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The sympathetic nervous system is an important regulator of coronary blood flow. The cold pressor test (CPT) is a powerful sympathoexcitatory stressor. We tested the hypotheses that: (1) CPT-induced sympathetic activation elicits coronary vasodilatation in young adults that is impaired with advancing age and (2) combined α- and β-adrenergic blockade diminishes/abolishes these age-related differences. Vascular responses of the left anterior descending artery to the CPT were determined by transthoracic Doppler echocardiography before (pre-blockade) and during (post-blockade) systemic co-administration of α- and β-adrenergic antagonists in young (n = 9; 26 ± 1 years old, mean ± SEM) and older healthy men (n = 9; 66 ± 2 years old). Coronary vascular resistance (CVR; mean arterial pressure/coronary blood velocity) was used as an index of vascular tone. CPT decreased CVR (i.e. coronary vasodilatation occurred) in young ( -33 ± 6%), but not older men ( -3 ± 4%; P < 0.05 vs. young) pre-blockade. Adrenergic blockade abolished CPT-induced coronary vasodilatation in young men ( -33 ± 6% vs. 0 ± 6%, pre-blockade vs. post-blockade, respectively; P < 0.05) such that responses post-blockade mirrored those of older men ( -3 ± 4% vs. 8 ± 9%; both P > 0.05 compared to young pre-blockade). Impaired CPT-induced coronary vasodilatation could not be explained by a reduced stimulus for vasodilatation as group and condition effects persisted when CVR responses were expressed relative to myocardial oxygen demand (rate-pressure product). These data indicate that the normal coronary vascular response to sympathetic activation in young men is pronounced vasodilatation and this effect is lost with age as the result of an adrenergic mechanism. These findings may help explain how acute sympathoexcitation may precipitate angina and coronary ischaemic events, particularly in older adults.

We tested the hypothesis that short-term mild- (M) and heavy-intensity (H) exercise training would enhance sympatholysis through a nitric oxide (NO)-dependent mechanism. Sprague-Dawley rats (n = 36) were randomly assigned to sedentary (S) or to M (20 m min(-1) 5% gradient) or H exercise training groups (40 m min(-1) 5% gradient). Rats assigned to M and H groups trained on 5 days week(-1) for 4 weeks, with the volume of training being matched between groups. Rats were anaesthetized and instrumented for stimulation of the lumbar sympathetic chain and the measurement of arterial blood pressure and femoral artery blood flow. The triceps surae muscle group was stimulated to contract rhythmically at 30 and 60% of maximal contractile force (MCF). The percentage change of femoral vascular conductance (%FVC) in response to sympathetic stimulation delivered at 2 and 5 Hz was determined at rest and during contraction at 30 and 60% MCF. The vascular response to sympathetic stimulation was reduced as a function of MCF in all rats (P < 0.05). At 30% MCF, the magnitude of sympatholysis (%FVC rest - contraction; %FVC) was greater in H compared with M and S groups (%FVC at 2 Hz, S, 9 ± 5; M, 11 ± 8; and H, 18 ± 7; and %FVC at 5 Hz, S, 6 ± 6; M, 12 ± 9; and H, 18 ± 7; P < 0.05) and was greater in H and M compared with S at 60% MCF (%FVC at 2 Hz, S, 15 ± 5; M, 25 ± 3; and H, 36 ± 6; and %FVC at 5 Hz, S, 22 ± 6; M, 33 ± 9; and H, 39 ± 9; P < 0.05). Blockade of NO synthase did not alter the magnitude of sympatholysis in S during contraction at 30 or 60% MCF. In contrast, NO synthase inhibition diminished sympatholysis in H at 30% MCF and in M and H at 60% MCF (P < 0.05). The present findings indicate that short-term exercise training augments sympatholysis in a training-intensity-dependent manner and through an NO-dependent mechanism.

Abstract  Mesenteric arteries (MAs) are studied widely in vitro but little is known of their reactivity in vivo. Transgenic animals have enabled Ca(2+) signalling to be studied in isolated MAs but the reactivity of these vessels in vivo is undefined. We tested the hypothesis that ageing alters MA reactivity to perivascular nerve stimulation (PNS) and adrenoreceptor (AR) activation during blood flow control. First- (1A), second- (2A) and third-order (3A) MAs of pentobarbital-anaesthetized Young (3-6 months) and Old (24-26 months) male and female Cx40(BAC)-GCaMP2 transgenic mice (C57BL/6 background; positive or negative for the GCaMP2 transgene) were studied with intravital microscopy. A segment of jejunum was exteriorized and an MA network was superfused with physiological salt solution (pH 7.4, 37°C). Resting tone was 10% in MAs of Young and Old mice; diameters were ∼5% (1A), 20% (2A) and 40% (3A) smaller (P 0.05) in Old mice. Throughout MA networks, vasoconstriction increased with PNS frequency (1-16 Hz) but was ∼20% less in Young vs. Old mice (P 0.05) and was inhibited by tetrodotoxin (1 μm). Capsaicin (10 μm; to inhibit sensory nerves) enhanced MA constriction to PNS (P 0.05) by ∼20% in Young but not Old mice. Phenylephrine (an α1AR agonist) potency was greater in Young mice (P 0.05) with similar efficacy (∼60% constriction) across ages and MA branches. Constrictions to UK14304 (an α2AR agonist) were less (∼20%; P 0.05) and were unaffected by ageing. Irrespective of sex or transgene expression, ageing consistently reduced the sensitivity of MAs to α1AR vasoconstriction while blunting the attenuation of sympathetic vasoconstriction by sensory nerves. These findings imply substantive alterations in splanchnic blood flow control with ageing.

Syncope is a common clinical condition occurring even in healthy people without manifest cardiovascular disease. The purpose of this study was to determine the role of cardiac output and sympathetic vasoconstriction in neurally mediated (pre)syncope. Twenty-five subjects (age 15–51) with no history of recurrent syncope but who had presyncope during 60 deg upright tilt were studied; 10 matched controls who completed 45 min tilting were analysed retrospectively. Beat-to-beat haemodynamics (Modelflow), muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex sensitivity (MSNA–diastolic pressure relation) were measured. MSNA, haemodynamic responses and baroreflex sensitivity during early tilting were not different between presyncopal subjects and controls. Hypotension was mediated by a drop in cardiac output in all presyncopal subjects, accompanied by a decrease in total peripheral resistance in 16 of them (64%, group A). In the other 9 subjects, total peripheral resistance was well maintained even at presyncope (36%, group B). Cardiac output was smaller (3.26 ± 0.34 (SEM) vs. 5.02 ± 0.40 l min(−1), P = 0.01), while total peripheral resistance was greater (1327 ± 117 vs. 903 ± 80 dyn s cm(−5), P < 0.01) in group B than group A at presyncope. The steeper fall in cardiac output in group B was due to a drop in heart rate. MSNA decreased rapidly at presyncope after the onset of hypotension. Thus, a moderate fall in cardiac output with coincident vasodilatation or a marked fall in cardiac output with no changes in peripheral vascular resistance may contribute to (pre)syncope. However, an intrinsic impairment of vasomotor responsiveness and sympathetic baroreflex function is not the cause of neurally mediated (pre)syncope in this population.

