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Summary The in vitro effects of adrenoceptor agonists and antagonists in the isthmus and ampulla of the pig oviduct were studied along well defined phases of the oestrous cycle. Concurrently, the two constituent isthmic muscle layers — isolated by dissection but maintaining proper histoarchitecture — were also challenged in vitro with the same agents. Noradrenaline and adrenaline elicited both contractile (α) and relaxatory (β) responses, while isoprenaline induced only β-responses, as demonstrated by pretreatment with selective blockers. α and β receptors were present in all muscle preparations checked, although a predominance of α-receptor-mediated effects was noticed in the isthmic circular layer and intact isthmus throughout the oestrous cycle, and during postovulation in the isthmic longitudinal layer and mid-ampulla. The isthmus reacted more strongly to noradrenaline and adrenaline than the ampulla, especially during the 3rd day of the cycle, when eggs are normally retained in the upper isthmic level (i. e. AIJ). The isthmic circular layer resembled the intact isthmus in the extent of the responses. The results obtained support the concept that a specific sphincter is present in the porcine isthmus during the very early luteal phase and that its normal function may be controlled by adrenergic nerves. Zusammenfassung Wirkung von Adrenergika auf die in vitro Motilitat der Eileiter beim Schwein An Isthmus und Ampulle der Eileiter von Schweinen wurde in vitro die Wirkung von Agonisten und Antagonisten der Adrenorezeptoren im Verlaufe genau definierter Zyklusphasen untersucht. Gleichzeitig wurde mit den gleichen Agentien die Wirkung auf die beiden freipraparierten Muskelschichten des Isthmus uberpruft. Noradrenalin und Adrenalin fuhrten beide zu Kontraktionen (α) und Relaxationen (β), wahrend Isoprenalin nur die β-Rezeptoren zu stimulieren vermochte. In allen untersuchten Muskeln liesen sich α-und β-Rezeptoren nachweisen; ein Uberwiegen der von α-Rezeptoren abhangigen Wirkungen wurde beobachtet in der zirkularen Muskelschicht des Isthmus und im intakten Isthmus wahrend des gesamten Brunstzyklus sowie in der Langsmuskelschicht des Isthmus und in der mittleren Ampulle in der postovulatorischen Phase. Der Isthmus reagierte auf Noradrenalin und Adrenalin starker als die Ampulle, besonders wahrend des dritten Zyklustages, wenn die Eizellen normalerweise im proximalen Isthmusteil zuruckgehalten werden. Bezuglich der Intensitat der Reaktionen glich die zirkulare Muskelschicht des Isthmus dem intakten Isthmus. Die Ergebnisse unterstutzen das Konzept, das wahrend der sehr fruhen Lutealphase im Isthmus ein Sphincter wirksam ist, dessen Funktionen durch adrenerge Nerven gesteuert werden. Resume Effet d'adrenergiques sur la mobilite in vitro de l'oviducte chez le porc On a examine au cours de phases exactement definies du cycle les effets d'agonistes et d'antagonistes des adrenorecepteurs de l'isthme et de l'ampoule de l'oviducte chez des porcs. On a teste en meme temps avec les memes agents l'effet sur les deux couches musculaires preparees de l'isthme. Noradrenaline et adrenaline ont provoque toutes les deux des contractions (α) et des relaxations (β), alors que l'isoprenaline n'a stimule que les recepteurs β. Des recepteurs α et β ont ete mis en evidence dans tous les muscles examines. Une predominance des effets dependant des recepteurs α a ete observee dans la couche musculaire circulaire de l'isthme et dans l'isthme intact pendant toute la duree du cycle des chaleurs et egalement la couche musculaire longitudinale de l'isthme et dans l'ampoule moyenne durant le troisieme jour du cycle, lorsque les ovules sont retenus normalement dans la partie proximale de l'isthme. En fonction de l'intensite des reactions, la couche musculaire circulaire de l'isthme fut egale a l'isthme intact. Les resultats confirment le concept d'un sphincter efficace dans l'isthme durant la phase luteinisante precoce, dont les fonctions sont reglees par des nerfs adrenergenes. Resumen Los efectos de agentes adrenergicos sobre la motilidad in vitro de los oviductos de cerdas Se examinaron in vitro en el istmo y ampolla de los oviductos de cerdas las acciones agonistas y antagonistas de los adrenorreceptores a lo largo del curso de fases del ciclo oestral bien definidas. Al mismo tiempo, se verifico con los mismos agentes la accion sobre las dos capas musculares en el istmo, que habian sido aisladas por diseccion manteniendo su histoarquitectura propia. La noradrenalina y adrenalina conducian a contracciones (α) y relajamientos (β), mientras que la isoprenalina era capaz de estimular solo los receptores β. En todos los musculos examinados se pudieron poner en evidencia receptores α y β; se observo una predominancia de las acciones dependientes de los receptores α en la capa muscular circular del istmo y en el istmo intacto durante todo el ciclo oestral asi como en la capa muscular longitudinal del istmo y en la ampolla media durante la fase postovulatoria. El istmo reaccionaba a la noradrenalina y adrenalina con intensidad mayor que la ampolla, en especial durante el dia tercero del ciclo, cuando los oocitos son retenidos normalmente en la parte proximal del istmo. Con respecto a la intensidad de las reacciones se asemejo la capa muscular circular del istmo al istmo intacto. Los resultados apoyan el concepto de que durante la fase lutea muy precoz se halla presente un esfinter especifico, cuyas funciones estan controladas por los nervios adrenergicos.

