Neurovascular responses to mental stress

The effects of mental stress (MS) on muscle sympathetic nerve activity (MSNA) and limb blood flows have been studied independently in the arm and leg, but they have not been studied collectively. Furthermore, the cardiovascular implications of postmental stress responses have not been thoroughly addressed. The purpose of the current investigation was to comprehensively examine concurrent neural and vascular responses during and after mental stress in both limbs. In Study 1, MSNA, blood flow (plethysmography), mean arterial pressure (MAP) and heart rate (HR) were measured in both the arm and leg in 12 healthy subjects during and after MS (5 min of mental arithmetic). MS significantly increased MAP (Δ15 ± 3 mmHg; P < 0.01) and HR (Δ19 ± 3 beats min⁻¹; P < 0.01), but did not change MSNA in the arm (14 ± 3 to 16 ± 3 bursts min⁻¹; n = 6) or leg (14 ± 2 to 15 ± 2 bursts min⁻¹; n = 8). MS decreased forearm vascular resistance (FVR) by −27 ± 7% ( P < 0.01; n = 8), while calf vascular resistance (CVR) did not change (−6 ± 5%; n = 11). FVR returned to baseline during recovery, whereas MSNA significantly increased in the arm (21 ± 3 bursts min⁻¹; P < 0.01) and leg (19 ± 3 bursts min⁻¹; P < 0.03). In Study 2, forearm and calf blood flows were measured in an additional 10 subjects using Doppler ultrasound. MS decreased FVR (−27 ± 10%; P < 0.02), but did not change CVR (5 ± 14%) as in Study 1. These findings demonstrate differential vascular control of the arm and leg during MS that is not associated with muscle sympathetic outflow. Additionally, the robust increase in MSNA during recovery may have acute and chronic cardiovascular implications.     

Single-unit analysis of sympathetic nervous discharges in patients with panic disorder

Patients with panic disorder are at increased cardiac risk. While the mechanisms responsible remain unknown, activation of the sympathetic nervous system may be implicated. Using isotope dilution methodology, investigations of whole-body and regional sympathetic nervous activity have failed to show any differences between patients with panic disorder and healthy subjects. Using direct recording of single unit efferent sympathetic vasoconstrictor nerve activity by microneurography we examined sympathetic nervous function in patients with panic disorder more precisely than previously reported. The activity of multiunit and single unit vasoconstrictor sympathetic nerves was recorded at rest at the level of the peroneal nerve in 10 patients diagnosed with panic disorder and in nine matched healthy volunteers. Multiunit sympathetic activity was not different between the two groups (26 ± 3 bursts min⁻¹ in patients with panic disorder and 28 ± 3 bursts min⁻¹ in controls). The firing frequency of single unit vasoconstrictor neurones was also similar between the two groups (0.38 ± 0.09 versus 0.22 ± 0.03 Hz). However, the probability of firing during a sympathetic burst was higher in patients with panic disorder compared with healthy controls (45 ± 5% versus 32 ± 3%, P < 0.05). When only the neural bursts during which the vasoconstrictor neurone was active were considered, we found that in patients with panic disorder the neurones tended to fire more often in a 'multiple spike' pattern than in the controls (i.e. the probability of the neurone firing twice was 25 ± 3% in patients with panic disorder compared with 14 ± 3% in controls). Quantification from single vasoconstrictor unit recording provides evidence of a disturbed sympathetic firing pattern in patients with panic disorder.     

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.     

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.     

Mechanisms of acute natriuresis in normal humans on low sodium diet

This study evaluates the relative importance of several mechanisms possibly involved in the natriuresis elicited by slow sodium loading, i.e. the renin-angiotensin-aldosterone system (RAAS), mean arterial blood pressure (MAP), glomerular filtration rate (GFR), atrial natriuretic peptide (ANP), oxytocin and nitric oxide (NO). Eight seated subjects on standardised sodium intake (30 mmol NaCl day⁻¹) received isotonic saline intravenously (NaLoading: 20 μmol Na⁺ kg⁻¹ min⁻¹ or ≈11 ml min⁻¹ for 240 min). NaLoading did not change MAP or GFR (by clearance of ⁵¹Cr-EDTA). Significant natriuresis occurred within 1 h (from 9 ± 3 to 13 ± 2 μmol min⁻¹). A 6-fold increase was found during the last hour of infusion as plasma renin activity, angiotensin II (ANGII) and aldosterone decreased markedly. Sodium excretion continued to increase after NaLoading. During NaLoading, plasma renin activity and ANGII were linearly related ( R = 0.997) as were ANGII and aldosterone ( R = 0.999). The slopes were 0.40 p m ANGII (mi.u. renin activity)⁻¹ and 22 p m aldosterone (p m ANGII)⁻¹. Plasma ANP and oxytocin remained unchanged, as did the urinary excretion rates of cGMP and NO metabolites (NO_x). In conclusion, sodium excretion may increase 7-fold without changes in MAP, GFR, plasma ANP, plasma oxytocin, and cGMP- and NO_x excretion, but concomitant with marked decreases in circulating RAAS components. The immediate renal response to sodium excess appears to be fading of ANGII-mediated tubular sodium reabsorption. Subsequently the decrease in aldosterone may become important.     