Is there an ordered pattern in the recruitment of postganglionic sympathetic neurones? Using new multi-unit action potential detection and analysis techniques we sought to determine whether the activation of sympathetic vasomotor neurones during stress is governed by the size principle of recruitment. Multi-unit postganglionic sympathetic activity (fibular nerve) was collected from five male subjects at rest and during periods of elevated sympathetic stress (end-inspiratory apnoeas; 178 ± 37 s(mean ± S.D.)). Compared to baseline (0.24 ± 0.04 V), periods of elevated stress resulted in augmented sympathetic burst size (1.34 ± 0.38 V, P < 0.05). Increased burst size was directly related to both the number of action potentials within a multi-unit burst of postganglionic sympathetic activity (r = 0.88 ± 0.04, P < 0.001 in all subjects), and the amplitude of detected action potentials (r = 0.88 ± 0.06, P < 0.001 in all subjects). The recruitment of larger, otherwise silent, neurons accounted for approximately 74% of the increase in detected action potentials across burst sizes. Further, action potential conduction velocities (inverse of latencies) were increased as a function of action potential size (R² = 0.936, P = 0.001). As axon diameter is positively correlated with action potential size and conduction velocity, these data suggest that the principle of ordered recruitment based on neuronal size applies to postganglionic sympathetic vasomotor neurones. This information may be pertinent to our understanding of reflex-specific recruitment strategies in postganglionic sympathetic nerves, patterns of vasomotor control during stress, and the malleability of sympathetic neuronal properties and recruitment in health and disease.

Exercise training is known to be an effective means of improving functional capacity and quality of life in patients with peripheral arterial insufficiency (PAI). However, the specific training-induced physiological adaptations occurring within collateral vessels remain to be clearly defined. The purpose of this study was to determine the effect of exercise training on vasomotor properties of isolated peripheral collateral arteries. We hypothesized that daily treadmill exercise would improve the poor vasodilatory capacity of collateral arteries isolated from rats exposed to surgical occlusion of the femoral artery. Following femoral artery ligation, animals were either kept sedentary or exercise trained daily for a period of 3 weeks. Hindlimb collateral arteries were then isolated, cannulated and pressurized via hydrostatic reservoirs to an intravascular pressure of either 45 or 120 cmH(2)O. Non-occluded contralateral vessels of the sedentary animals served as normal Control. Vasodilatory responses to acetylcholine (ACh; 1 x 10(9)-1 x 10(5)m) and sodium nitroprusside (SNP; 1 x 10(9)-1 x 10(4)m), constrictor responses to phenylephrine (PE; 1 x 10(9)-1 x 10(4)m), and flow-induced vasodilatation were determined. Endothelium-mediated vasodilatation responses were significantly greater to either ACh (P < 0.02) or intravascular flow (P < 0.001) in collateral arteries of trained rats. Neither blockade of cyclooxygenase with indomethacin (Indo; 5 microm) nor blockade of endothelial nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L-NAME; 300 microm) eliminated this ACh- or flow-induced vasodilatation. The depressed vasodilatory response to SNP caused by vascular occlusion was reversed with training. These data indicate that exercise training improves endothelium-mediated vasodilatory capacity of hindlimb collateral arteries, apparently by enhanced production of the putative endothelium-derived hyperpolarizing factor(s). If these findings were applicable to patients with PAI, they could contribute to an improved collateral vessel function and enhance exercise tolerance during routine physical activity.

Activation of neurons in the dorsomedial hypothalamus (DMH) evokes increases in mean arterial pressure (MAP), sympathetic activity, heart rate (HR) and respiratory activity. Results of previous studies suggest that the DMH-evoked increases in MAP and HR are mediated by neurons within the periaqueductal grey (PAG), but a recent study has proposed that the converse is also true, i.e. that increases in MAP and HR evoked from the PAG depend upon neuronal activity in the DMH. In this study in anaesthetized rats, we examined the functional relationship between the DMH and PAG in regulating renal sympathetic nerve activity (RSNA) and respiratory activity (determined by measuring phrenic nerve activity (PNA)). Bilateral microinjections of the neuronal inhibitor muscimol into the DMH virtually abolished the increases in MAP, RSNA and PNA burst rate and amplitude evoked from the dorsolateral (dl) PAG. In contrast, multiple bilateral injections of much larger (10 times) doses of muscimol or of the local anaesthetic lignocaine into sites in the dlPAG at three different rostrocaudal levels did not reduce the magnitude or duration of the sympathetic vasomotor and respiratory responses evoked by disinhibition of neurons in the DMH. Thus, sympathetic vasomotor and respiratory responses generated from the dlPAG are dependent upon neuronal activity in the DMH, but not the converse. The results of this study together with those of previous studies indicate that the PAG regulates cardiovascular and respiratory function via both ascending projections to the DMH and descending projections to the ventral medulla, that originate from different PAG subregions.

The physiological roles of constitutively expressed nitric oxide synthase (NOS) isoforms in humans, in vivo, are unknown. Cutaneous vasodilatation during both central nervous system-mediated, thermoregulatory reflex responses to whole-body heat stress and during peripheral axon reflex-mediated, local responses to skin warming in humans depend on nitric oxide (NO) generation by constitutively expressed NOS of uncertain isoform. We hypothesized that neuronal NOS (nNOS, NOS I) effects cutaneous vasodilatation during whole-body heat stress, but not during local skin warming. We examined the effects of the nNOS inhibitor 7-nitroindazole (7-NI) administered by intradermal microdialysis on vasodilatation induced by whole-body heat stress or local skin warming. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry (LDF). Blood pressure (MAP) was monitored and cutaneous vascular conductance calculated (CVC = LDF/MAP). In protocol 1, whole-body heat stress was induced with water-perfused suits. In protocol 2, local skin warming was induced through local warming units at LDF sites. At the end of each protocol, 56 mm sodium nitroprusside was perfused at microdialysis sites to raise SkBF to maximal levels for data normalization. 7-NI significantly attenuated CVC increases during whole-body heat stress (P < 0.05), but had no effect on CVC increases induced by local skin warming (P > 0.05). These diametrically opposite effects of 7-NI on two NO-dependent processes verify selective nNOS antagonism, thus proving that the nNOS isoform affects NO increases and hence vasodilatation during centrally mediated, reflex responses to whole-body heat stress, but not during locally mediated, axon reflex responses to local skin warming. We conclude that the constitutively expressed nNOS isoform has distinct physiological roles in cardiovascular control mechanisms in humans, in vivo.