Zusammenfassung Bei wachen, laktierenden Kuhen wurden elektromagnetische Blutflusmessungen an der Euterarterie und arterielle Blutdruckmessungen in der A. carotis vorgenommen, um die adrenergischen Rezeptoren im vaskularen Bett des Euters zu untersuchen. Intravenose Injektionen von Adrenalin, Noradrenalin, Phenylephrin und Isoprenalin, vor und nach Verabreichung von den die α- oder β-Rezeptoren-blockierenden Substanzen, konnten deutlich machen, das die Blutgefase des Euters der laktierenden Kuh sowohl α- als auch β-adrenergische Rezeptoren befassen. Summary Adrenergic receptors in blood vessels in the udder of lactating cows In actively lactating cows electromagnetic blood flow measurements on the mammary arteries and arterial pressure measurements on the carotid arteries were carried out to seek for adrenergic receptors within the vascular bed of the udder. Intravenous injection of adrenalin, noradrenalin, phenylephrin and isoprenalin, before and after administration of α or β receptor-blocking substances showed clearly that the blood vessels of the udder of the lactating cow contain both α and β adrenergic receptors. Resume Recepteurs adrenergiques des vaisseaux sanguins de la mamelle chez des vaches en lactation On a effectue la mesure electromagnetique du debit sanguin dans l'artere de la glande mammaire et la pression sanguine dans l'artere carotide de vaches en lactation pour etudier les recepteurs adrenergiques du reseau vasculaire de la mamelle. Des injections intraveineuses d'adrenaline, de noradrenaline, de phenylephrine et d'isoprenaline, avant et apres l'application de substances bloquant les recepteurs α et β, ont nettement montre que les vaisseaux sanguins de la mamelle possedent aussi bien des recepteurs adrenergiques α que β. Resumen Receptores adrenergicos de los vasos mamarios en vacas lactantes En vacas lactantes conscientes se llevaron a cabo mediciones electro-magneticas del flujo sanguineo en la arteria mamaria y mediciones de la tension arterial en la carotida, con el fin de examinar los receptores adrenergicos en el lecho vascular de la glandula mamaria. Inyecciones intravenosas de adrenalina, noradrenalina, fenilefrina e isoprenalina, antes y despues de administrar substancias bloqueadoras de los receptores α o β, podian poner en evidencia que los vasos sanguineos de la mama de vaca lactante interesan tanto los receptores adrenergicos α como los β.

Current research in left ventricular hypertrophy (LVH) has largely focused on its progression and therapeutic mechanisms to prevent or slow its development. Few studies have centered on the regression or treatment of existing LVH. Nuclear factor-κB (NF-κB) is an inflammatory transcription factor that has been shown to be involved in LVH development. We hypothesized that proteasome-mediated NF-κB inhibition would prevent the development of LVH and promote its regression. A murine model of reversible hypertrophy was employed by administering isoproterenol (Iso) subcutaneously for 7–14 days. The proteasome inhibitor, PS-519, was delivered both concurrently and after Iso treatment. LVH was quantified by heart weight-to-body weight ratios, histology, transthoracic echocardiography, and hypertrophic gene expression. After 7 days of Iso treatment, all measures indicated successful development of LVH. Another group was treated for 7 days and then observed for an additional 7 days. This group experienced normalization of Iso-induced cell size, wall thickness, and β-myosin heavy chain expression. When administered concurrently, PS-519 prevented Iso-induced LVH at 7 days. Furthermore, when PS-519 was given to animals during the second week of continued Iso treatment, these animals also experienced regression of hypertrophy by several measures. The success of proteasome inhibition in preventing LVH development and in promoting LVH regression, even in the face of continued hypertrophic stimulation, demonstrates its potential use as a clinically accessible strategy for treating patients with a variety of LVH-associated cardiomyopathies.

