calcimycin and Chronic-Disease

Basophils (BAs) are the least common granulocytes of all leukocytes, but they play an important role in orchestrating of chronic allergic inflammation. The Notch signaling pathway is a highly conserved pathway that influences cell lineage decisions and differentiation during various stages of development. However, the relationship between Notch signaling and BA remains to be elucidate. Here, we report that several Notch signaling molecules were found to be expressed in BAs. γ-secretase inhibitor (GSI) treatment increase BAs apoptosis, and suppress BAs proliferation. Furthermore, GSI reduced BAs in the S phase, with a concomitant accumulation in G1 and G2 phases. In addition, GSI also significantly down-regulated mRNA levels of cytokines IL-4, IL-6 and IL-13 induced by A23187, and this effect was dependent on MAPK pathway. Finally, IL-6 inhibition was specifically associated with ERK and IL-13 with JNK. Therefore, Notch signaling regulates BA biological function, at least partially via the modulation of MAPK.

Topics: Animals; Basophils; Calcimycin; Cell Cycle; Cells, Cultured; Chronic Disease; Cytokines; Extracellular Signal-Regulated MAP Kinases; Hypersensitivity; Inflammation; Inflammation Mediators; Mice; Oligopeptides; Receptors, Notch; Signal Transduction

Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exercise-induced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release.. The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated.. Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls.. Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.

Topics: Adolescent; Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma, Exercise-Induced; Basophils; Benzoates; Calcimycin; Cell Degranulation; Cells, Cultured; Child; Chronic Disease; Cyclooxygenase Inhibitors; Enzyme Activation; Female; Food Hypersensitivity; Histamine Release; Humans; Immunoglobulin E; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Phosphorylation; Protein-Tyrosine Kinases; Signal Transduction; Syk Kinase; Tartrazine; Urticaria; Young Adult

The present study tested the hypothesis that chronic hypoxia alters pregnancy-mediated adaptation of Ca2+ homeostasis and contractility in the uterine artery. Uterine arteries were isolated from nonpregnant and near-term pregnant ewes of normoxic control or high-altitude (3820 m) hypoxic (oxygen pressure in the blood [PaO2], 60 mm Hg) treatment for 110 days. Contractions and intracellular-free Ca2+ concentration ([Ca2+]i) were measured simultaneously in the same tissue. In normoxic animals, pregnancy increased norepinephrine (NE), but not 5-hydroxy-thymide (5-HT) or KCl, contractile sensitivity in the uterine artery. Chronic hypoxia significantly attenuated NE-induced contractions in the pregnant, but not nonpregnant, uterine arteries. Similarly, 5-HT-mediated contractions of nonpregnant arteries were not changed. In the pregnant uterine artery, chronic hypoxia significantly increased NE-mediated Ca2+ mobilization, but decreased the Ca2+ sensitivity. In addition, hypoxia increased the calcium ionophore A23187-induced relaxation in pregnant, but not nonpregnant, uterine arteries. However, the A23187-mediated reduction of [Ca2+]i was significantly impaired in hypoxic arteries. In contrast, hypoxia significantly increased the slope of the [Ca2+]i-tension relationship of A23187-induced reductions in [Ca2+]i and tension in the pregnant uterine artery. The results suggest that the contractility of nonpregnant uterine artery is insensitive to moderate chronic hypoxia, but the adaptation of sympathetic tone that normally occurs in the uterine artery during pregnancy is inhibited by chronic hypoxia. In addition, changes in Ca2+ sensitivity of myofilaments play a predominant role in the adaptation of uterine artery contractility to pregnancy and chronic hypoxia.

Topics: Animals; Arteries; Calcimycin; Calcium; Chronic Disease; Female; Homeostasis; Hypoxia; Intracellular Membranes; Ionophores; Norepinephrine; Osmolar Concentration; Potassium Chloride; Pregnancy; Pregnancy, Animal; Serotonin; Sheep; Uterus; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

Pulmonary hypertension and blunted pulmonary vascular responses to ACh develop when newborn pigs are exposed to chronic hypoxia for 3 days. To determine whether a cyclooxygenase (COX)-dependent contracting factor, such as thromboxane, is involved with altered pulmonary vascular responses to ACh, newborn piglets were raised in 11% O(2) (hypoxic) or room air (control) for 3 days. Small pulmonary arteries (100-400 microm diameter) were cannulated and pressurized, and their responses to ACh were measured before and after either the COX inhibitor indomethacin; a thromboxane synthesis inhibitor, dazoxiben or feregrelate; or the thromboxane-PGH(2)-receptor antagonist SQ-29548. In control arteries, indomethacin reversed ACh responses from dilation to constriction. In contrast, hypoxic arteries constricted to ACh before indomethacin and dilated to ACh after indomethacin. Furthermore, ACh constriction in hypoxic arteries was nearly abolished by either dazoxiben, feregrelate, or SQ-29548. These findings suggest that thromboxane is the COX-dependent contracting factor that underlies the constrictor response to ACh that develops in small pulmonary arteries of piglets exposed to 3 days of hypoxia. The early development of thromboxane-mediated constriction may contribute to the pathogenesis of chronic hypoxia-induced pulmonary hypertension in newborns.