Quantitative differences are known to exist between the vasomotor control of hairy and hairless skin, but it is unknown whether they are regulated by common central mechanisms. We made simultaneous recordings from sympathetic cutaneous vasoconstrictor (CVC-type) fibres supplying back skin (hairy) and tail (hairless) in urethane-anaesthetized, artificially ventilated rats. The animal's trunk was shaved and encased in a water-perfused jacket. Both tail and back skin CVC-type fibres were activated by cooling the trunk skin, and independently by the resultant fall in core (rectal) temperature, but their thresholds for activation differed (skin temperatures 38.8 +/- 0.4 degrees C versus 36.8 +/- 0.4 degrees C, core temperatures 38.1 +/- 0.2 degrees C versus 36.8 +/- 0.2 degrees C, respectively; P < 0.01). Back skin CVC-type fibres were more responsive to skin than to core cooling, while the reverse applied to tail fibres. Back skin CVC-type fibres were less responsive than tail fibres to prostaglandin E2 (PGE2) microinjected into the preoptic area. Spectral analysis showed no significant coherence between tail and back skin CVC-type fibre activities during cooling. After preoptic PGE2 injection, a coherent peak at 1 Hz appeared in some animals; this disappeared after partialization with respect to ventilatory pressure, indicating that it was attributable to common ventilatory modulation. Neuronal inhibition in the rostral medullary raphé by microinjected muscimol (2 mM, 60-120 nl) suppressed both tail and back skin CVC-type fibre activities, and prevented their responses to subsequent skin cooling. These results indicate that thermoregulatory responses of hairless and hairy skin vessels are controlled by independent neural pathways, although both depend on synaptic relays in the medullary raphé.

Vasomotor sympathetic activity plays an important role in arterial pressure maintenance via the baroreflex during acute orthostasis in humans. If orthostasis is prolonged, blood pressure may be supported additionally by humoral factors with a possible reduction in sympathetic baroreflex sensitivity. We tested the hypothesis that baroreflex control of muscle sympathetic nerve activity (MSNA) decreases during prolonged upright posture. MSNA and haemodynamics were measured supine and during 45 min 60 deg upright tilt in 13 healthy individuals. Sympathetic baroreflex sensitivity was quantified using the slope of the linear correlation between MSNA and diastolic pressure during spontaneous breathing. It was further assessed as the relationship between MSNA and stroke volume, with stroke volume derived from cardiac output (C2H2 rebreathing) and heart rate. Total peripheral resistance was calculated from mean arterial pressure and cardiac output. We found that MSNA increased from supine to upright (17+/-8 (S.D.) versus 38+/-12 bursts min-1; P<0.01), and continued to increase to a smaller degree during sustained tilt (39+/-11, 41+/-12, 43+/-13 and 46+/-15 bursts min-1 after 10, 20, 30 and 45 min of tilt; between treatments P<0.01). Sympathetic baroreflex sensitivity increased from supine to upright (-292+/-180 versus -718+/-362 units beat-1 mmHg-1; P<0.01), but remained unchanged as tilting continued (-611+/-342 and -521+/-221 units beat-1 mmHg-1 after 20 and 45 min of tilt; P=0.49). For each subject, changes in MSNA were associated with changes in stroke volume (r=0.88+/-0.13, P<0.05), while total peripheral resistance was related to MSNA during 45 min upright tilt (r=0.82+/-0.15, P<0.05). These results suggest that the vasoconstriction initiated by sympathetic adrenergic nerves is maintained by ongoing sympathetic activation during sustained (i.e. 45 min) orthostasis without obvious changes in vasomotor sympathetic neural control.

The present study explores how elevations in brain P(CO(2)) increase the sympathetic nerve discharge (SND). SND, phrenic nerve discharge (PND) and putative sympathoexcitatory vasomotor neurons of the rostral ventrolateral medulla (RVLM) were recorded in anaesthetized sino-aortic denervated and vagotomized rats. Hypercapnia (end-expiratory CO(2) from 5% to 10%) increased SND (97 +/- 6%) and the activity of RVLM neurons (67 +/- 4%). Injection of kynurenic acid (Kyn, ionotropic glutamate receptor antagonist) into RVLM or the retrotrapezoid nucleus (RTN) eliminated or reduced PND, respectively, but did not change the effect of CO(2) on SND. Bilateral injection of Kyn or muscimol into the rostral ventral respiratory group (rVRG-pre-Bötzinger region, also called CVLM) eliminated PND while increasing the stimulatory effect of CO(2) on SND. Muscimol injection into commissural part of the solitary tract nucleus (commNTS) had no effect on PND or SND activation by CO(2). As expected, injection of Kyn into RVLM or muscimol into commNTS virtually blocked the effect of carotid body stimulation on SND in rats with intact carotid sinus nerves. In conclusion, CO(2) increases SND by activating RVLM sympathoexcitatory neurons. The relevant central chemoreceptors are probably located within or close to RVLM and not in the NTS or in the rVRG-pre-Bötzinger/CVLM region. RVLM sympathoexcitatory neurons may be intrinsically pH-sensitive and/or receive excitatory synaptic inputs from RTN chemoreceptors. Activation of the central respiratory network reduces the overall sympathetic response to CO(2), presumably by activating barosensitive CVLM neurons and inhibiting RTN chemoreceptors.

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 beta1-adrenergic blockade (metoprolol, 0.15 +/- 0.003 mg kg(-1)) or parasympathetic blockade (glycopyrrolate, 13.6 +/- 1.5 microg 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)) ofthe 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.

