Xanthine oxidase does not contribute to impaired peripheral conduit artery endothelium-dependent dilatation with ageing

Vascular oxidative stress is the key mechanism involved in the age-related decline in endothelium-dependent dilatation (EDD). We tested the hypothesis that xanthine oxidase (XO), a major vascular source of reactive oxygen species, contributes to the impairment in EDD with ageing. At baseline, brachial artery flow-mediated dilatation (FMD) was 55% lower in older ( n = 9, 64 ± 2 years, 8M/1F, mean ± s.e.m. ) versus young ( n = 9, 26 ± 1 years, 8M/1F) healthy adults (3.41 ± 0.44 versus 7.53 ± 0.67%, P < 0.001), whereas endothelium-independent dilatation (EID; sublingual nitroglycerin) did not differ between groups. Plasma oxidized low-density lipoprotein (oxi-LDL), a measure of systemic oxidative stress, was greater at baseline in the older subjects (58.3 ± 5.9 versus 46.8 ± 2.4 U l⁻¹, P < 0.05) and inversely correlated with baseline FMD ( r =− 0.54; P < 0.05). Acute administration of allopurinol, a competitive inhibitor of XO, reduced plasma uric acid concentrations similarly in both groups ( P < 0.001), but did not affect FMD, EID, or oxi-LDL in either group. Vascular endothelial protein expression of XO (immunofluorescence) was not different in antecubital venous cells from the young and older subjects (0.56 ± 0.12 versus 0.68 ± 0.19 XO intensity/human umbilical vein endothelial cell intensity, P = 0.49). We conclude that XO does not contribute to oxidative stress-associated reductions in peripheral conduit artery EDD with ageing in humans, possibly due to an absence of age-associated up-regulation of endothelial XO.     

Effects of Perfusion Rate on Permeability of Frog and Rat Mesenteric Microvessels to Sodium Fluorescein

The permeability, P _S, to sodium fluorescein (Stokes-Einstein radius = 0.45 nm) has been measured in single mesenteric capillaries of pithed frogs and anaesthetised rats as perfusion velocity, U , was varied over a range from 400 up to 2000–10 000 μm s⁻¹. P _S increased linearly with U . In 20 frog capillaries, mean (± S.E.M.) P _S (in μm s⁻¹) = 9.35 (± 1.55) U × 10⁻⁵+ 0.244 (± 0.0291). Similarly, in nine rat venules, mean P _S= 1.62 (± 0.385) U × 10⁻⁴+ 0.375 (± 0.025). The flow-dependent component of permeability could be reversibly abolished in frog capillaries by superfusing with 100 μM noradrenaline and by superfusing rat venules with the nitric oxide synthase inhibitor, N ^G-nitro-L-arginine (20 μM). It was shown that changes in microvascular pressure accompanying changes in U during free perfusion could account for only 15 % of the changes in P _S, i.e. 85 % of the changes in P _S were changes in the permeability coefficient itself. A comparison between the changes in P _S with U and the previously described changes in microvascular permeability to K⁺ with U , suggest that if the flow-dependent component of permeability is modelled as a population of pores of constant size, these have radii of 0.8 nm. Such a pathway would limit flow-dependent permeability to small hydrophilic molecules and have minimal effect on net fluid exchange.     

Reduced mitochondrial coupling in vivo alters cellular energetics in aged mouse skeletal muscle