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.     

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.     

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.     

Specific control of sympathetic nerve activity to the mammalian heart and kidney

There is a large body of evidence indicating that sympathetic nerves to individual organs are specifically controlled, but only few studies have compared the control of cardiac sympathetic nerve activity (CSNA) with activity in other sympathetic nerves. In this review, changes in sympathetic activity to the heart and kidneys are described during increases in brain [Na⁺] and in heart failure (HF). In conscious sheep, increases in brain [Na⁺] increased CSNA and arterial pressure and, conversely, decreased renal sympathetic nerve activity (RSNA), promoting urinary sodium loss. These organ-specific effects are mediated via a neural pathway that includes an angiotensinergic synapse, the lamina terminalis and the paraventricular nucleus of the hypothalamus. There is also evidence of differential control of SNA in HF. In normal sheep, the resting burst incidence of CSNA was much lower than that of RSNA, whereas in HF they increased to similar, almost maximal levels in both nerves. Arterial baroreflex control of both these nerves was unchanged in HF, but the response of CSNA to changes in blood volume was almost absent. These data indicate that in HF the lower arterial pressure leads to reduced baroreflex inhibition of SNA, which, together with the lack of an inhibitory response to the increased volume and cardiac pressures, would contribute to the sympathoexcitation observed. These studies demonstrate differences in the control of CSNA and RSNA, enabling selective actions on the heart and kidney to restore fluid and electrolyte homeostasis in the case of elevated brain [Na⁺] and to increase cardiac output in HF.     

Baroreflex-Mediated Changes in Cardiac Output and Vascular Conductance in Response to Alterations in Carotid Sinus Pressure during Exercise in Humans

We sought to quantify the contribution of cardiac output ( Q ) and total vascular conductance (TVC) to carotid baroreflex (CBR)-mediated changes in mean arterial pressure (MAP) during mild to heavy exercise. CBR function was determined in eight subjects (25 ± 1 years) at rest and during three cycle exercise trials at heart rates (HRs) of 90, 120 and 150 beats min⁻¹ performed in random order. Acute changes in carotid sinus transmural pressure were evoked using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr (+5.33 to −10.67 kPa). Beat-to-beat changes in HR and MAP were recorded throughout. In addition, stroke volume (SV) was estimated using the Modelflow method, which incorporates a non-linear, three-element model of the aortic input impedance to compute an aortic flow waveform from the arterial pressure wave. The application of NP and NS did not cause any significant changes in SV either at rest or during exercise. Thus, CBR-mediated alterations in Q were solely due to reflex changes in HR. In fact, a decrease in the carotid-HR response range from 26 ± 7 beats min⁻¹ at rest to 7 ± 1 beats min⁻¹ during heavy exercise (   P = 0.001  ) reduced the contribution of Q to the CBR-mediated change in MAP. More importantly, at the time of the peak MAP response, the contribution of TVC to the CBR-mediated change in MAP was increased from 74 ± 14 % at rest to 118 ± 6 % (   P = 0.017  ) during heavy exercise. Collectively, these findings indicate that alterations in vasomotion are the primary means by which the CBR regulates blood pressure during mild to heavy exercise.     

Influence of hypernatraemia and urea excretion on the ability to excrete a maximally hypertonic urine in the rat

Rats normally excrete 20-25 mmol of sodium (Na⁺) + potassium (K⁺) per kilogram per day. To minimize the need for a large water intake, they must excrete urine with a very high electrolyte concentration (tonicity). Our objective was to evaluate two potential factors that could influence the maximum urine tonicity, hypernatraemia and the rate of urea excretion. Balance studies were carried out in vasopressin-treated rats fed a low-electrolyte diet. In the first series, the drinking solution contained an equivalent sodium chloride (NaCl) load at 150 or 600 mmol l⁻¹. In the second series, the maximum urine tonicity was evaluated in rats consuming 600 mmol l⁻¹ NaCl with an 8-fold range of urea excretion. Hypernatraemia (148 ± 1 mmol l⁻¹) developed in all rats that drank 600 mmol l⁻¹ saline. Although the rate of Na⁺+ K⁺ excretion was similar in both saline groups, the maximum urine total cation concentration was significantly higher in the hypernatraemic group (731 ± 31 vs . 412 ± 37 mmol l⁻¹). Only when the rate of excretion of urea was very low, was there a further increase in the maximum urine total cation concentration (1099 ± 118 mmol l⁻¹). Thus hypernatraemia was the most important factor associated with a higher urine tonicity.     