The body is from time to time exposed to nonnormothermic conditions; both hypo- and hyperthermia can occur as a result of external (environment) or internal (pathogens, allergens) stressors. To preserve life under hypo- and hyperthermic conditions, adequate perfusion of vital organs is mandated. Although cardiac output regulation under hyperthermic conditions has been studied, the mechanical response of basic contractile function of the myocardium itself is incompletely understood. Accordingly, we set out to test mechanical output of isolated myocardium under hyperthermic conditions and to compare the results with the hypo- and normothermic response in the same tissue. We observed that, in absence of a frequency change, developed force decreased markedly. At a physiological normal stimulation rate of 6 Hz, developed force decreases to 67.2 +/- 2.6% at 42 degrees C compared with 37 degrees C. In addition, twitch timing characteristics also accelerate, allowing for a faster relaxation; time from peak tension to 50% relaxation is approximately 23% faster (from 31.4 +/- 2.6 to 24.4 +/- 1.7 ms). Although this faster relaxation in turn prevents a steep increase in diastolic tension at high frequencies, the very fast calcium kinetics now prevent a more complete activation of the myofilaments, resulting in a lower twitch-force maximum at hyperthermic conditions. Even at maximal beta-adrenergic stimulation, developed force is well below levels reached at physiological temperature.

We have shown reduced density and altered kinetics in slowly activating K+ currents ( IKs) in epicardial border zone (EBZ) cells (IZs) of the 5-day-infarcted canine heart (Jiang M, Cabo, C, Yao J-A, Boyden PA, and Tseng G-N. Cardiovasc Res 48: 34–43, 2000). β-Adrenergic stimulation with isoproterenol increases IKs in normal cells (NZs). In this study, we used a voltage-clamp protocol with an external solution to isolate IKs from contaminating currents to determine the effects of 1 μM isoproterenol on IKs in IZs and NZs. Under our recording conditions, 10 μM azimilide-sensitive currents were stimulated with isoproterenol to compare responsiveness of IKs to isoproterenol in the two cell groups. IKs tail density was reduced 67% in IZs ( group I, n = 26) compared with NZs ( n = 24, P < 0.05). Isoproterenol-stimulated azimilide-sensitive tail currents were increased 1.72 ± 0.2-fold in NZs and 2.2 ± 0.3-fold in IZs ( P > 0.05). In 33% of IZs ( group II, n = 13), native currents showed no tail currents; however, isoproterenol-stimulated azimilide-sensitive currents were voltage dependent, fast activating, and large in amplitude compared with group I IZs, similar to “lone” KCNQ1 currents. Using short clamp pulses, we also found an increase in sustained currents sensitive to tetraethylammonium chloride (TEA) and no change in C-9356-sensitive currents in IZs with little or no transient outward current. In some IZs where IKs is downregulated, the effect of isoproterenol on IKs was similar to that on IKs in NZs. In others, the existence of lone KCNQ1-type currents, which are sensitive to β-adrenergic stimulation, is consistent with our findings of an increased KCNQ1-to-KCNE1 mRNA ratio (Jiang et al.). Accompanying altered IKs in IZs are an enhanced TEA-sensitive current and a normal C-9356-sensitive current.

