Leukotriene D4 increases nasal blood flow in humans

The effect of leukotriene D₄ on the nassal musocal blood flow in humans was measured using a laser doppler flow meter. The leukotriene solution was applied topically to the nasal mucosa in 9 healthy subjects, and changes in blood flow were measured non-traumatically by the laser doppler instrument. The response showed a consistent increases in blood flow. A dose-response was found in the range of 0.063 – 4.0 nanomole. These results confirm an earlier study on the human skin, implicating leukotriene D₄ as an important vasodilator in humans. No increase in nasal secretion was noted by the subjects tested.     

A Study of the Oscillatory Components of the Skin Microhemodynamics in Mice by Laser Doppler Flowmetry

A skin blood flow was studied by laser doppler flowmetry. Fourteen male BALB/c mice were used. The skin blood flow was registered in the left hind paw. To measure the skin microhemodynamics, we proposed a protocol of animal immobilization with two types of anesthesia, injection with zoletil and inhalation with nitrous oxide. The borders of low-frequency intervals of oscillations of the microhemodynamics in mice have been determined; they coincided with those for humans and rats that were determined earlier.     

Physical dilatation of the nostrils lowers the thermal strain of exercising humans

Increased nasal air flow during exercise was examined as a possible heat loss avenue contributing to selective brain cooling in hyperthermic humans. On 2 separate days, eight subjects [mean (SE) age, 26.4 (1.2) years] exercised on a cycle ergometer in a warm room [28 (0.2)°C; 28 (5)% relative humidity] to induce a moderate level of hyperthermia. In one session the nostrils were physically dilatated [average dilatation 1.55 (0.17) times] and in the other they were not (control). Both sessions started with a 5-min resting period; then subjects pedaled at 60 W for 5 min, 100 W for 15 min, and 150 W for 20 min. During dilatation both tympanic temperature (T _ty) and forehead skin blood flow, estimated by laser doppler velocimetry, were significantly lower than during the control exercise of 150 W. Rates of increase of (T _ty) during the 100-W exercise were the same in both conditions; however, during the 150-W exercise with dilatated nostrils (T _ty) increased at a rate significantly lower than during control [1.1 (0.3)°C·h^–1 vs 1.5 (0.4)°C·h^–1]. The change in the rate of increase of T _ty between conditions was significantly correlated to the degree of nostril dilatation (r = –0.77, P = 0.02), suggesting that the lower (T _ty) observed was due to nostril dilatation. Facial skin temperature was not significantly different between sessions. The results suggest that the nasal cavity may act as a heat exchanger in selective brain cooling of exercising humans.     

Effects of n-3 polyunsaturated fatty acids on indomethacin-induced changes in eicosanoid production and blood flow in the gastric mucosa of rats

We investigated the effects of n-3 polyunsaturated fatty acids (PUFAs) on non-steroidal anti-inflammatory drug (NSAID)-induced changes in microcirculation and eicosanoid production in the gastrointestinal mucosa. We measured gastric mucosal blood flow using laser Doppler flowmetry, assessed the fatty acid composition in the mucosal phospholipids, and quantified the production of prostaglandin E2 (PGE2), leukotriene B4, and leukotriene C4 (LTB4 and C4) from the mucosa with the stimulation of calcium ionophore 20 min after an injection of indomethacin or vehicle in rats fed a diet containing different compositions of alpha-linolenic acid. Four weeks after the initiation of the test diet the arachidonic acid level in gastric mucosal phospholipids was significantly lower in the perilla group than in the other three groups. Conversely, alpha-linolenic acid and eicosapentaenoic acid (EPA) were significantly higher in the perilla group than in the other three groups. The percent of gastric mucosal blood flow in the three groups administered indomethacin were significantly lower than that in the control group injected with vehicle alone. The percent of gastric mucosal blood flow in the perilla group was significantly higher than that in the corn group. LTB4 and LTC4 production from the gastric mucosa in the soybean and corn groups were significantly higher than those in the control group, and the LTC4 production in the perilla group was significantly lower than that in the corn group. There were no significant differences in PGE2 production among the four groups. Our results suggest that alpha-linolenic acid affectively suppressed the indomethacin-induced decreases in gastric mucosal blood flow by increasing EPA and decreasing the levels of arachidonic acid and LTC4 in the gastric mucosa.     