Attenuated vascular responsiveness to noradrenaline release during dynamic exercise in dogs

During dynamic exercise, there is reduced responsiveness to α₁- and α₂-adrenergic receptor agonists in skeletal muscle vasculature. However, it is desirable to examine the sympathetic responsiveness to endogenous release of neurotransmitter, since exogenous sympathomimetic agents are dependent upon their ability to reach the abluminal receptor. Therefore, to further our understanding of sympathetic control of vasomotor tone during exercise, we employed a technique that would elicit the release of endogenous noradrenaline (norepinephrine) during dynamic exercise. Mongrel dogs ( n = 8, 19-24 kg) were instrumented chronically with transit time ultrasound flow probes on both external iliac arteries. A catheter was placed in a side branch of the femoral artery for intra-arterial administration of tyramine, an agent which displaces noradrenaline from the nerve terminal. Doses of 0.5, 1.0 and 3.0 μg ml⁻¹ min⁻¹ of iliac blood flow were infused for 1 min at rest and during graded intensities of exercise. Dose-related decreases in iliac vascular conductance were achieved with these concentrations of tyramine. The reductions in iliac vascular conductance (means ± s.e.m .) were 45 ± 6 %, 30 ± 4 %, 26 ± 3 % and 17 ± 2 %, for the 1.0 μg ml⁻¹ min⁻¹ dose at rest, 3.0 miles h⁻¹, 6.0 miles h⁻¹ and 6.0 miles h⁻¹, 10 % gradient, respectively. At all doses, the magnitude of vasoconstriction caused by administration of tyramine was inversely related to workload. We conclude that there is a reduced vascular responsiveness to sympathoactivation in dynamically exercising skeletal muscle.     

Fluid replacement and heat stress during exercise alter post-exercise cardiac haemodynamics in endurance exercise-trained men

It has been reported that endurance exercise-trained men have decreases in cardiac output with no change in systemic vascular conductance during post-exercise hypotension, which differs from sedentary and normally active populations. As inadequate hydration may explain these differences, we tested the hypothesis that fluid replacement prevents this post-exercise fall in cardiac output, and further, exercise in a warm environment would cause greater decreases in cardiac output. We studied 14 trained men (     4.66 ± 0.62 l min⁻¹) before and to 90 min after cycling at 60%     for 60 min under three conditions: Control (no water was consumed during exercise in a thermoneutral environment), Fluid (water was consumed to match sweat loss during exercise in a thermoneutral environment) and Warm (no water was consumed during exercise in a warm environment). Arterial pressure and cardiac output were measured pre- and post-exercise in a thermoneutral environment. The fall in mean arterial pressure following exercise was not different between conditions ( P = 0.453). Higher post-exercise cardiac output (Δ 0.41 ± 0.17 l min⁻¹; P = 0.027), systemic vascular conductance (Δ 6.0 ± 2.2 ml min⁻¹ mmHg⁻¹ ; P = 0.001) and stroke volume (Δ 9.1 ± 2.1 ml beat⁻¹; P < 0.001) were seen in Fluid compared to Control, but there was no difference between Fluid and Warm (all P > 0.05). These data suggest that fluid replacement mitigates the post-exercise decrease in cardiac output in endurance-exercise trained men. Surprisingly, exercise in a warm environment also mitigates the post-exercise fall in cardiac output.     

Prolonged strenuous exercise alters the cardiovascular response to dobutamine stimulation in male athletes