The mitochondrial theory of ageing proposes that the accumulation of oxidative damage to mitochondria leads to mitochondrial dysfunction and tissue degeneration with age. However, no consensus has emerged regarding the effects of ageing on mitochondrial function, particularly for mitochondrial coupling (P/O). One of the main barriers to a better understanding of the effects of ageing on coupling has been the lack of in vivo approaches to measure P/O. We use optical and magnetic resonance spectroscopy to independently quantify mitochondrial ATP synthesis and O₂ uptake to determine in vivo P/O. Resting ATP demand (equal to ATP synthesis) was lower in the skeletal muscle of 30-month-old C57Bl/6 mice compared to 7-month-old controls (21.9 ± 1.5 versus 13.6 ± 1.7 nmol ATP (g tissue)⁻¹ s⁻¹, P = 0.01). In contrast, there was no difference in the resting rates of O₂ uptake between the groups (5.4 ± 0.6 versus 8.4 ± 1.6 nmol O₂ (g tissue)⁻¹ s⁻¹). These results indicate a nearly 50% reduction in the mitochondrial P/O in the aged animals (2.05 ± 0.07 versus 1.05 ± 0.36, P = 0.02). The higher resting ADP (30.8 ± 6.8 versus 58.0 ± 9.5 μmol g⁻¹, P = 0.05) and decreased energy charge (ATP/ADP) (274 ± 70 versus 84 ± 16, P = 0.03) in the aged mice is consistent with an impairment of oxidative ATP synthesis. Despite the reduced P/O, uncoupling protein 3 protein levels were not different in the muscles of the two groups. These results demonstrate reduced mitochondrial coupling in aged skeletal muscle that alters cellular metabolism and energetics.     

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

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

Comparative study of the effects of nedocromil sodium (4 mg) and sodium cromoglycate (10 mg) on adenosine-induced bronchoconstriction in asthmatic subjects

The effect of nedocromil sodium (4 mg; 7.8 × 10⁻⁶ m ) on adenosine-induced bronchoconstriction was compared with that of a higher dose of sodium cromoglycate (10 mg; 24.1 × 10⁻⁶ m ). Eleven allergic asthmatic patients (mean age 26.28 ± 12.21 years) were studied. Adenosine (0.03–4.00 mg) was administered as nebulized aerosol. The dose of adenosine producing a 20% change in FEV₁(PD₂₀) was calculated from the individual semi-logarithmic dose-response curves. Patients were studied on 4 separate days. On the first day the adenosine challenge was performed; on subsequent days patients were pretreated (20 min before challenge) with either placebo or test drug (nedocromil sodium 2 × 2 mg or sodium cromoglycate 2 × 5 mg) administered by pressurized aerosol in a randomized, double-blind manner. Statistical analysis was performed by two-way analysis of variance. Neither sodium cromoglycate nor nedocromil sodium showed a significant bronchodilator effect. In patients treated with placebo, inhalation of adenosine produced a dose-related bronchoconstriction with a geometric mean PD₂₀ of 0.42 mg. After drug administration the mean PD₂₀ values were 1.29 mg with sodium cromoglycate and 2.30 mg with nedocromil sodium. Both drugs produced a significant increase in mean PD₂₀ value in comparison with placebo and baseline ( P < 0.01). These results demonstrate that nedocromil sodium (4 mg) is significantly more potent than a larger dose of sodium cromoglycate (10 mg) in inhibiting adenosine-induced bronchoconstriction ( P < 0.05).     

Possible mechanisms of the concentration-dependent action of substance P to induce histamine release from rat peritoneal mast cells and the effect of extracellular calcium on mast-cell activation

Rat peritoneal mast cells purified on a Percoll gradient were loaded with the fluorescent Ca²⁺ indicator fura-2 and were challenged with different concentrations of substance P (SP), and intracellular calcium concentrations ([Ca²⁺]_i) were measured by a spectrofluorometric assay. SP at 5 × 10⁻⁶ mol/1 and 10⁻⁵ mol/1 caused a significant histamine release with a significant increase in [Ca²⁺]_i in a dose-dependent manner. However, SP at 10⁻⁸-10⁻⁶ mol/1 did not induce either histamine release or increase in [Ca²⁺]_i. Extracellular calcium at 0.9 mM inhibited the histamine release with a significant reduction of [Ca²⁺]ⁱ compared with that of the cells in a nominally calcium-free condition. These results indicate that the action of SP on rat mast cells relies upon [Ca²⁺]_i to induce histamine release.     