L-arginine protects from ischemia-reperfusion-induced endothelial dysfunction in humans in vivo.

It has been shown that nitric oxide (NO) protects from myocardial ischemia-reperfusion injury in animal models. The present study investigated whether administration of the NO substrate l-arginine protects against ischemia-reperfusion-induced endothelial dysfunction in humans. Forearm blood flow was measured with venous occlusion plethysmography in 16 healthy male subjects who were investigated on two occasions. Forearm ischemia was induced for 20 min followed by 60-min reperfusion. With the use of a crossover protocol, the subject received a 15-min intrabrachial artery infusion of l-arginine (20 mg/min) and vehicle (saline, n = 12 or d-arginine, n = 4) starting at 15 min of ischemia on two separate occasions. Compared with preischemia, endothelium-dependent increase in forearm blood flow induced by intra-arterial acetylcholine (3-30 microg/min) was significantly impaired at 15 and 30 min of reperfusion when the subjects received saline (P < 0.001). When the subjects received l-arginine, the acetylcholine-induced increase in forearm blood flow was not significantly affected by ischemia-reperfusion. The recovery of endothelium-dependent vasodilatation at 15- and 30-min reperfusion was significantly greater after administration of l-arginine than after saline (P < 0.05). d-Arginine did not affect the response to acetylcholine. Endothelium-independent vasodilatation to nitroprusside was not affected during reperfusion. These results demonstrate that the NO substrate l-arginine significantly attenuates ischemia-reperfusion-induced endothelial dysfunction in humans in vivo. This suggests that l-arginine may be useful as a therapeutic agent in the treatment of ischemia-reperfusion injury in humans.     

Recovery of nasal prostaglandin production after inhibition by aspirin

We have investigated the duration of the inhibitory effects of aspirin in eight healthy volunteers after oral administration of a single 500 mg dose. Prostaglandin E2, D2 and leukotriene C4 levels in nasal lavage fluid were measured by radioimmunoassay without purification by high performance liquid chromatography. The inhibitory effects of aspirin on eicosanoid synthesis were maximum between 1 h to 24 h, showing total recovery within 3-5 days. LTC4 synthesis was not modified by aspirin.     

Pulmonary hypertension in infants with congenital heart defects: are leukotrienes involved?

The circulating levels of leukotriene E4 in infants with congenital heart defects, increased pulmonary blood flow and pulmonary arterial hypertension, were determined and compared with infants with decreased pulmonary blood flow (Tetralogy of Fallot). There was no correlation (r=0.38) between the pulmonary arterial pressure (56+/-4 mmHg) and the leukotriene E4 levels (1.37+/-0.67 ng/ml blood) measured in peripheral blood samples from the hypertensive group prior to surgery. There was considerable variation in the detectable leukotriene E4 levels in blood samples from different patients. The levels detected in the blood samples between the two groups of patients was similar. These data suggest that neither the surgical repair during cardiopulmonary bypass nor the pulmonary hypertension appeared to modify the leukotriene E4 blood levels in the small number of patients studied.     