Prolonged strenuous exercise has been associated with transient impairment in left ventricular (LV) systolic and diastolic function that has been termed 'cardiac fatigue'. It has been postulated that cardiac β-adrenoreceptor desensitization may play a central role; however, data are limited. Accordingly, we assessed the cardiovascular response to progressive dobutamine stimulation after prolonged strenuous exercise (2 km swim, 90 km bike, 21 km run). Nine experienced male athletes were studied: PRE (2–3 days before), POST (after) and REC (1–2 days later). The cardiovascular response to progressive continuous dobutamine stimulation (0, 5, 20, and 40 μg kg⁻¹ min⁻¹) was assessed, including heart rate (HR), systolic blood pressure (SBP), LV cavity areas (two-dimensional echocardiography) and contractility (end-systolic elastance, SBP/end-systolic cavity area (ESCA)). POST there was limited evidence of myocardial necrosis (measured by troponin I), while catecholamines were elevated. HR was higher POST (mean ± s.d. ; PRE, 58 ± 9; POST, 79 ± 9; REC, 57 ± 7 beats min⁻¹; P < 0.05), while SBP was lower (PRE, 127 ± 15; POST, 116 ± 9; REC, 121 ± 12 mmHg; P < 0.05). A blunted HR, SBP and LV contractility (SBP/ESCA; PRE 29 ± 6 versus POST 20 ± 6 mmHg cm⁻²; P < 0.05) response to dobutamine was demonstrated POST, with values returning towards baseline in REC. Following prolonged strenuous exercise, the chronotropic and inotropic response to dobutamine stimulation is blunted. This study supports the hypothesis that beta-receptor downregulation and/or desensitization may play a major role in prolonged-strenuous-exercise-mediated cardiac fatigue.     

Reduced Left Ventricular Compliance and Mechanical Efficiency after Prolonged Inhibition of NO Synthesis in Conscious Dogs

Acute inhibition of NO synthesis decreases left ventricular (LV) work and external efficiency, but it is unknown whether compensatory mechanisms can limit the alterations in LV mechanoenergetics after prolonged NO deficiency. Eight chronically instrumented male mongrel dogs received 35 mg kg⁻¹ day⁻¹ of N ^ω-nitro-L-arginine methyl ester orally for 10 days to inhibit NO synthesis. At spontaneous beating frequency, heart rate, coronary blood flow, peak LV pressure, end-diastolic LV pressure and the maximum derivative of LV pressure (d P /d t _max) were not significantly different vs. baseline, whereas LV end-diastolic diameter (32.5 ± 1.0 vs. 37.6 ± 1.4 mm) and LV stroke work (515 ± 38 vs. 650 ± 44 mmHg mm), were reduced (all P < 0.05). The slope of the LV end-systolic pressure-diameter relationship was increased at 10 days vs. baseline (13.9 ± 1.0 vs. 9.6 ± 0.9 mmHg mm⁻¹, P < 0.05), while the end-diastolic LV diameter was smaller at matched LV end-diastolic pressures. At fixed heart rate (130 beats min⁻¹), cardiac oxygen consumption was increased (12.2 ± 1.5 vs. 9.9 ± 1.0 ml min⁻¹), and the ratio between stroke work and oxygen consumption was decreased by 33 ±7 % (all P < 0.05) after NO inhibition. We conclude that sustained inhibition of NO synthesis in dogs causes a decrease in LV work despite an increased contractility, which is most probably due to reduced diastolic compliance and a decrease in external efficiency. Thus, prolonged NO deficiency is not compensated for on the level of LV mechanoenergetics in vivo .     

Long-term effects of streptozotocin-induced diabetes on the electrocardiogram, physical activity and body temperature in rats

In vivo biotelemetry studies have demonstrated that short-term streptozotocin (STZ)-induced diabetes is associated with a reduction in heart rate (HR) and heart rate variability (HRV) and prolongation of QT and QRS intervals. This study investigates the long-term effects of STZ-induced diabetes on the electrocardiogram (ECG), physical activity and body temperature. Transmitter devices were surgically implanted in the peritoneal cavity of young adult male Wistar rats. Electrodes from the transmitter were arranged in Einthoven bipolar lead II configuration. ECG, physical activity and body temperature data were continuously recorded with a telemetry system before and following the administration of STZ (60 mg kg⁻¹) for a period of 22 weeks. HR, physical activity and body temperature declined rapidly 3–5 days after the administration of STZ. The effects became conspicuous with time reaching a new steady state approximately 1–2 weeks after STZ treatment. HR at 4 weeks was 268 ± 5 beats min⁻¹ in diabetic rats compared to 347 ± 12 beats min⁻¹ in age-matched controls. HRV at 4 weeks was also significantly reduced after STZ treatment (18 ± 3 beats min⁻¹) compared to controls (33 ± 3 beats min⁻¹). HR and HRV were not additionally altered in either diabetic rats (266 ± 5 and 20 ± 4 beats min⁻¹) or age-matched controls (316 ± 6 and 25 ± 4 beats min⁻¹) at 22 weeks. Reduced physical activity and/or body temperature may partly underlie the reductions in HR and HRV. In addition, the increased power spectral low frequency/high frequency ratio from 4 weeks after STZ treatment may indicate an accompanying disturbance in sympathovagal balance.     

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.     

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.     

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.