Influence of cerebrovascular function on the hypercapnic ventilatory response in healthy humans

An important determinant of [H⁺] in the environment of the central chemoreceptors is cerebral blood flow. Accordingly we hypothesized that a reduction of brain perfusion or a reduced cerebrovascular reactivity to CO₂ would lead to hyperventilation and an increased ventilatory responsiveness to CO₂. We used oral indomethacin to reduce the cerebrovascular reactivity to CO₂ and tested the steady-state hypercapnic ventilatory response to CO₂ in nine normal awake human subjects under normoxia and hyperoxia (50% O₂). Ninety minutes after indomethacin ingestion, cerebral blood flow velocity (CBFV) in the middle cerebral artery decreased to 77 ± 5% of the initial value and the average slope of CBFV response to hypercapnia was reduced to 31% of control in normoxia (1.92 versus 0.59 cm⁻¹ s⁻¹ mmHg⁻¹, P < 0.05) and 37% of control in hyperoxia (1.58 versus 0.59 cm⁻¹ s⁻¹ mmHg⁻¹, P < 0.05). Concomitantly, indomethacin administration also caused 40–60% increases in the slope of the mean ventilatory response to CO₂ in both normoxia (1.27 ± 0.31 versus 1.76 ± 0.37 l min⁻¹ mmHg⁻¹, P < 0.05) and hyperoxia (1.08 ± 0.22 versus 1.79 ± 0.37 l min⁻¹ mmHg⁻¹, P < 0.05). These correlative findings are consistent with the conclusion that cerebrovascular responsiveness to CO₂ is an important determinant of eupnoeic ventilation and of hypercapnic ventilatory responsiveness in humans, primarily via its effects at the level of the central chemoreceptors.     

Sustained Inhibition of Antigen-Induced Histamine Release from Human Lung by the β2-Adrenoceptor Agonist Terbutaline

Antigen-induced histamine release from passively sensitized human lung tissue was inhibited in the presence of the β₂-adrenoceptor agonist, terbutaline. A sustained and statistically significant suppression was detected in the concentration interval 3 × 10⁻⁸-1 × 10⁻⁶ M. Fifty per cent inhibition IC₅₀, was obtained at an interpolated concentration of 5.3 × 10⁻⁸± 0.4 × 10⁻⁸ M ( n = 13), when the histamine secretion was elicited with optimum concentration of antigen. Histamine release induced with a suboptimum concentration of antigen was inhibited to a greater extent than release initiated with optimum concentration. The data in the present investigation support the concept that terbutaline-induced inhibition of mediator release from human lung tissue can contribute to the clinical effectiveness of the drug during treatment of allergic asthma.     

An association between cutaneous sensitivity to histamine and HLA phenotype

Four hundred and twenty randomly chosen subjects from a normal population were HLA typed and tested for cutaneous sensitivity to histamine by prick testing with 5 concentrations of histamine (10⁻³, 10⁻², 10⁻¹, 1, 10 mg ± ml⁻¹). Positive responses to 10⁻¹ mg ± ml⁻¹ histamine occurred in 41% of the subjects, and particularly those with HLA-B7 (55%) (p < 0.005). It is concluded that genes within the major histocomptability complex influence cutaneous responses to histamine.     

Increased responsiveness of rat colonic splanchnic afferents to 5-HT after inflammation and recovery

5-Hydroxytryptamine (5-HT) activates colonic splanchnic afferents, a mechanism by which it has been implicated in generating symptoms in postinfectious and postinflammatory states in humans. Here we compared mechanisms of colonic afferent activation by 5-HT and mechanical stimuli in normal and inflamed rat colon, and after recovery from inflammation. Colonic inflammation was induced in rats by dextran sulphate sodium. Single-fibre recordings of colonic lumbar splanchnic afferents revealed that 58% of endings responded to 5-HT (10⁻⁴ m ) in controls, 88% in acute inflammation ( P < 0.05) and 75% after 21 days recovery ( P < 0.05 versus control). Maximal responses to 5-HT were also larger, and the estimated EC₅₀ was reduced from 3.2 × 10⁻⁶ to 8 × 10⁻⁷ m in acute inflammation and recovered to 2 × 10⁻⁶ m after recovery. Responsiveness to mechanical stimulation was unaffected. 5-HT₃ receptor antagonism with alosetron reduced responses to 5-HT in controls but not during inflammation. Responses to the mast cell degranulator 48/80 mimicked those to 5-HT in inflamed tissue but not in controls, and more 5-HT-containing mast cells were seen close to calcitonin gene-related peptide-containing fibres in inflamed serosa. We conclude that colonic serosal and mesenteric endings exhibit increased sensitivity to 5-HT in inflammation, with both an increase in proportion of responders and an increase in sensitivity, which is maintained after healing of inflammation. This is associated with alterations in the roles of 5-HT₃ receptors and mast cells.     

Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing

Peripheral conduit artery flow-mediated dilatation decreases with ageing in humans. The underlying mechanisms and efficacy of preventive strategies are unknown. Brachial artery flow-mediated dilatation was determined at baseline and after ascorbic acid (vitamin C) intravenous infusion and chronic supplementation (500 mg day⁻¹ for 30 days) in three groups of healthy men: young sedentary ( n = 11; 25 ± 1 years, mean ± s.e.m. ), older sedentary ( n = 9; 64 ± 2), and older endurance-exercise trained ( n = 9; 64 ± 2). At baseline, flow-mediated dilatation (normalized for the hyperaemic stimulus) was ∼45% lower in the older (0.015 ± 0.001) versus young (0.028 ± 0.004) sedentary men ( P < 0.01), but was preserved in older exercising men (0.028 ± 0.004). Ascorbic acid infusion increased plasma concentrations > 15-fold in all groups and restored flow-mediated dilatation in the sedentary older men (to 0.023 ± 0.002; P > 0.1 versus other groups), with no effects in the other two groups. Oral ascorbic acid supplementation did not affect flow-mediated dilatation in any group. Brachial artery endothelium-independent dilatation (sublingual nitroglycerin) did not differ among the groups at baseline nor change with ascorbic acid administration. These results provide the first evidence for an important role of oxidative stress in both the impairment in peripheral conduit artery flow-mediated dilatation with sedentary human ageing and the preservation of flow-mediated dilatation with physically active ageing.     

The effect of tezosentan, a non-selective endothelin receptor antagonist, on shear stress-induced changes in arterial diameter of the anaesthetized dog

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-(2-1 H -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.     

Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness

Recent data from transgenic mice suggest that orexin plays an important role in the ventilatory response to CO₂ during wakefulness. We hypothesized that orexin receptor-1 (OX₁R) in the retrotrapezoid nucleus (RTN) contributes to chemoreception. In unanaesthetized rats, we measured ventilation using a whole-body plethysmograph, together with EEG and EMG. We dialysed the vehicle and then SB-334867 (OX₁R antagonist) into the RTN to focally inhibit OX₁R and studied the effects of both treatments on breathing in air and in 7% CO₂. During wakefulness, SB-334867 caused a 30% reduction of the hyperventilation induced by 7% CO₂ (mean ± S.E.M., 135 ± 10 ml (100 g)⁻¹ min⁻¹) compared with vehicle (182 ± 10 ml (100 g)⁻¹ min⁻¹) ( P < 0.01). This effect was due to both decreased tidal volume and breathing frequency. There was a much smaller, though significant, effect in sleep (9% reduction). Neither basal ventilation nor oxygen consumption was affected. The number and duration of apnoeas were similar between control and treatment periods. No effect was observed in a separate group of animals who had the microdialysis probe misplaced (peri-RTN). We conclude that projections of orexin-containing neurons to the RTN contribute, via OX₁Rs in the region, to the hypercapnic chemoreflex control during wakefulness and to a lesser extent, non-rapid eye movement sleep.     

Effect of dexamethasone on skeletal muscle Na+,K+ pump subunit specific expression and K+ homeostasis during exercise in humans