This study investigated, in vivo, the mechanisms underlying the development of cardiovascular function in the horse fetus, with particular relevance to baroreflex function and hind limb vascular arterial reactivity to constrictor agonists. Under general anaesthesia, vascular catheters were inserted and a Transonic flow probe was implanted around one of the metatarsal arteries of 13 horse fetuses, either at 0.6 of gestation (n= 6) or at 0.9 of gestation (n= 7, term approximately 335 days). At least 5 days after surgery, pressor, vasoconstrictor and cardiac chronotropic responses to exogenous bolus doses of phenylephrine, angiotensin II and arginine vasopressin were recorded. Fetal cardiac baroreflex slopes were obtained using the peak pressor and heart rate responses to increasing doses of phenylephrine. Fetal treatment with phenylephrine, angiotensin II and vasopressin produced significant changes in arterial blood pressure, hind limb vascular resistance and heart rate. Pressor and vasopressor responses to all agonists were greater at 0.9 than at 0.6 of gestation; however, fetal cardiac baroreflex sensitivity decreased with advancing gestational age. Correlation analysis revealed that fetal plasma cortisol rather than gestational age was a greater determinant of pressor and vasopressor reactivity. In contrast, gestational age rather than cortisol better determined heart rate and baroreflex responsiveness in the equine fetus. The data show that development of cardiovascular function in the equine fetus occurs via cortisol-dependent and -independent pathways.

Physical diminishes with ageing, but little is known of how the microvascular supply to skeletal muscle fibres is affected. To test the hypothesis that ageing alters blood flow control, we investigated network architecture and vasomotor responses of arterioles in the gluteus maximus muscle of young (2-3 months), adult (12-14 months) and old (18-20 months) C57BL6 male mice (n = 83) (Young, Adult and Old, respectively). Microvascular casts revealed that the total number, length and surface area of arteriolar segments (diameter, 10-50 microm) were not significantly different across age-groups. However, for arterioles with diameter of 30 microm, tortuosity and branch angles increased with age (P < 0.05). In anaesthetized mice, second-order (2A) distributing arterioles had similar resting (17 +/- 1 microm) and maximal (37 +/- 1 microm) diameters and similar responsiveness to cumulative (10(-10)-10(-4) M) superfusion of acetylcholine or phenylephrine. With superfusate oxygen level raised from 0 to 21%, 2A arteriolar constriction in Young (11 +/- 1 microm) was greater (P < 0.05) than Adult and Old (5 +/- 1 microm). Observed 1 mm upstream from microiontophoresis of ACh (1 microA, 1 s), conducted vasodilatation was 10 +/- 1 microm in Young, 17 +/- 1 microm in Adult and 6 +/- 1 microm in Old (P < 0.05). With muscle contractions (2, 4 and 8 Hz; 30 s) arteriolar diameter increased similarly across age-groups (6 +/- 1, 11 +/- 1 and 18 +/- 1 microm, respectively). Muscle mass and active tension were similar across age-groups yet postcontraction vasodilatation recovered more rapidly in Old versus Adult and Young (P < 0.05). With arteriolar network architecture maintained during ageing, the impairment in conducted vasodilatation and attenuation of postcontraction vasodilatation may compromise exercise tolerance.

We compared haemodynamic and peripheral vasomotor responses to lower body negative pressure (LBNP) in cardiac transplant recipients who had undergone bicaval anastomoses, involving right atrial deafferentation (-RA), and the conventional procedure in which some atrial baroreceptor afferents remain intact (+RA). We measured mean forearm blood flow (FBF) responses using Doppler/ultrasound during three randomised trials involving 0 (baseline), -20 and -40 mmHg LBNP in 15 transplant recipients (9 -RA, 6 +RA) and in eight healthy matched controls. A significant effect of LBNP on FBF existed between control and transplant groups (P < 0.05; two-way ANOVA). Mild LBNP (-20 mmHg), significantly decreased FBF by 29.7 +/- 10.0% relative to baseline in +RA subjects (P < 0.05), whereas the 17.7 +/- 10.3% decrease in -RA subjects was not significant. In response to -40 mmHg LBNP, FBF significantly decreased in control (42.4 +/- 4.6%, P < 0.05) and +RA subjects (33.3 +/- 11.4%, P < 0.05) with no significant change in the -RA group. The response of systolic blood pressure (SBP) to -40 mmHg significantly differed between groups (P < 0.05): -RA subjects decreased significantly (P < 0.05) whilst the decrease in SBP in +RA subjects did not achieve significance and control subjects exhibited an increase. The heart rate increase from baseline to -40 mmHg was significantly attenuated in -RA relative to controls and the +RA group (P < 0.05). The present study demonstrates that atrial deafferentation impairs reflex vasomotor control of the circulation in response to low- and high-level LBNP, indicating that atrial deafferentation may contribute to abnormal arterial pressure regulation.

The effects of changes in the mean (S(m)) and pulsatile (S(p)) components of arterial wall shear stress on arterial dilatation of the iliac artery of the anaesthetized dog were examined in the absence and presence of the endothelin receptor antagonist tezosentan (10 mg kg(-1) I.V.; Ro 61-0612; [5-isopropyl-pyridine-2-sulphonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide]). Changes in shear stress were brought about by varying local peripheral resistance and stroke volume using a distal infusion of acetylcholine and stimulation of the left ansa subclavia. An increase in S(m) from 1.81 +/- 0.3 to 7.29 +/- 0.7 N m(-2) (means +/- S.E.M.) before tezosentan caused an endothelium-dependent arterial dilatation which was unaffected by administration of tezosentan for a similar increase in S(m) from 1.34 +/- 0.6 to 5.76 +/- 1.4 N m(-2) (means +/- S.E.M.). In contrast, increasing the S(p) from 7.1 +/- 0.8 to a maximum of 11.5 +/- 1.1 N m(-2) (means +/- S.E.M.) before tezosentan reduced arterial diameter significantly. Importantly, after administration of tezosentan subsequent increases in S(p) caused arterial dilatation for the same increase in S(p) achieved prior to tezosentan, increasing from a baseline of 4.23 +/- 0.4 to a maximum of 9.03 +/- 0.9 N m(-2) (means +/- S.E.M.; P < 0.001). In conclusion, the results of this study provide the first in vivo evidence that pulsatile shear stress is a stimulus for the release of endothelin from the vascular endothelium.

