscles of facial expression in man

The capacity of the vascular endothelium locally to release tissue-type plasminogen activator (t-PA) is critical for effective endogenous fibrinolysis. We determined the influence of ageing and regular aerobic exercise on the net release of t-PA across the human forearm in vivo using both cross-sectional and intervention approaches. First, we studied 62 healthy men aged 22-35 or 50-75 years of age who were either sedentary or endurance exercise-trained. Net endothelial release rates of t-PA were calculated as the product of the arteriovenous concentration gradient and forearm plasma flow to intra-arterial bradykinin and sodium nitroprusside. Second, we studied 10 older (60 ± 2 years) healthy sedentary men before and after a 3 month aerobic exercise intervention. Net endothelial t-PA release was significantly blunted with age in the sedentary men. At the highest dose of bradykinin the increase in t-PA antigen release was ≈35 % less (   P < 0.05  ) in the older (from −1.0 ± 0.4 to 37.8 ± 3.8 ng (100 ml tissue)⁻¹ min⁻¹) compared with young (from 0.1 ± 0.6 to 56.6 ± 9.2 ng (100 ml tissue)⁻¹ min⁻¹) men. In contrast, the endurance-trained men did not demonstrate an age-related decline in the net release of t-PA antigen. After the exercise intervention, the capacity of the endothelium to release t-PA increased ≈55 % (   P < 0.05  ) to levels similar to those of the young adults and older endurance-trained men. Regulated endothelial t-PA release declines with age in sedentary men. Regular aerobic exercise may not only prevent, but could also reverse the age-related loss in endothelial fibrinolytic function.     

Dynamic changes in the direction of blood flow through the ductus arteriosus at birth

Major cardiovascular changes occur at birth, including increased pulmonary blood flow (PBF) and closure of the ductus arteriosus (DA), which acts as a low resistance shunt between the fetal pulmonary and systemic circulations. Although the pressure gradient between these circulations reverses after birth, little is known about DA blood flow changes and whether reverse DA flow contributes to PBF after birth. Our aim was to describe the changes in PBF and DA flow before, during and after the onset of pulmonary ventilation at birth. Flow probes were implanted on the left pulmonary artery (LPA) and DA in preterm fetal sheep ( n = 8) ∼3 days before they were delivered and ventilated. Blood flow was measured in the LPA and DA, before and after umbilical cord occlusion (UCO) and for 2 h after ventilation onset. Following UCO, DA flow decreased from 534 ± 57 ml min⁻¹ to 237 ± 29 ml min⁻¹ which reflected a similar reduction in right ventricular output. Within 5 min of ventilation onset, PBF increased from 11 ± 6 ml min⁻¹ to 230 ± 13 ml min⁻¹ whereas DA flow decreased to −172 ± 54 ml min⁻¹; negative values indicate reverse DA flow (left-to-right shunting). Reverse flow through the DA contributed up to 50% of total PBF at 30 min and a decrease in this contribution accounted for 71 ± 13% of the time-related decrease in PBF after birth. DA blood flow is very dynamic after birth and depends upon the pressure gradient between the pulmonary and systemic circulations. Following ventilation, reverse DA flow provided a significant contribution to total PBF after birth.     

Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l -NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5- to 10-fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)⁻¹ min⁻¹ at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)⁻¹ min⁻¹ at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively ( P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction.     

Cardiac and vasomotor components of the carotid baroreflex control of arterial blood pressure during isometric exercise in humans

We sought to examine the importance of the cardiac component of the carotid baroreflex (CBR) in control of blood pressure during isometric exercise. Nine subjects performed 4 min of ischaemic isometric calf exercise at 20% of maximum voluntary contraction. Trials were repeated with β₁-adrenergic blockade (metoprolol, 0.15 ± 0.003 mg kg⁻¹) or parasympathetic blockade (glycopyrrolate, 13.6 ± 1.5 μg kg⁻¹). CBR function was determined using rapid pulses of neck pressure and neck suction from +40 to −80 mmHg, while heart rate (HR), mean arterial pressure (MAP) and changes in stroke volume (SV, Modelflow method) were measured. Metoprolol decreased and glycopyrrolate increased HR and cardiac output both at rest and during exercise ( P < 0.05), while resting and exercising blood pressure were unchanged. Glycopyrrolate reduced the maximal gain ( G _max) of the CBR-HR function curve (−0.58 ± 0.10 to −0.06 ± 0.01 beats min⁻¹ mmHg⁻¹, P < 0.05), but had no effect on the G _max of the CBR-MAP function curve. During isometric exercise the CBR-HR curve was shifted upward and rightward in the metoprolol and no drug conditions, while the control of HR was significantly attenuated with glycopyrrolate ( P < 0.05). Regardless of drug administration isometric exercise produced an upward and rightward resetting of the CBR control of MAP with no change in G _max. Thus, despite marked reductions in CBR control of HR following parasympathetic blockade, CBR control of blood pressure was well maintained. These data suggest that alterations in vasomotor tone are the primary mechanism by which the CBR modulates blood pressure during low intensity isometric exercise.     