Topics: Acetylcholine; Animals; Animals, Newborn; Calcimycin; Chronic Disease; Endothelium, Vascular; Female; Hypoxia; Male; Muscle Tonus; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; S-Nitroso-N-Acetylpenicillamine; Swine; Thromboxanes

We tested the hypothesis that chronic high-altitude (3,820 m) hypoxia during pregnancy was associated with the upregulation of endothelial nitric oxide (NO) synthase (eNOS) protein and mRNA in ovine uterine artery endothelium and enhanced endothelium-dependent relaxation. In pregnant sheep, norepinephrine-induced dose-dependent contractions were increased by removal of the endothelium in both control and hypoxic uterine arteries. The increment was significantly higher in hypoxic tissues. The calcium ionophore A23187-induced relaxation of the uterine artery was significantly enhanced in hypoxic compared with control tissues. However, sodium nitroprusside- and 8-bromoguanosine 3',5'-cyclic monophosphate-induced relaxations were not changed. Accordingly, chronic hypoxia significantly increased basal and A23187-induced NO release. Chronic hypoxia increased eNOS protein and mRNA levels in the endothelium from uterine but not femoral or renal arteries. In nonpregnant animals, chronic hypoxia increased eNOS mRNA in uterine artery endothelium but had no effects on eNOS protein, NO release, or endothelium-dependent relaxation. Chronic hypoxia selectively augments pregnancy-associated upregulation of eNOS gene expression and endothelium-dependent relaxation of the uterine artery.

Topics: Altitude Sickness; Animals; Calcimycin; Chronic Disease; Cyclic GMP; Endothelium, Vascular; Female; Femoral Artery; Gene Expression Regulation, Enzymologic; Hypoxia; Ionophores; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroprusside; Norepinephrine; Pregnancy; Pregnancy, Animal; Renal Artery; RNA, Messenger; Sheep; Umbilical Arteries; Uterus; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Alterations of vasoreactivity are a well-known phenomenon in chronic heart failure (CHF), and activation of the endogenous endothelin (ET) system is suspected to contribute significantly. Regional differences in alterations of vasoreactivity exist; however, nothing is known about cerebrovascular reactivity in CHF. This is of interest in view of increased stroke risk in CHF. Therefore, 12 weeks after coronary artery ligation to induce CHF in rats, studies of vasoreactivity of the isolated basilar artery (BA) were performed and compared with third-order branches (MA-A3) and the main trunk (MA) of the superior mesenteric artery. Some of the animals received long-term ET-receptor antagonism by 11 weeks of treatment with the selective ET(A)-receptor antagonist LU 135252 or the mixed ET(A)/ET(B)-receptor antagonist bosentan. In rats with CHF, endothelium-dependent relaxation by acetylcholine and A23187 as well as endothelium-independent relaxation by sodium nitroprusside (SNP) was largely unaffected in BA or MA. However, in MA-A3, potency of SNP was diminished without change of maximal effect. ET-1-induced contraction did not differ in arteries from CHF and control rats, either in placeboor ET-receptor antagonist-treated animals. In summary, there was essentially no change of vascular reactivity in similar sized arteries obtained from brain and mesentery. This is in contrast to results on arteries from a variety of vascular regions published previously, thus supporting the concept of organ- and probably time-related changes of vascular function in the development of CHF. The absence of significant alteration of cerebral vasoreactivity may be taken to indicate that changes in cerebral blood flow and increased incidence of ischemic stroke in patients with CHF are caused not by local alterations of vascular function.

Topics: Acetylcholine; Animals; Basilar Artery; Calcimycin; Cardiac Output, Low; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Male; Mesenteric Arteries; Nitroprusside; Rats; Rats, Wistar; Vasoconstriction; Vasodilation; Vasodilator Agents