Using an isolated nonworking rat heart model, this study investigated the role of beta-adrenergic preconditioning (beta-PC) to attenuate myocardial dysfunction after an ischemia/reperfusion injury. After a 20-min stabilization period, the noradrenaline depleted hearts were perfused for 5 min with isoproterenol (ISO) before 40-min global ischemia (I) followed by 30-min reperfusion (R). ISO 0.02 microM provided significant protection versus unconditioned in vivo reserpinized IR control, causing a decrease of creatine kinase (CK) release (mIU/min/g wet weight) on reperfusion in coronary effluent, a preservation of the mean coronary flow (MCF) and preservation of left ventricular function assessed by the rate-pressure product (RPP). These beneficial effects were similar to those of ischemic preconditioning (I-PC) in both nonreserpinized and reserpinized rats. Propranolol (1 microM) and atenolol (10 microM) completely suppressed the ISO preconditioning. In contrast, ICI 118551 (2 microM) a highly selective beta -blocker, did not blunt the salutary effects of ISO on CK release and MCF preservation. These results indicate that ISO pretreatment provides a significant cardioprotection against prolonged ischemic myocardial injury. Although endogenous catecholamines are not necessary for I-PC in isolated rat hearts, cardioprotection provided by beta-adrenergic stimulation is quite similar to I-PC. This significant cardioprotection is mediated less by beta -adrenoceptor than by beta -adrenoceptor activation, which seems to play a crucial role in the beta-PC mechanism.

The purpose of this investigation was to study the effect of isoproterenol (IPR) treatment on the regulation of phosphofructokinase-1 of submandibular salivary glands of rats. The animals were divided into control and experimental groups. In the first set of experiments, the rats received 5 mg of IPR/kg b.w. and were sacrificed at 24 hours after 1, 2, 3 and 4 doses. The content of fructose-2,6-bisphosphate (Fru-2,6-P(2)) and the activity of 6-phosphofructo-2-kinase (PFK-2) (active and total) were determined. The Fru-2,6-P(2) content was found to be reduced and the activity of PFK-2 (active and total) showed differences from the control. The active/total ratio, was higher for the group of one dose sacrificed 12 hours after the agonist injection as compared to the control. In the other groups, there were reductions which varied from 25 to 33%. In the second set of the experiment, the animals were injected with 23.0 mg of IPR/kg b.w. and were sacrificed from 5 up to 720 minutes after the administration of the agonist. After the sacrifice, salivary gland samples were analyzed for Fru-2,6-P(2). Again, a reduction in the metabolite content was observed. Using beta and alpha receptor blockers, it was found that both inhibited only partially the effect of IPR. The purification of PFK-1 up to homogeneity, from submandibular glands of rats which received 5 mg of IPR/mg b.w. as well as from the control, was performed and the Km and state of phosphorylation were determined. Rats from the group sacrificed 12 hours after the injection of the agonist showed the lowest Km for Fru-6-P. Animals which received 3 doses of IPR showed the highest phosphate content/mol of enzyme. Experiments of dephosphorylation of the purified PFK-1 from this latter group revealed that the presence of the phosphate groups influence the kinetic properties of the enzyme.

On a emis l'hypothese que la reaction vaso-depressive fait suite a l'apparition d'une forte contraction ventriculaire alors qu'il y a diminution du volume cardiaque. La bradycardie paradoxale est une manifestation majeure des reactions vaso-depressives. Compte tenu de ce lien entre la bradycardie paradoxale et la reaction vaso-depressive, nous avons examine le role du calcium, element essentiel de la contraction cardiaque, dans la reaction de bradycardie paradoxale. La bradycardie paradoxale a ete induite par la veine cave inferieure durant une perfusion d'isoproterenol, et le role du calcium a ete examine en verifiant si le verapamil inhibe et le CaCl 2 induit la bradycardie paradoxale, respectivement. Les variations maximales de l'intervalle R-R ont ete mesurees pendant 60 s lors d'une occlusion de la veine cave inferieure, dans les conditions suivantes : (i) en condition temoin, le taux a augmente (R-R -21,8 ± 2,4 ms, p < 0,001) ; (ii) durant la perfusion d'isoproterenol, une bradycardie paradoxale a ete observee (R-R 98,0 ± 8,1 ms, p < 0,001) ; celle-ci a ete inhibee par le verapamil (R-R 5,0 ± 2,1 ms, p = ns) et retablie par le CaCl 2 (R-R 109,3 ± 6,5 ms, p < 0,001) ; (iii) durant la perfusion de CaCl 2 (sans isoproterenol), une bradycardie paradoxale a aussi ete observee (R-R 82,1 ± 22,9 ms, p < 0,001), laquelle a aussi ete inhibee par le verapamil (R-R -18,5 ± 4,7 ms, p < 0,001). Nous concluons que le verapamil inhibe la bradycardie paradoxale induite par l'occlusion de la veine cave inferieure durant une perfusion d'isoproterenol ou de calcium ; de plus, ces resultats sont en accord avec l'hypothese qu'une force contractile cardiaque accrue declenche une reaction vaso-depressive.