Variations in blood supply allocations for quadrupedal and for bipedal posture and locomotion

Hemodynamics and orthodynamics were investigated in quadrupeds (dogs) and in bipeds (humans). The subjects were investigated at rest in supine or lateral posture, in quadrupedal and then in bipedal posture, and during locomotion. Quadrupedalism in humans was with subjects on their hands and knees. Bipedalism in dogs was on hindlimbs with the forelimbs held by a technician. Blood flow in the main arteries of the body (aorta, external and internal carotid, subclavian, and femoral) was measured by sonography. Positional variations between the main bones of the body were determined from X-rays. This study investigated the reallocation of blood supply to different regions of the body when it switches from quadrupedal to bipedal posture and locomotion. Compared with resting posture, the principal findings are 1) cardiac output shows a minimal increase for humans in bipedal stance and a noticeable increase for dogs as well as humans in quadrupedal stance; 2) quadrupedal stance in humans and dogs and bipedal stance in dogs require increased blood supply to the muscles of the neck, back, and limbs, while human bipedal stance requires none of these; 3) cerebral blood flow (internal carotid) in humans did not change as a result of bipedal posture or locomotion, but showed a noticeable drop in quadrupedal posture and an even further drop in quadrupedal locomotion. The conclusion is that erect posture and encephalization produced a noticeable readjustment and reallocation of blood flow among the different regions of the body: This consisted in shifting a large volume of blood supply from the musculature to the human brain.     

Effect of Fluticasone propionate Aqueous Nasal Spray Treatment on Platelet Activating Factor and Eicosanoid Production By nasal Mucosa in Patients with A house Dust Mite Allergy

The relationship between the release of platelet activating factor (PAF), leukotriene C(4)/D(4)/E(E) (LTC(4)/D(4)/E(4)) and prostaglandin D(2) (PGD(2)) from nasal mucosa in vivo was examined in 24 rhinitis patients allergic to the house dust mite (HDM). During a double blind placebo controlled cross-over study 200 mug fluticasone propionate aqueous nasal spray (FPANS) was administered twice daily for two weeks. In response to allergen provocation (100, 1 000, 10 000 Bu/ml) and during the 9.5 h after this challenge the nasal fluid was obtained by washing the nose with saline and the levels of PAF, LTC(4)/D(4)/E(4) and PGD(2), as indicators of mediator release, were measured at the following time-points: baseline (t = - 1/2), allergen provocation with 10 000 Bu/ml (t = 0), 3.5 and 7.5 h (late phase). After allergen provocation the levels of the mediators increased in the nasal fluids of placebo treated patients (x-fold increase to baseline: PAF, 15; LTC(4)/D(4)/E(4), 12; PGD(2), 1.5). In fluids of patients treated with FPANS these levels tended to decrease. At the time of provocation the levels of PAF, LTC(4)/D(4)/E(4) and PGD(2) showed a significant correlation. The results indicate that these mediators can be used as markers of allergic reactions against house dust mites and that fluticasone propionate aqueous nasal spray tended to reduce the release of mediators of inflammation correlated with beneficial effects on clinical symptoms in this type of allergic reactions.     

Measurement of hemodynamics in human carotid artery using ultrasound and computational fluid dynamics.

The objective of the study was to investigate the feasibility of using computational fluid dynamic modeling (CFD) with noninvasive ultrasound measurements to determine time-variant three-dimensional (3D) carotid arterial hemodynamics in humans in vivo. The effects of hyperoxia and hypoxic hypercapnia on carotid artery local hemodynamics were examined by use of this approach. Six normotensive volunteers followed a double-blind randomized crossover design. Blood pressure, heart rate, and carotid blood flow were measured while subjects breathed normal air, a mixture of 5% CO(2) and 15% O(2) (hypoxic hypercapnia), and 100% O(2) (hyperoxia). Carotid artery geometry was reconstructed on the basis of B-mode ultrasound images by using purpose-built image processing software. Time-variant 3D carotid hemodynamics were estimated by using finite volume-based CFD. Systemic blood pressure was not significantly affected by hyperoxia or hypoxic hypercapnia, but heart rate decreased significantly with hyperoxia. There was an increase in diastolic flow velocity in the external carotid artery after hypoxic hypercapnia, but otherwise carotid blood flow velocities did not change significantly. Compared with normal air, hyperoxic conditions were associated with a decrease in the width of the region of flow separation in the external carotid artery. During hyperoxia, there was also an increase in the minimum and a decrease in maximum shear stress in the bifurcation and hence a reduction in cyclic variation in shear stress. Hypoxic hypercapnia was associated with a reduced duration of flow separation in the external carotid artery and an increase in the minimum shear stress without affecting the cyclic variation in shear stress. This study demonstrates the feasibility of using noninvasive ultrasound techniques in conjunction with CFD to describe time-variant 3D hemodynamics in the human carotid arterial bifurcation in vivo.     