The effect of dexamethasone on Na⁺,K⁺ pump subunit expression and muscle exchange of K⁺ during exercise in humans was investigated. Nine healthy male subjects completed a randomized double blind placebo controlled protocol, with ingestion of dexamethasone (Dex: 2 × 2 mg per day) or placebo (Pla) for 5 days. Na⁺,K⁺ pump catalytic α1 and α2 subunit expression was ∼17% higher ( P < 0.05) and the structural β1 and β2 subunit expression was ∼6–8% higher ( P < 0.05) after Dex compared with Pla. During one-legged knee-extension for 10 min at low intensity (LI; 18.6 ± 1.0 W), two moderate intensity (51.7 ± 2.4 W) exercise bouts (MI₁: 5 min; 2 min recovery; MI₂: exhaustive) and two high-intensity (71.7 ± 2.5 W) exercise bouts (HI₁: 1 min 40 s; 2 min recovery; HI₂: exhaustive), femoral venous K⁺ was lower ( P < 0.05) in Dex compared with Pla. Thigh K⁺ release was lower ( P < 0.05) in Dex compared with Pla in LI and MI, but not in HI. Time to exhaustion in MI₂ tended to improve (393 ± 50 s versus 294 ± 41 s; P = 0.07) in Dex compared with Pla, whereas no difference was detected in HI₂ (106 ± 10 s versus 108 ± 9 s). The results indicate that an increased Na⁺,K⁺ pump expression per se is of importance for thigh K⁺ reuptake at the onset of low and moderate intensity exercise, but less important during high intensity exercise.     

Cholinergic regulation of the evoked quantal release at frog neuromuscular junction

The effects of cholinergic drugs on the quantal contents of the nerve-evoked endplate currents (EPCs) and the parameters of the time course of quantal release (minimal synaptic latency, main modal value of latency histogram and variability of synaptic latencies) were studied at proximal, central and distal regions of the frog neuromuscular synapse. Acetylcholine (ACh, 5 × 10⁻⁴ m ), carbachol (CCh, 1 × 10⁻⁵ m ) or nicotine (5 × 10⁻⁶ m ) increased the numbers of EPCs with long release latencies mainly in the distal region of the endplate (90–120 μm from the last node of Ranvier), where the synchronization of transmitter release was the most pronounced. The parameters of focally recorded motor nerve action potentials were not changed by either ACh or CCh. The effects of CCh and nicotine on quantal dispersion were reduced substantially by 5 × 10⁻⁷ m (+)tubocurarine (TC). The muscarinic agonists, oxotremorine and the propargyl ester of arecaidine, as well as antagonists such as pirenzepine, AF-DX 116 and methoctramine, alone or in combination, did not affect the dispersion of the release. Muscarinic antagonists did not block the dispersion action of CCh. Cholinergic drugs either decreased the quantal content m _o (muscarinic agonist, oxotremorine M, and nicotinic antagonist, TC), or decreased m _o and dispersed the release (ACh, CCh and nicotine). The effects on m _o were not related either to the endplate region or to the initial level of release dispersion. It follows that the mechanisms regulating the amount and the time course of transmitter release are different and that, among other factors, they are altered by presynaptic nicotinic receptors.     

Effects of lipoxin A4 on chemotaxis and degranulation of human eosinophils stimulated by platelet-activating factor and N-formyl-L-methionyl-L-leucyl-L-phenylalanine

Lipoxins are trihydroxytetraene metabolites derived through a double lipoxygenation of arachidonic acid. Lipoxin A₄ (LXA₄) was prepared by total chemical synthesis, and its capacity to modulate eosinophil migration has been evaluated. LXA₄ is a weak and partial chemotactic agent; at 10⁻⁶ M, it achieved about 20% of the response of 10⁻⁶ M platelet-activating factor (PAF). Preincubation of eosinophils with increasing doses of LXA₄ (10⁻¹⁰−10⁻⁵ M) resulted in a concentration-dependent inhibition of cell migration induced by 10^-6 M formyl-methionyl-leucyl-phenylalanine (FMLP) and 10^-6 M PAF. The concentration of LXA₄ which produced 50% inhibition (IC₅₀) of eosinophil migration was approximately 10^-6 M. LXA₄ (10^-10-10^-6 M) did not elicit ECP release or modulate ECP release induced by 10^-6 M FMLP. LXA₄ may have antiallergic properties in preventing eosinophilic migration.     