The role of endothelium-derived hyperpolarizing factor (EDHF) in the regulation of blood flow in vivo was examined in the mesenteric and hindlimb circulations of anaesthetized rats. Basal mesenteric conductance decreased from 57 +/- 5 to 20 +/- 6 microl min(-1) mmHg(-1) when nitric oxide (NO) production was inhibited, and combined blockade of intermediate- and small-conductance Ca(2+)-activated K(+) (K(Ca)) channels with charybdotoxin (ChTx) and apamin had no further effect. Basal hindlimb conductance was reduced from 39 +/- 3 to 22 +/- 2 microl min(-1) mmHg(-1) by NO synthesis inhibition, with no effect of the K(Ca) channel blockers. Endothelial stimulation with acetylcholine (ACh) infusion directly into the mesenteric bed increased conductance by 20 +/- 2 microl min(-1) mmHg(-1). Blockade of NO synthesis decreased this conductance to 15 +/- 1 microl min(-1) mmHg(-1), leaving the response attributable to EDHF. This was reduced to 2 +/- 1 microl min(-1) mmHg(-1) by ChTx plus apamin but not by iberiotoxin, which selectively blocks large-conductance K(Ca) channels. Similar results were obtained when bradykinin (BK) was used to stimulate the endothelium. Nitroprusside, which directly relaxes smooth muscle, evoked an increase in conductance that was resistant to all blockers tested. ACh-induced increases in hindlimb conductance were reduced from 19 +/- 1 to 12 +/- 1 microl min(-1) mmHg(-1) by NO synthesis inhibition and further reduced to 2 +/- 2 microl min(-1) mmHg(-1) by ChTx plus apamin. In contrast to NO, ChTx- and apamin-sensitive EDHF appears to contribute little to basal conductance in rat mesenteric and hindlimb beds. However, EDHF accounts for a significant component of the conductance increase during endothelial stimulation by ACh and BK. In these beds, intermediate- and small-conductance K(Ca) channels underpin EDHF-mediated vasodilatation.

Single nerve fibres innervating tooth pulp were isolated from filaments dissected from the inferior alveolar nerve in 17 anaesthetized cats. The fibres were studied to determine whether electrical stimulation of single units produced detectable changes in pulpal blood flow. Single pulpal nerve fibres were electrically stimulated at just above their thresholds and blood flow was recorded with a laser-Doppler flow meter from the pulp of the ipsilateral canine. The thresholds of single fibres in dissected filaments were determined either by recording antidromic action potentials from the tooth or by using a novel technique based on collision. Units that produced blood flow changes were further characterized by recording their response to hot, cold, osmotic and hydrostatic pressure, and mechanical stimulation of exposed dentine and to drying the dentine. Of 93 units isolated, 14 produced changes in pulpal blood flow when stimulated electrically at 1 or 10 Hz. All had conduction velocities (0.8-2.0 m s(-1)) in the C-fibre range. Ten produced vasodilatation and the remaining four, vasoconstriction. Five of the fibres that produced vasodilatation also responded to the hot stimulus, suggesting that they may form part of an axon reflex or similar mechanism. The four vasoconstrictor units did not respond to any form of stimulus other than electrical and were presumed to be sympathetic post-ganglionic fibres.

1. This investigation was designed to determine the contribution of the exercise pressor reflex to the resetting of the carotid baroreflex during exercise. 2. Ten subjects performed 3.5 min of static one-legged exercise (20 % maximal voluntary contraction) and 7 min dynamic cycling (20 % maximal oxygen uptake) under two conditions: control (no intervention) and with the application of medical anti-shock (MAS) trousers inflated to 100 mmHg (to activate the exercise pressor reflex). Carotid baroreflex function was determined at rest and during exercise using a rapid neck pressure/neck suction technique. 3. During exercise, the application of MAS trousers (MAS condition) increased mean arterial pressure (MAP), plasma noradrenaline concentration (dynamic exercise only) and perceived exertion (dynamic exercise only) when compared to control (P < 0.05). No effect of the MAS condition was evident at rest. The MAS condition had no effect on heart rate (HR), plasma lactate and adrenaline concentrations or oxygen uptake at rest and during exercise. The carotid baroreflex stimulus-response curve was reset upward on the response arm and rightward to a higher operating pressure by control exercise without alterations in gain. Activation of the exercise pressor reflex by MAS trousers further reset carotid baroreflex control of MAP, as indicated by the upward and rightward relocation of the curve. However, carotid baroreflex control of HR was only shifted rightward to higher operating pressures by MAS trousers. The sensitivity of the carotid baroreflex was unaltered by exercise pressor reflex activation. 4. These findings suggest that during dynamic and static exercise the exercise pressor reflex is capable of actively resetting carotid baroreflex control of mean arterial pressure; however, it would appear only to modulate carotid baroreflex control of heart rate.

1. The question of whether neurones in the paraventricular nucleus (PVN) of the hypothalamus have an excitatory influence on reticulo-spinal vasomotor neurones of the rostral ventrolateral medulla (RVL) has been addressed in this study using anaesthetized rats. 2. Extracellular microelectrode recordings were made from sixty vasomotor neurones in the RVL, identified by their cardiac cycle-related probability of discharge, by the decrease in activity in response to an increase in arterial blood pressure produced by intravenous phenylephrine and by the increase in activity in response to a decrease in blood pressure produced by intravenous nitroprusside. 3. More than 70 % of these RVL vasomotor neurones were identified as spinally projecting by antidromically activating their axons via a stimulating electrode in the lateral funiculus of the T2 or T10 segment of spinal cord. 4. Activation of neurones at different sites in the PVN with a microinjection of d,l-homocysteic acid (DLH) elicited either pressor or depressor responses. 5. At PVN pressor sites fifteen RVL vasomotor neurones were shown to be activated prior to the blood pressure change. A further twenty RVL vasomotor neurones were observed to decrease activity following the blood pressure rise. At PVN depressor sites twelve RVL neurones were inhibited prior to the blood pressure change whereas another thirteen identified RVL neurones increased their discharge following the fall in blood pressure. 6. In three rats single shock electrical stimulation at a PVN pressor site, first identified with DLH, elicited a single or double action potential in thirteen RVL neurones with a latency of 27 +/- 1 ms. 7. It is concluded that PVN neurones may elicit increases in blood pressure via excitatory connections with RVL-spinal vasomotor neurones, and that other PVN neurones may elicit decreases in blood pressure via inhibitory connections with these RVL neurones.