A 70-year-old patient who had been fitted with a pacemaker for 27 years consulted his cardiologist to check the latest device, which had been changed in 1998. During the examination there was a sudden malfunction of the pacemaker, which became uncontrollable, resulting in an escape rhythm of 15 beats/min and circulatory insufficiency. Attempted treatment by isoprenaline and external transcutaneous systolic stimulation failed, and an intraventricular catheter was therefore positioned successfully as an emergency prehospital manoeuvre. This produced good haemodynamic stability, allowing the transfer of the patient to hospital where his pacemaker was changed.

We investigated left ventricular (LV) mechanical work and energetics in the cross-circulated (blood-perfused) isoproterenol [Iso 1.2 mg·kg−1·day−1 for 3 days (Iso3) or 7 days (Iso7)]-induced hypertrophied rat heart preparation under isovolumic contraction-relaxation. We evaluated pressure-time curves per beat, end-systolic pressure-volume and end-diastolic pressure-volume relations, and myocardial O2 consumption per beat (V̇o2)-systolic pressure-volume area (PVA; a total mechanical energy per beat) linear relations at 240 beats/min, because Iso-induced hypertrophied hearts failed to completely relax at 300 beats/min. The LV relaxation rate at 240 beats/min in Iso-induced hypertrophied hearts was significantly slower than that in control hearts [saline 24 μl/day for 3 and 7 days (Sa)] with unchanged contraction rate. The V̇o2-intercepts (composed of basal metabolism and Ca2+ cycling energy consumption in excitation-contraction coupling) of V̇o2-PVA linear relations were unchanged associated with their unchanged slopes in Sa, Iso3, and Iso7 groups. The oxygen costs of LV contractility were also unchanged in all three groups. The amounts of expression of sarcoplasmic reticulum Ca2+-ATPase, phospholamban (PLB), phosphorylated-Ser16 PLB, phospholemman, and Na+-K+-ATPase are significantly decreased in Iso3 and Iso7 groups, although the amount of expression of NCX1 is unchanged in all three groups. Furthermore, the marked collagen production (types I and III) was observed in Iso3 and Iso7 groups. These results suggested the possibility that lowering the heart rate was beneficial to improve mechanical work and energetics in isoproterenol-induced hypertrophied rat hearts, although LV relaxation rate was slower than in normal hearts.

OBJECTIVE—To assess the diagnostic value and safety of sublingual glyceryl trinitrate tilt testing compared with isoprenaline infusion in patients with unexplained syncope. DESIGN—Glyceryl trinitrate and isoprenaline tilt tests were performed in two successive days on a random basis in cases and controls. SETTING—Outpatient cases with syncope referred to Shahid Rajaii Heart Hospital. SUBJECTS—65 consecutive patients with unexplained syncope after thorough work up; 20 healthy volunteers. RESULTS—Positive responses were observed in 20 patients during the passive phase. Of the other 45 patients, positive responses occurred in 25 cases during the glyceryl trinitrate phase and in 26 cases during the isoprenaline phase. In the control group, positive responses during the passive, glyceryl trinitrate, and isoprenaline phases occurred in one, one, and two cases, respectively. The sensitivity and specificity of the protocols were 55% and 94.7%, respectively, for glyceryl trinitrate v 58% and 89.4% for isoprenaline. Owing to discordant responses in 75% of the cases, the sequential use of the tests (if one was negative) would increase the sensitivity to 84% while decreasing the specificity slightly (to 84%). Side effects were less frequent with glyceryl trinitrate. CONCLUSIONS—Sublingual glyceryl trinitrate tilt testing is an effective and safe alternative to the isoprenaline infusion test and can be used as a complementary test. Keywords: syncope; tilt table test; isoprenaline; glyceryl trinitrate