Increased Number of IgG Fc Receptors on Monocyte-Enriched Peripheral Blood Leucocytes from Patients with Rheumatoid Arthritis

The number of free Fc receptors (FcR) per cell and the association constant (K_ass) for the binding of monomeric IgG were determined for monocyte-enriched peripheral blood mononuclear cells, isolated from 16 patients with active classical rheumatoid arthritis (RA) and from 15 normal healthy donors. The assay system was based on binding under equili brium conditions of ¹²⁵I-labelled monomeric rabbit IgG to monocytes purified from peripheral blood on a continuous gradient of Petcoll. Monocytes from 14 untreated RA patients (6 seropositive, 8 seronegative) expressed on the average 4.8±1.3 × 10⁴ FcR/cell. This number was significantly higher (P<0.01) than that found in the control group (3.46±0.7 × 10⁴ FcR/cell). There was also a significant difference between the mean K _ass of the RA group and the control group-2.1±0.7 × 10³1/mol and 2.6±1.0 × 10³ 1/mol, respectively (0.05 >P> 0.01). Two seropositive RA patients receiving systemic treatment with penicillamine expressed the same number of FcR/cell as the mean of the control group (3.6 ± 10⁴). Levels of circulating immune complexes (CIC) and of the complement-factor C3 split product C3d were also measured. No correlation was found between the number of FcR/cell and the concentration of C3d, but there was a weak correlation between the number of FcR/ccll and the level of CIC.     

Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans

We investigated the functional roles of circulating and locally produced angiotensin II (Ang II) in fasting and postprandial adipose tissue blood flow (ATBF) regulation and examined the interaction between Ang II and nitric oxide (NO) in ATBF regulation. Local effects of the pharmacological agents (or contralateral saline) on ATBF, measured with ¹³³Xe wash-out, were assessed using the recently developed microinfusion technique. Fasting and postprandial (75 g glucose challenge) ATBF regulation was investigated in nine lean healthy subjects (age, 29 ± 3 years; BMI, 23.4 ± 0.7 kg m⁻²) using local Ang II stimulation, Ang II type 1 (AT₁) receptor blockade, and angiotensin-converting enzyme (ACE) inhibition. Furthermore, NO synthase (NOS) blockade alone and in combination with AT₁ receptor blockade was used to examine the interaction between Ang II and NO. Ang II induced a dose-dependent decrease in ATBF (10⁻⁹ m : −16%, P = 0.04; 10⁻⁷ m : −33%, P < 0.01; 10⁻⁵ m : −53% P < 0.01). Fasting ATBF was not affected by ACE inhibition, but was increased by ∼55% ( P < 0.01) by AT₁ receptor blockade. NOS blockade induced a ∼30% ( P = 0.001) decrease in fasting ATBF. Combined AT₁ receptor and NOS blockade increased ATBF by ∼40% ( P = 0.003). ACE inhibition and AT₁ receptor blockade did not affect the postprandial increase in ATBF. We therefore conclude that circulating Ang II is a major regulator of fasting ATBF, and a major proportion of the Ang II-induced decrease in ATBF is NO independent. Locally produced Ang II does not appear to regulate ATBF. Ang II appears to have no major effect on the postprandial enhancement of ATBF.     

Nitric oxide contributes to the augmented vasodilatation during hypoxic exercise

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

A study of inbreeding and kinship in intracranial aneurysms in the Saguenay Lac-Saint-Jean region (Quebec, Canada)

The genealogies of 533 individuals with an intracranial aneurysm (IA) born in the Saguenay-Lac-Saint-Jean region, a geographically isolated area located in northeastern Quebec, were reconstructed using a population-based register. A control group consisting of three individuals of the same sex and born on the same day and in the same municipality than the IA patients was created; the genealogies of the 1599 controls were also reconstructed. The coefficients of inbreeding and kinship were calculated. Familial aggregation, i.e. the presence of IA in two or more first- to third-degree relatives, was also sought. The mean inbreeding coefficient was lower in the IA group than in the control group (7·92 × 10⁻⁴ versus 10·04 × 10⁻⁴). The mean kinship coefficient was higher in the IA group than in the control group (2·17 × 10⁻⁴ versus 1·55 × 10⁻⁴). Forty-eight IA patients (9·0%) were first-degree relatives compared to only 1·9% of the control individuals. The proportion of individuals showing familial aggregation was higher in the IA group than in the control group (29·8% and 18·6% respectively). These results strongly suggest that some IA are genetically determined in this population.