These studies tested whether fetal artery reactivity is sensitive to both acute changes in oxygen levels (in vitro) and chronic changes (in utero).. Pregnant guinea pigs near term were exposed to either normoxia or hypoxia (12% oxygen) for 4 or 7 days. The effect of decreasing PO (2 ) in vitro (acute hypoxia) on relaxation in response to acetylcholine, A23187, sodium nitroprusside, and 8-bromo-cyclic guanosine monophosphate was measured in isolated carotid arteries from normoxic fetuses. In separate experiments relaxation in response to acetylcholine and sodium nitroprusside of endothelially intact and denuded fetal arteries from fetuses exposed to normoxic conditions and long-term (4 and 7 days) hypoxic conditions was measured in the presence and absence of nitro-L -arginine (10(-4) mol/L).. Acute hypoxia inhibited endothelium-dependent relaxation in response to acetylcholine and A23187, increased sensitivity to sodium nitroprusside, but had no effect on relaxation in response to 8-bromo-cyclic guanosine monophosphate. Chronic hypoxia (4 but not 7 days) inhibited maximal relaxation of arteries in response to acetylcholine but not relaxation of arteries in response to sodium nitroprusside with respect to relaxation seen in arteries from normoxic fetuses. Nitro-L -arginine attenuated the differences between normoxic and hypoxic fetuses in acetylcholine response.. Hypoxia may alter relaxation of fetal arteries by decreasing the availability of oxygen for nitric oxide production and causing vascular adaptations related to altered nitric oxide release.

Topics: Acetylcholine; Acute Disease; Animals; Arteries; Calcimycin; Chronic Disease; Cyclic GMP; Disease Models, Animal; Female; Guinea Pigs; Hypoxia; Muscle, Smooth, Vascular; Nitric Oxide; Nitroprusside; Pregnancy; Vasodilator Agents

Neonatal pulmonary hypertension is associated with increased pulmonary vascular reactivity. We studied the responses of isolated porcine intrapulmonary arteries after exposure of piglets to chronic hypobaric hypoxia (CHH) from 0 to 2.5, 3 to 6, or 14 to 17 days of age. CHH inhibited the postnatal development of endothelium-dependent vasorelaxation to acetylcholine (ACh) and the calcium ionophore A-23187. Basal accumulation of guanosine 3', 5'-cyclic monophosphate (cGMP) was unaffected, but cGMP response to ACh was inhibited. Endothelium-independent relaxation to nitric oxide (NO) and zaprinast (a phosphodiesterase inhibitor) was also inhibited, but cGMP accumulation in response to these agonists was normal. The ability of sodium nitroprusside (SNP) to cause vasorelaxation and increase cGMP accumulation was unaffected. Contractile responses to potassium chloride and prostaglandin F2 alpha (PGF2 alpha) were similar to normal after exposure from birth and 3 days and were decreased in the older group, but the ability of NG-monomethyl-L-arginine acetate to increase PGF2 alpha-induced contractions decreased. Thus exposure of newborn piglets to CHH causes 1) no increase in contractile responses and 2) impairment of endothelium-dependent and -independent relaxation by impairing signal transduction mechanisms involved in the release of NO and the effectiveness of cGMP.

Topics: Acetylcholine; Animals; Animals, Newborn; Atmospheric Pressure; Calcimycin; Chronic Disease; Cyclic GMP; Dinoprost; Endothelium, Vascular; Heart; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Nitric Oxide; omega-N-Methylarginine; Potassium Chloride; Pulmonary Artery; Purinones; Swine; Vasodilation; Vasomotor System

To define the isoform of phospholipases A2 active in inflammation we evaluated the effects of low-molecular-weight inhibitors of secretory and cytosolic phospholipases A2. We found that inhibitors of cytosolic phospholipase A2 had therapeutic efficacy in an in vivo model of chronic inflammation (rat adjuvant arthritis), whereas inhibitors of secretory phospholipase A2 had no beneficial effect. In vitro, inhibitors of cytosolic phospholipase A2 diminished surface expression of Mac-1 (CD11b/CD18) beta2-integrin on calcium ionophore-stimulated human blood granulocytes and suppressed synthesis of interleukin-1beta in lipopolysaccharide-stimulated human blood monocytes and U937 cells by reducing mRNA levels. Lipid mediators promote Mac-1 exocytosis and transcription of interleukin-1beta, which further enhances cytosolic phospholipase A2 activity and expression. Thus, superinduction of cytosolic phospholipase A2 may establish a positive feedback loop, converting acute inflammation into chronic inflammation. Consequently, inhibitors of cytosolic phospholipase A2 may prevent inflammation in vivo by interfering with cellular activation and infiltration. We conclude that cytosolic phospholipase A2 but not secretory phospholipase A2 is the predominant enzyme in inflammatory signalling.