Previous work showed that local cooling (LC) attenuates the vasoconstrictor response to whole body cooling (WBC). We tested the extent to which this attenuation was due to the decreased baseline skin blood flow following LC. In eight subjects, skin blood flow was assessed using laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was expressed as LDF divided by blood pressure. Subjects were dressed in water-perfused suits to control WBC. Four forearm sites were prepared with microdialysis fibers, local heating/cooling probe holders, and laser-Doppler probes. Three sites were locally cooled from 34 to 28°C, reducing CVC to 45.9 ± 3.9, 42 ± 3.9, and 44.5 ± 4.8% of baseline ( P < 0.05 vs. baseline; P > 0.05 among sites). At two sites, CVC was restored to precooling baseline levels with sodium nitroprusside (SNP) or isoproterenol (Iso), increasing CVC to 106.4 ± 12.4 and 98.9 ± 10.1% of baseline, respectively ( P > 0.05 vs. precooling). Whole body skin temperature, apart from the area of blood flow measurement, was reduced from 34 to 31°C. Relative to the original baseline, CVC decreased ( P < 0.05) by 44.9 ± 2.8 (control), 11.3 ± 2.4 (LC only), 29 ± 3.7 (SNP), and 45.8 ± 8.7% (Iso). The reductions at LC only and SNP sites were less than at control or Iso sites ( P < 0.05); the responses at those latter sites were not different ( P > 0.05), suggesting that the baseline change in CVC with LC is important in the attenuation of reflex vasoconstrictor responses to WBC.

To test the hypothesis that the training-induced improvement in the age-related decline in left ventricular (LV) function is mediated by enhanced inotropic responses to β-adrenergic stimulation, 10 sedentary healthy men, 65 ± 1 yr (mean ± SE) of age, exercised for 9 mo, which resulted in a 28% increase in aerobic exercise capacity. Training induced a greater increase in LV systolic shortening, assessed with two-dimensional echocardiography, in response to isoproterenol with a steeper slope of the fractional shortening-end-systolic wall stress (ςes) relationship and an upward shift of the ςes-systolic diameter relationship without an acute increase in heart rate or preload. The increase in the early-to-late diastolic flow velocity ratio, normalized for heart rate and preload, in response to isoproterenol was larger after training. LV systolic reserve and cardiac output during peak exercise were higher after training. β-Adrenergic blockade with esmolol HCl abolished the adaptive increases in LV systolic reserve capacity and cardiac output during peak exercise in the trained state. The results suggest that one of the underlying mechanisms responsible for the adaptive increase in LV systolic function in response to exercise training is an enhanced inotropic sensitivity to catecholamines. Furthermore, the enhanced inotropic responses are associated with increased diastolic filling.

Patients with syncope underwent head-up tilt testing at 60 degrees and 80 degrees followed by edrophonium or isoproterenol challenge when indicated. The 80 degrees tilt protocol and edrophonium provocation were found to be as effective or more effective in eliciting neurally mediated syncope in susceptible patients.

To investigate the direct effect of leukocyte adherence to microvessel walls on microvessel permeability, we developed a method to measure changes in hydraulic conductivity ( L p) before and after leukocyte adhesion in individually perfused venular microvessels in frog mesentery. In 19 microvessels that were initially free of leukocyte sticking or rolling along the vessel wall, control L p was measured first with Ringer-albumin perfusate. Blood flow was then restored in each vessel with a reduced flow rate in the range of 30–116 μm/s to facilitate leukocyte adhesion. Each vessel was recannulated in 45 min. The mean number of leukocytes adhering to the vessel wall was 237 ± 22 leukocytes/mm2. At the same time, L pincreased to 4.7 ± 0.5 times the control value. Superfusion of isoproterenol (10 μM) after leukocyte adhesion brought the increased L p back to 1.1 ± 0.2 times the control in 5–10 min ( n = 9). Superfusing isoproterenol before leukocyte adhesion prevented the increase in L p( n = 6). However, the number of leukocytes adhering to the vessel wall was not significantly affected. These results demonstrated that leukocyte adhesion caused an increase in microvessel permeability that could be prevented or restored by increasing cAMP levels in endothelial cells using isoproterenol. Thus cAMP-dependent mechanisms that regulate inflammatory agent-induced increases in permeability also modulate leukocyte adhesion-induced increases in permeability but act independently of mechanisms that regulate leukocyte adhesion to the microvessel wall. Application of ketotifen, a mast cell stabilizer, and desferrioxamine mesylate, an iron-chelating reagent, attenuated the increase in L p induced by leukocyte adhesion, suggesting the involvement of oxidants and the activation of mast cells in leukocyte adhesion-induced permeability increase. Furthermore, with the use of an in vivo silver stain technique, the locations of the adherent leukocytes on the microvessel wall were identified quantitatively in intact microvessels.