Experimental studies on the effects of vibration and noise on sympathetic nerve activity in skin

Multi-unit sympathetic activity was recorded at elbow level from median nerve fascicles supplying glabrous skin of the left hand in five healthy subjects. The resultant vasomotor responses accompanying the neural activity were monitored by simultaneous recordings of skin blood flow using the laser doppler method and skin temperature in the innervation zones. No significant change in sympathetic activity was observed during handgrip exercise of the right hand under a constant gripping force of 2 kg. Subjects maintained the same gripping force of the right hand during exposure in random order to local vibration and/or noise, each type of exposure lasting 5 min with intervals of 20 min. A two-peaked significant increase in outflow from sympathetic nerves was observed during local exposure of the right hand to vibration with a frequency of 60 Hz and an acceleration of 50 m.s-2, followed by a postexposure period which revealed a relative suppression of sympathetic nerve activity and a significant increase in blood flow. Noise at 100 dB(A) showed only an initial effect on skin sympathetic nerve activity (SSA), whereas when combined with local vibration at 60 Hz, a pronounced increase in neural activity was noticed, indicating a combined effect of vibration and noise. These results from direct recordings of SSA suggest a sympathetic vasomotor reflex mechanism triggered by local vibration stimuli to the hand.     

Basic taste stimuli elicit unique responses in facial skin blood flow

Facial expression changes characteristically with the emotions induced by basic tastes in humans. We tested the hypothesis that the five basic tastes also elicit unique responses in facial skin blood flow. Facial skin blood flow was measured using laser speckle flowgraphy in 16 healthy subjects before and during the application of basic taste stimuli in the oral cavity for 20 s. The skin blood flow in the eyelid increased in response to sweet and umami taste stimuli, while that in the nose decreased in response to a bitter stimulus. There was a significant correlation between the subjective hedonic scores accompanying these taste stimuli and the above changes in skin blood flow. These results demonstrate that sweet, umami, and bitter tastes induce unique changes in facial skin blood flow that reflect subjective hedonic scores.     

Changes in lectin-induced chemiluminescence of neutrophilic granulocytes after irradiation of blood with helium-neon lasers]

Blood obtained from 33 healthy donors was irradiated with He-Ne laser. During this process the count of segmented neutrophils decreased, while the content of radioimmunologically determined leukotriene B4 and thromboxane B2 increased in the other neutrophils. Application of mannose-specific lectins (Con A, PSL) as inductors caused the increase, while application of other carbohydrate-specific lectins caused the decrease of luminol-dependent chemiluminescence in neutrophilic granulocyte suspension after the irradiation. As a result of direct laser effect on the blood cells some portion of the less resistant cells were eliminated from the blood flow, i.e. "rejuvenation" of the neutrophilic granulocyte population in the cells takes place.     

Optic Nerve Head Blood Flow Autoregulation during Changes in Arterial Blood Pressure in Healthy Young Subjects

Aim

In the present study the response of optic nerve head blood flow to an increase in ocular perfusion pressure during isometric exercise was studied. Based on our previous studies we hypothesized that subjects with an abnormal blood flow response, defined as a decrease in blood flow of more than 10% during or after isometric exercise, could be identified.