1. Controversy exists as to whether a fall in the intracellular Ca2+ concentration ([Ca2+]i) is a requisite element of the vasodilatory response to nitric oxide (NO). 2. We studied the effect of NO on the coupling between [Ca2+]i and vasoconstriction in arterial segments loaded with the [Ca2+]i-sensitive, intracellular dye fura-2. As data interpretation is equivocal when fura-2 is loaded into both endothelial and smooth muscle cells, we compared results from in vitro experiments on segments of the rat tail artery in which fura-2 and noradrenaline were applied on the luminal or adventitial side, and endothelium was removed 'physically' (rubbing or air) or 'functionally' (Nomega-nitro-L-arginine methyl ester). The use of air perfusion to remove endothelium is of considerable benefit since it allows paired observations in a single tissue. 3. Fura-2 loaded into endothelial cells but endothelial 'contamination' of the smooth muscle cell [Ca2+]i signal was minimal. 4. Endogenous NO decreased vasoconstrictor responses to noradrenaline but had no effect on [Ca2+]i. 5. Nitroglycerine decreased vasoconstrictor responses in a concentration-dependent fashion but had no effect on [Ca2+]i. 6. In conclusion, NO causes vasodilatation via a mechanism which is downstream of [Ca2+]i mobilization.

1. Vasomotor responses (VMR) induced by local electrical stimulation were studied in the vasculature of the split hydronephrotic rat kidney by in vivo microscopy. 2. Unipolar pulses, which were applied by a micropipette positioned close to the vessel wall, elicited local and propagated VMR. Depolarizing and hyperpolarizing currents caused vasoconstriction and vasodilatation, respectively. 3. The magnitude of VMR could be controlled within seconds by variation of pulse frequency, pulse width and voltage. VMR were abolished by slight retraction of the stimulating micropipette. Repetitive electrical stimulation resulted in reproducibly uniform VMR. 4. Propagated VMR decayed with increasing distance from the stimulation site. They decayed more rapidly in the upstream than in the downstream flow direction in interlobular arteries. The longitudinal decay was well approximated by an exponential function with significantly different length constants of 150 +/- 40 microns (upstream, n = 5) and 420 +/- 90 microns (downstream, n = 8). 5. Our results show that vasomotor responses, which are initiated by changes in membrane potential, are propagated over distances of potential physiological importance in interlobular arteries.

1. The cardiovascular responses, together with the effects on medullary sympathoexcitatory (vasomotor) neurones of the rostral ventrolateral medulla, of area postrema stimulation have been studied in vivo. 2. Electrical (10 Hz) or chemical stimulation using microinjections of L-glutamate of the area postrema produced a vasodepressor response and an inhibition of the medullary sympathoexcitatory neurones in the nucleus reticularis rostroventrolateralis (RVL), while similar stimulation in the adjacent nucleus tractus solitarii (NTS) caused increases in arterial pressure. 3. Single-pulse stimulation of the area postrema revealed at least three influences on the activity of RVL vasomotor neurones, one being excitatory and two inhibitory. 4. The inhibitions evoked in the medullary vasomotor neurones on area postrema stimulation were blocked by ionophoretic application of bicuculline, a GABAA receptor antagonist, without altering the excitatory input to the same neurones. Bilateral microinjections of bicuculline into the RVL in regions where the vasomotor neurones had been identified totally eliminated the vasodepression due to area postrema stimulation. 5. These data support a role for the area postrema in cardiovascular control. It is concluded that the area postrema exerts its action on cardiovascular control in part via GABAergic inhibition of the 'vasomotor' neurones in the nucleus reticularis rostroventrolateralis.

1. Myogenic responses may account for control of organ blood flow. The study of these responses without interference from the organ requires an isolation technique for vessels which contribute significantly to flow resistance. This study reports on experiments on isolated small mesenteric arteries. 2. Distal rat mesenteric arcade arteries and first-order branches (diameter range 145-365 microns, mean 293 microns) were manually dissected and cannulated using a double-barrelled micro-cannula. Luminal cross-sectional area of these vessels was continuously monitored by means of a fluorescence technique. 3. Nine out of eighteen vessels developed basal tone at 80 mmHg distending pressure, resulting in a 45.2 +/- 5.1% (mean +/- S.E.M) decrease of cross-sectional area. Tone was induced in the other vessels by 0.3-1 microM-noradrenaline, resulting in a 59.5 +/- 7.1% decrease in cross-sectional area. 4. In vessels with either spontaneous or induced tone, stepwise changes of pressure resulted in passive effects, followed by myogenic responses. 5. Steady-state pressure-cross-sectional area relations of vessels with basal tone showed a significant negative slope (-0.5% mmHg-1), while pressure-cross-sectional area relations of vessels with induced tone were essentially flat between 40 and 120 mmHg. 6. Five vessels with basal tone and eight vessels with induced tone developed vasomotion at 80 mmHg. Frequencies of spontaneous and induced vasomotion were 14 (range 4-31) and 21 (9-25) cycles min-1 respectively. Amplitudes were 5 (1-10) and 8 (3-17)% of the passive cross-sectional area. In both groups, frequency was positively, and amplitude negatively correlated with pressure. 7. These data show that myogenic responses are induced by wall stress, rather than by distension of the vascular wall. Basal tone is not a prerequisite for the appearance of myogenic responses.

1. In anaesthetized rats recordings were made from thirty-eight neurones in the rostral ventrolateral medulla (RVL) with spinal-projecting axons. Their responses to mechanical, thermal and/or electrical stimulation were examined as were the accompanying changes in arterial pressure. 2. Mechanical, thermal and electrical stimulation of either hindpaw at a strength that can be regarded as noxious produced a consistent rise in arterial pressure. RVL-spinal-projecting 'vasomotor' neurones were excited by the noxious mechanical and thermal (52 degrees C) stimulation at a latency that was shorter than that of the evoked pressor response. 3. Percutaneous electrical stimulation of either hindlimb extremity resulted in an early peak of excitation (fourteen out of fourteen), an early trough of inhibition (twelve out fourteen), and a later peak of excitation (two out of fourteen). This response pattern to stimulation of either limb was independent of which limb was activated, but contralateral hindpaw stimulation elicited excitation at a shorter latency. The differences in latency of responses to stimulating two locations along the tail suggested that the early excitation and inhibition of RVL-spinal 'vasomotor' neurones were evoked by activation of peripheral fibres with a mean conduction velocity in the A delta range. 4. Short-latency excitatory and inhibitory responses in RVL-spinal 'vasomotor' neurones were observed also when single-pulse stimuli were delivered within the lateral part of the spinal cord. 5. Ionophoretic application of bicuculline, a GABAA receptor antagonist, blocked the evoked inhibition of these neurones on electrical stimulation of the hindpaw without attenuating the excitatory input from the same stimulus. 6. These results indicate that RVL-spinal 'vasomotor' neurones receive an input from cutaneous nociceptive afferents. This suggests that these neurones mediate, at least partly, the cardiovascular responses related to nociceptor stimulation.