Differential effect of angiotensin II on blood circulation in the renal medulla and cortex of anaesthetised rats

The renal medulla is sensitive to hypoxia, and a depression of medullary circulation, e.g. in response to angiotensin II (Ang II), could endanger the function of this zone. Earlier data on Ang II effects on medullary vasculature were contradictory. The effects of Ang II on total renal blood flow (RBF), and cortical and medullary blood flow (CBF and MBF: by laser-Doppler flux) were studied in anaesthetised rats. Ang II infusion (30 ng kg⁻¹ min⁻¹ i.v. ) decreased RBF 27 ± 2 % (mean ± s.e.m. ), whereas MBF increased 12 ± 2 % (both P < 0.001). Non-selective blockade of Ang II receptors with saralasin (3 μg kg⁻¹ min⁻¹ i.v. ) increased RBF 12 ± 2 % and decreased MBF 8 ± 2 % ( P < 0.001). Blockade of AT₁ receptors with losartan (10 mg kg⁻¹) increased CBF 10 ± 2 % ( P < 0.002) and did not change MBF. Losartan given during Ang II infusion significantly increased RBF (53 ± 7 %) and decreased MBF (27 ± 7 %). Blockade of AT₂ receptors with PD 123319 (50 μg kg⁻¹ min⁻¹ i.v. ) did not change CBF or MBF. Intramedullary infusion of PD 123319 (10 μg min⁻¹) superimposed on intravenous Ang II infusion did not change RBF, but slightly decreased MBF (4 ± 2 %, P < 0.05). We conclude that in anaesthetised surgically prepared rats, exogenous or endogenous Ang II may not depress medullary circulation. In contrast to the usual vasoconstriction in the cortex, vasodilatation was observed, possibly related to secondary activation of vasodilator paracrine agents rather than to a direct action via AT₂ receptors.     

Local metabolite accumulation augments passive muscle stretch-induced modulation of carotid–cardiac but not carotid–vasomotor baroreflex sensitivity in man

We examined the effects of muscle mechanoreflex stimulation by passive calf muscle stretch, at rest and during concurrent muscle metaboreflex activation, on carotid baroreflex (CBR) sensitivity. Twelve subjects either performed 1.5 min one-legged isometric plantarflexion at 50% maximal voluntary contraction with their right or left calf [two ischaemic exercise (IE) trials, IER and IEL] or rested for 1.5 min [two ischaemic control (IC) trials, ICR and ICL]. Following exercise, blood pressure elevation was partly maintained by local circulatory occlusion (CO). 3.5 min of CO was followed by 3 min of CO with passive stretch (STR-CO) of the right calf in all trials. Carotid baroreflex function was assessed using rapid pulses of neck pressure from +40 to −80 mmHg. In all IC trials, stretch did not alter maximal gain of carotid–cardiac (CBR–HR) and carotid–vasomotor (CBR–MAP) baroreflex function curves. The CBR–HR curve was reset without change in maximal gain during STR-CO in the IEL trial. However, during the IER trial maximal gain of the CBR–HR curve was smaller than in all other trials (−0.34 ± 0.04 beats min⁻¹ mmHg⁻¹ in IER versus −0.76 ± 0.20, −0.94 ± 0.14 and −0.66 ± 0.18 beats min⁻¹ mmHg⁻¹ in ICR, IEL and ICL, respectively), and significantly smaller than in IEL ( P < 0.05). The CBR–MAP curves were reset from CO values by STR-CO in the IEL and IER trials with no changes in maximal gain. These results suggest that metabolite sensitization of stretch-sensitive muscle mechanoreceptive afferents modulates baroreflex control of heart rate but not blood pressure.     

An acute decrease in TCA cycle intermediates does not affect aerobic energy delivery in contracting rat skeletal muscle

We tested the hypothesis that an acute decrease in muscle TCA cycle intermediates during contraction would compromise aerobic energy delivery. Male Wistar rats were anaesthetized and the gastrocnemius–plantaris–soleus (GPS) muscle complex from one leg was isolated and perfused with a red cell medium containing either saline (Con) or cycloserine (Cyclo; 0.05 mg g⁻¹), an inhibitor of alanine aminotransferase (AAT). After 1 h of perfusion, the GPS muscle was either snap frozen (Con-Rest, n = 11; Cyclo-Rest, n = 9) or stimulated to contract for 10 min (1 Hz, 0.3 ms, 2 V) with blood flow fixed at 30 ml min⁻¹ (100 g)⁻¹ and then snap frozen (Con-Stim, n = 10; Cyclo-Stim, n = 10). Maximal AAT activity was > 80% lower ( P < 0.001) in both Cyclo-treated groups (Rest: 0.61 ± 0.02; Stim: 0.63 ± 0.01 mmol (kg wet wt)⁻¹ min⁻¹; mean ± s.e.m. ) compared to Con (Rest: 3.56 ± 0.16; Stim: 3.92 ± 0.29). The sum of five measured TCAI (ΣTCAI) was reduced by 23% in Cyclo-Rest versus Con-Rest but this was not different ( P = 0.08). However, after 10 min of contraction, the ΣTCAI was 25% lower ( P = 0.006) in Cyclo-Stim compared to Con-Stim (1.88 ± 0.15 versus 2.48 ± 0.11 mmol (kg dry wt)⁻¹). Despite the acute decrease in TCAI after Cyclo treatment, the contraction-induced changes in markers of non-oxidative energy provision (phosphocreatine, ATP and lactate) and the decline in tension after 10 min of stimulation were similar compared to Con. These data do not support the hypothesis that the total muscle concentration of TCAI is causally linked to the rate of mitochondrial respiration during contraction.