Methods

A total of 40 healthy subjects were included in this study. Three periods of isometric exercise were scheduled, each consisting of 2 minutes of handgripping. Optic nerve head blood flow was measured continuously before, during and after handgripping using laser Doppler flowmetry. Blood pressure was measured non-invasively in one-minute intervals. Intraocular pressure was measured at the beginning and the end of the measurements and ocular perfusion pressure was calculated as 2/3*mean arterial pressure –intraocular pressure.

Results

Isometric exercise was associated with an increase in ocular perfusion pressure during all handgripping periods (p < 0.001). By contrast no change in optic nerve head blood flow was seen. However, in a subgroup of three subjects blood flow showed a consistent decrease of more than 10% during isometric exercise although their blood pressure values increased. In addition, three other subjects showed a consistent decline of blood flow of more than 10% during the recovery periods.

Conclusion

Our data confirm previous results indicating that optic nerve head blood flow is autoregulated during an increase in perfusion pressure. In addition, we observed a subgroup of 6 subjects (15%) that showed an abnormal response, which is in keeping with our previous data. The mechanisms underlying this abnormal response remain to be shown.     

Leukotriene D4-induced increases in the cytoplasmic pH of human myelocytic leukocytes

The effects of leukotriene D4 on the intracellular pH of human myelocytes, derived from cultured HL-60 cells by dimethylsulfoxide-induced differentiation, were quantified with the fluorescent indicator 2',7'-bis-(2-carboxy-ethyl)-5,6-carboxyfluorescein. Leukotriene D4, but not C4 or E4, increased intracellular pH optimally by 3 min with a half-maximal effect at 1-2 nM. The increases in intracellular pH stimulated by leukotriene D4 were prevented by pretreatment of myelocytes with leukotriene D4 but not peptide chemotactic factors. Analogs of amiloride that inhibit selectively the Na+/H+ antiport also prevented the intracellular alkalinization induced by leukotriene D4. The rate of recovery of intracellular pH after an acid load with 30 mM sodium propionate was approximately 30% higher at each level of intracellular pH for myelocytes exposed to leukotriene D4 than for those challenged in buffer alone. The increase elicited by leukotriene D4 in the adherence of myelocytic leukocytes to surfaces thus is associated with an enhanced sensitivity of the Na+/H+ antiport to intracellular pH, that is, not coupled to an earlier rise in the cytosolic level of Ca+2.     

The actions of leukotrienes C4 and D4 in the porcine renal vascular bed

The kidney of anaesthetised pigs was perfused in situ with carotid arterial blood. Renal blood flow and perfusion pressure were recorded. Close intra-arterial injection of leukotriene (LT) C4, D4 or noradrenaline (NA) caused a dose-related increase in vascular resistance. Both LTs were more active than NA by one to two orders of magnitude. Systemically-administered indomethacin potentiated the effect of all three agonists. Incubation of renal artery tissue with calcium ionophore A23187 in the presence of indomethacin resulted in the generation of LT-like material which, when assayed on guinea-pig ileum, was indistinguishable from LTD4. The results show that pig renal vessels produce LT-like material and suggest that the potent vasoconstriction induced by exogenous NA and LTs is modulated in vivo by a vasodilator cyclo-oxygenase product.     

Leukotriene D4 reduces coronary blood flow in the anesthetized dog

We studied the effects of intracoronary administration of leukotriene (LT)D4 on coronary blood flow and myocardial function in chloralose anesthetized dogs. For comparison, the effects of injections of U-46619 were examined in the same dogs. Both LTD4 and U-46619 decreased coronary blood flow, left ventricular dP/dt and cardiac output. LTD4 was ten times more potent than U-46619 in decreasing coronary blood flow. The effects of neither drug were different after indomethacin administration.     

Alpha-adrenoreceptor blockade with phenoxybenzamine does not affect the ability of the nose to condition air.