1. The goal of this study was to examine ionic mechanisms that modulate spontaneous rhythmic changes in vascular calibre or 'vasomotion' in the basilar artery in vivo. 2. Diameter of the basilar artery was measured through a craniotomy in anaesthetized rats under control conditions and during topical application of antagonists or alteration in the ionic composition of artificial cerebrospinal fluid (CSF). 3. Both Ca2(+)-free CSF and the Ca2+ channel blocker, nimodipine, produced moderate dilatation of the basilar artery and abolished vasomotion. Increasing the concentration of Ca2+ in CSF from 1.7 to 5.0 mM did not affect the frequency of vasomotion, although the amplitude was increased slightly. 4. Both K(+)-free CSF and ouabain produced mild to moderate vasoconstriction and abolished vasomotion. In contrast, increasing the concentration of K+ in CSF produced vasodilatation of the basilar artery and decreased or abolished vasomotion depending on the degree of vasodilatation. 5. Tetrodotoxin had no effect on vasomotion. 6. These results suggest that vasomotion of the basilar artery in vivo is dependent on extracellular Ca2+ and K+, and on the activity of Na(+)-K(+)-ATPase, and not dependent on Na+ channel.

1. Sympathetic nerve activity occurring as bursts of multi-unit impulses was recorded with tungsten microelectrodes in the supraorbital nerve of awake healthy subjects. Within the fascicular innervation zone on the forehead, skin resistance was measured as an indicator of sweat gland activity, and skin blood flow was measured with laser-doppler flowmetry. 2. At room temperature, there was little or no background burst activity, but arousal stimuli or mental stress evoked bursts followed by a vasodilator response. Provided repeated arousal stimuli were delivered, individual bursts were followed by a decrease in skin resistance. 3. Body heating induced increasing background burst activity. After an initial period without associated electrodermal activity, there were decreases in skin resistance, which showed a positive linear correlation with the amplitude of the preceding burst. Individual bursts were followed by a vasodilator response with an average onset latency of 2.8 s and an average duration of 9.1 s, and rapid increases in blood flow coincided with a marked increase in burst activity. Arousal stimuli evoked bursts followed by both vasodilator and skin resistance responses. 4. During body cooling, there was no background burst activity, but signs of relatively weak, probably neurally mediated vasoconstriction were observed and arousal-evoked bursts were reduced or abolished, as were the associated vasodilator and skin resistance responses. 5. It is concluded that body heating induces active sympathetic vasodilatation in the skin of the human forehead, and that this is either sudomotor-mediated or caused by vasodilator fibres firing in synchrony with sudomotor fibres. A similar sympathetic mechanism probably underlies the vasodilator responses evoked by arousal stimuli and mental stress.

1. The innervation of feline cerebral (pial) vessels by nerve fibres containing noradrenaline, substance P or vasoactive intestinal polypeptide (VIP) has been examined using the Falck-Hillarp histo-fluorescence method and immunohistochemical techniques. Cerebral veins were shown to be innervated by nerve fibres containing noradrenaline, substance P or VIP. Nerve fibres containing noradrenaline were the most numerous, while fibres containing substance P were observed least frequently in both types of vessel. For each putative neurotransmitter, the density of the innervation of the cerebral veins was less than that of cerebral arteries.2. The vasomotor responses of individual pial arteries and veins on the convexity of the cerebral cortex to perivascular micro-injection of noradrenaline, substance P and VIP were examined in twenty-five cats anaesthetized with alpha-chloralose.3. The perivascular micro-application of noradrenaline resulted in pronounced dose-dependent reductions in the diameter of pial veins (maximum calibre reduction: 32+/-3% noradrenaline 10(-5) M) and arteries (22+/-3% noradrenaline 10(-5) M). Pial veins were more sensitive to noradrenaline than were pial arteries tested under similar conditions. The reductions in the diameter of cerebral veins and arteries resulting from the administration of noradrenaline could be attenuated by the concomitant micro-application of phentolamine (10(-6) M).4. The perivascular micro-application of substance P effected significant dose-dependent increases in the calibre of pial veins (maximum calibre increase: 16+/-4% substance P 10(-7) M) which were of a similar magnitude to those observed in pial arteries in response to this peptide (21+/-4% substance P 10(-6) M).5. The perivascular micro-application of VIP resulted in small increases in the calibre of pial veins (maximum calibre increase: 9+/-2% VIP 10(-8) M) which were proportionately smaller than those observed in pial arteries in response to this peptide (23+/-5% VIP 10(-7) M).

1. Six healthy humans were immersed sequentially in baths maintained at a steady temperature of either 28 +/- 1 or 38-8 +/- 1 degree C. 2. Metabolic heat production was calculated by respiratory gas analysis. A ventilated capsule was placed on the forehead and sweat secretion was calculated from psychrometric recordings. Convective heat loss from one hand to water-perfused glove provided a continuous measurement of vasomotor response. 3. Heat production, sweating, and vasomotor heat loss were proportional to core temperature. 4. Sweating and vasomotor response were parallel. Vasoconstriction was complete, before the onset of shivering. 5. The thresholds for heat loss and heat production were superimposed, without a 'dead band' core temperature.

1. In rabbits under pentobarbitone anaesthesia stimulation of the nasal mucous membrane with ether vapour causes apnoea, bradycardia and a rise in arterial blood pressure. 2. Simultaneous measurements of femoral arterial blood pressure and of femoral arterial or venous blood flow show that vascular resistance increases in both the intact and skinned hind limb in response to nasal stimulation. Evidence is presented to show that the increase in hind-limb vascular resistance is due to vasoconstriction which is relfex in nature. 3. The change in vascular resistance in the hind limb following nasal stimulation may be divided into two distinct phases. The primary (early) phase is mediated by the efferent sympathetic nerves to the limb whereas the secondary (late) phase is mediated by adrenal gland hormones. 4. The secondary phase of the hind-limb vascular response is invariably less pronounced than the primary phase, and with regard to the time course of the appearance of the two phases of the response it appears that following stimulation of the nose there is no mutual reinforcement of sympathetic neural and humoral influences on the hind-limb blood vessels. 5. The cardiovascular response occur in the absence of changes in pulmonary ventilation.