The primary function of the nose is to warm and humidify air. We have previously shown that raising nasal mucosal temperature by immersing feet in warm water increases the amount of water evaporated by the nose as air passes through it (nasal conditioning capacity; Abbott D, Baroody F, Naureckas E, and Naclerio R. Am J Rhinol 15: 41-45, 2001). To investigate further the effect of nasal mucosal temperature on nasal conditioning capacity, we raised the temperature through alpha-adrenoreceptor blockade by intranasally administering phenoxybenzamine. We hypothesized that blocking alpha-adrenoreceptors during inhalation of cold, dry air would lead to an increase in nasal blood flow, surface temperature, and nasal conditioning capacity, as measured by the water gradient. After appropriate pilot studies, we performed a double-blind, placebo-controlled, two-way crossover study in nine nonatopic, healthy subjects by studying the effect of treatment with intranasal phenoxybenzamine. Nasal mucosal temperature increased significantly after administration of phenoxybenzamine and was associated with a significantly smaller net decrease in nasal mucosal temperature after exposure to cold, dry air (P < 0.05). However, there were no significant differences in nasal conditioning capacity between treatments (P > 0.05). Phenoxybenzamine decreased the symptom of rhinorrhea after exposure to cold, dry air (P < 0.05), but congestion was not different between individuals given phenoxybenzamine and placebo (P > 0.05). Our data demonstrate that phenoxybenzamine, despite raising mucosal temperature and not affecting nasal volume, did not affect the ability of the nose to warm and humidify air.     

Effects of cold dry air nasal stimulation on airway mucosal blood flow in humans

Several studies have demonstrated that nasal challenges can induce reflex responses in the respiratory system. Some authors have described bronchoconstriction and modification of the pattern of breathing following nasal challenges by irritants and cold air. We propose to determine the effect of nasal stimulation with cold dry air on airway mucosal blood flow (Qaw) in the proximal tracheal bronchial tree of healthy humans. Nine healthy subjects participated in the study. Baseline measurement Qaw, nasal airway resistance (NAR) and airway caliber by specific airways conductance (SGaw) were followed by nasal challenge with cold dry air. Qaw, NAR and Sgaw were determined after the challenge. In those subjects in which a significant decline in Qaw was recorded the protocol was repeated after pretreatment with nasal anesthesia using topical lidocaine. Cold dry air challenge produced a significant decrease in mean Qaw for the nine subjects and this response was abolished by pretreatment with nasal anesthesia using topical lidocaine. There was no significant change in Sgaw and NAR after the challenge and topical lidocaine anesthesia. Our data indicates that nasal stimulation with cold dry air leads to a reduction in Qaw and that this effect may be mediated by a nasal reflex.     

Local vasodilatation with metacholine, but not with nitroprusside, increases forearm glucose uptake

Insulin is known to increase blood flow in parallel to glucose uptake in skeletal muscle. However, it is not known if an increase in blood flow by itself is associated with an increase in glucose uptake in the absence of hyperinsulinemia. To investigate further this matter, the effect of increased blood flow on forearm glucose uptake was studied in the fasting state during intra-arterial infusions of two different vasodilators, metacholine and nitroprusside, in 19 hypertensive subjects. Both metacholine (4 microg/min) and nitroprusside (10 microg/min) increased resting forearm blood flow, measured by venous occlusion plethysmography, to a similar degree (180 % and 170 %, respectively, p<0.0001 for both). However, metacholine infusion increased the forearm glucose uptake from 2.0+/-0.9 (S.D.) during rest to 5.5+/-3.0 umol/min/100 ml tissue (p<0.0001), while no significant change in glucose uptake was seen during nitroprusside infusion (2.3+/-1.4 micromol/min/100 ml tissue). In conclusion, vasodilatation induced by metacholine, but not by nitroprusside, increased glucose uptake in the forearm of hypertensive patients. Thus, an increase in forearm blood flow does not necessarily improve glucose uptake in the forearm during the fasting state.