In chloralose-anaesthetized, artificially ventilated cats, the effects have been studied of inactivating neurones of the 'glycine-sensitive area' of the rostral ventrolateral medulla on evoked renal sympathetic and vasomotor responses. Glycine applied topically and bilaterally to the 'glycine-sensitive area' besides markedly lowering blood pressure and heart rate, reversibly abolished or severely attenuated both the pressor response and the renal nerve volley produced by electrical stimulation of the fastigial nucleus as well as the tibial to renal nerve somatosympathetic reflex. Bilateral radio-frequency lesions of the 'glycine-sensitive area' similarly lowered blood pressure and heart rate, blocked the fastigial pressor response and abolished renal nerve responses to fastigial nucleus or tibial nerve stimulation. Effective lesions extended greater than or equal to 1 mm deep from the medullary surface. These results are discussed with reference to the view that the 'glycine-sensitive area' contains neurones constituting a final descending bulbo-spinal pathway to preganglionic vasomotor neurones.

1. The responses to sympathetic nerve stimulation and to the adrenal medullary hormones have been studied in the hind limb vascular beds of the anaesthetized rabbit.2. Simultaneous measurements of femoral arterial blood pressure and of femoral venous blood flow indicate that stimulation of the sympathetic nerves decreases the calculated vascular conductance in both the intact and skinned hind limbs. Evidence is presented to show that these changes are due to vasoconstriction.3. The vasoconstriction in both skin and muscle vascular beds reaches a maximum at frequencies of stimulation around 15 Hz. No vasodilatation is obtained at any frequency of stimulation.4. The rabbit adrenal gland secretes only adrenaline during splanchnic nerve stimulation at frequencies between 3 and 60 Hz. The amounts liberated from both glands over this frequency range are 25-500 ng.kg body wt.(-1) min(-1).5. Intravenous infusions of adrenaline in concentrations similar to those liberated by the adrenal glands during splanchnic nerve stimulation, and of noradrenaline, cause only vasoconstrictor responses in skin and muscle.6. Simultaneous stimulation of the sympathetic nerves to the hind limb and infusion of adrenaline in quantities that could be liberated by splanchnic nerve stimulation at equivalent frequencies shows that the vasoconstrictor effects exerted by the individual components are additive, though the effects produced by the direct sympathetic nerve supply overshadow those produced by the catecholamine.7. The results are discussed in the context of the possible vascular role of the adrenal medullary hormones in the rabbit.

1. Lung lobes of Macaca mulatta and Papio species were isolated from the body and perfused by a pump delivering a constant volume inflow. The left atrial pressure was kept constant and therefore any recorded change in pulmonary arterial pressure reflected a change in pulmonary vascular resistance. 2. In five Macaca mulatta preparations stimulation of the upper thoracic sympathetic chain, the stellate ganglion, the middle cervical ganglion and the thoracic vagosympathetic nerve caused a small increase in calculated pulmonary vascular resistance usually followed by a larger decrease. Evidence is produced which suggests that the depressor response is mediated by adrenergic beta-receptors. In three preparations no change in pulmonary vascular resistance occurred. 3. In four Papio preparations stimulation of similar nerves invariably caused an increase in calculated pulmonary vascular resistance. In one animal no change in vascular resistance occurred. 4. A regression analysis of the results showed an inverse relationship between the magnitude of the pulmonary vascular response to nerve stimulation and the degree of excitement of the animals during capture, restraint and anaesthesia (P less than 0.01).

1. Five human subjects pedalled on a bicyle ergometer for at least two 74 min periods at 10 degrees C ambient temperature. During the first period the subjects cycled for 42 min with face fanning, followed by 32 min with the head thermally insulated. In the second period, this procedure was reversed. Oesophageal (tes), tympanic (Tty), forehead and hand skin temperatures were recorded. In addition, heart rate (H.R.) was counted throughout the experiments, and the technique of perceptual rating of cool and warm stimuli was used in order to appreciate whether the subjects were hypo-, normo-, or hyperthermic. 2. Face fanning resulted in decreased Tty, decreased H.R., mild skin vasoconstriction but increased Tes. 3. Head covering resulted in increased Tty and H.R., while Tes decreased slightly, due to peripheral vasodilatation. 4. When their faces were being fanned so that Tty was low and Tes was high, the subjects gave slightly hypothermic ratings. Ratings were clearly hyperthermic when their heads were covered and Tty was high and Tes was low. 5. The close correlation between vasomotor response and H.R. on the one hand and Tty on the other confirms that this variable is a better approximation of regulated core temperature than Tes. 6. Increase in Tes during face fanning and decrease in Tes during face insulation is new evidence for the possibility of the human brian being cooled during exercise by cool blood returning from the face. 7. We suggest that this selective brain cooling determines the apparent upper resetting of core temperature during exercise while brain temperature remains precisely regulated and constant.

1. During operative aorto-femoral vascular reconstructions on sixteen patients, the sympathetic chain was stimulated electrically between the L2 and L4 ganglia while blood flow was monitored by laser doppler flowmeters from the skin on the sole of the foot and the ankle and by an electromagnetic flowmeter from the deep femoral artery. Epidural anaesthesia to at least the T6 level was used which excluded reflex effects. 2. Stimulation (10 Hz) at 1-12 mA current strengths for 30 s evoked both reductions and increases of blood flow in glabrous and hairy skin. Initial short-lasting flow increases (durations 9-19 s) followed by sustained decreases were common: sometimes there were sustained flow increases at low and decreases at high current strengths. 3. In the deep femoral artery (supplying predominantly muscle) only flow reductions were evoked. 4. The results provide evidence for sympathetically mediated vasodilatation in the skin of the human foot whereas leg muscles may be supplied by vasoconstrictor nerves only.

1. In anaesthetized dogs the reflex vascular resistance changes in a perfused hind limb were studied following carotid baroreceptor or chemoreceptor stimulation. 2. The observed rises in resistance were sympathetically mediated and thus provided a means of studying the action of the cholinergic antagonists on the sympathetic ganglion transmission. 3. The reflex response to carotid baroreceptor stimulation produced by lowering the pressure in the carotid sinuses was abolished by hexamethonium bromide but not reduced by hyoscine methyl bromide. 4. The reflex response to carotid body chemoreceptor stimulation, by hypoxia, was not altered by hexamethonium bromide but was greatly reduced by the hyoscine methyl bromide. No reflex response was seen when both antagonists were present. 5. These results indicate that sympathetic ganglion synaptic transmission during the baroreceptor reflex is mediated by nicotinic receptor activation. The transmission evoked by chemoreceptor stimulation involves muscarinic receptors with a subsidiary nicotinic pathway. High doses of an antagonist were necessary to block the muscarinic component of transmission and this is discussed in relation to previous work. 6. No non-cholinergic transmission of the reflex responses was observed.