Topics: Animals; Arthritis, Experimental; Calcimycin; Cell Line; Chronic Disease; Cytokines; Cytosol; Depression, Chemical; Disease Models, Animal; Enzyme Inhibitors; Humans; Inflammation; Integrins; Male; Molecular Weight; Phospholipases A; Phospholipases A2; Rats; Rats, Inbred Lew

We have previously demonstrated that arginine vasopressin (AVP) dilates the preconstricted pulmonary vasculature via the release of nitric oxide (NO). However, recent evidence suggests that NO release in response to other agents may be suppressed in lungs from animals that have been chronically exposed to hypoxia. The purpose of the present experiment was to determine whether vasopressinergic pulmonary vasodilation is similarly affected by chronic exposure to hypoxia (barometric pressure = 380 Torr for 4 wk). Inhibition of NO synthesis with N omega-nitro-L-arginine (L-NNA) had no effect on baseline perfusion pressure in isolated salt-perfused lungs from either control or chronically hypoxic rats. Similarly, pulmonary vasodilatory responses to AVP and the calcium ionophore A23187 were unaffected by chronic hypoxic exposure. Pretreatment with the cyclooxygenase inhibitor meclofenamate did not alter vasopressinergic pulmonary vasodilation in lungs from either control or chronically hypoxic animals, ruling out involvement of vasodilator prostaglandins in the response to AVP. In contrast, vasodilatory responses to both AVP and A23187 were inhibited by L-NNA pretreatment not only in lungs from control animals but also in lungs from chronically hypoxic rats, suggesting the involvement of NO in the vasodilatory response. The inhibition by L-NNA was reversible by prior addition of excess L-arginine but not by D-arginine. In addition, vasodilatory responses to the endothelium-independent vasodilators sodium nitroprusside and isoproterenol were unaffected by chronic hypoxic exposure. We conclude that endothelium-dependent vasodilation remains intact in male Sprague-Dawley rats after chronic hypoxic exposure.

Topics: Air Pressure; Animals; Arginine; Arginine Vasopressin; Calcimycin; Chronic Disease; Endothelium, Vascular; Hypoxia; In Vitro Techniques; Isoproterenol; Male; Meclofenamic Acid; Nitroarginine; Nitroprusside; Prostaglandins; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Vasodilation; Vasodilator Agents

We investigated whether loss of endothelial-derived relaxing factor (EDRF) activity in the pulmonary vessels of chronically hypoxic rats could be restored by pretreatment with L-arginine. We measured vasodilation to acetylcholine (ACh), calcium ionophore A23187, or linsidomine (Sin-1) under conditions of increased vascular tone induced by U-46619 (50 pmol/min), as well as vasoconstriction to endothelin-1 (ET) in isolated lungs pretreated with meclofenamate (3 microM). In lungs from normoxic (N) rats, in vitro L- or D-arginine (10(-3) M) did not alter vasodilation to the endothelium-dependent agents ACh (10(-9)-10(-6) M) and A23187 (10(-9)-10(-7) M), but NG-monomethyl-L-arginine (10(-3) M) completely abolished it. In lungs from rats exposed to 3 wk of hypoxia (H), vasodilation to ACh or A23187 was fully restored after in vitro L-arginine (10(-3) M) or N alpha-benzoyl-L-arginine (5 x 10(-5) M) but remained abolished after D-arginine, L-citrulline, L-ornithine, or L-argininosuccinic acid. In vivo pretreatment of H rats with L-arginine (300 mg/kg iv) 30 min before isolating the lung also restored vasodilation to A23187. Vasodilation to the endothelium-independent agent Sin-1 was similar in both groups of lungs and was not altered by in vitro L-arginine. L-arginine attenuated the increased pressor response to ET (300 pmol) of H rat lungs but had no effect in N rats. Our results demonstrate that loss of EDRF activity associated with hypoxic pulmonary hypertension may be reversed by supplying L-arginine.

Topics: Acetylcholine; Animals; Arginine; Calcimycin; Chronic Disease; Endothelins; Endothelium, Vascular; Hypoxia; Male; Pulmonary Circulation; Rats; Rats, Inbred Strains; Reference Values; Vasodilation

Platelet-activating factor (PAF) was measured in human nasal polyps obtained from patients with chronic sinusitis. PAF was quantitated by platelet-aggregating activity and was found to be 7.8 +/- 1.8 pg/micrograms phosphorus of polyp phospholipid (mean +/- SE; n = 23). In the polyps, phosphatidylcholine constituted 30% of the total phospholipids, of which 8.5% was the ether-linked type. Incubations of replicates of the fresh polyps in Tyrode's solution in the presence of calcium ionophore A23187 and antihuman immunoglobulin E resulted in 295 and 65% increases in the amount of PAF, respectively. Thus, nasal polyps in humans with chronic sinusitis possess PAF and have the potential to produce PAF upon stimulation. The participation of PAF in nasal polyp formation is discussed.

Topics: Adolescent; Adult; Aged; Antibodies, Anti-Idiotypic; Calcimycin; Child; Chronic Disease; Female; Humans; Immunoglobulin E; Male; Middle Aged; Nasal Polyps; Phospholipids; Platelet Activating Factor; Platelet Aggregation; Sinusitis

Acetylcholine produces less dilatation of pial arterioles in stroke-prone spontaneously hypertensive rats (SHRSP) than in normotensive (WKY) rats. Responses of cerebral vessels to acetylcholine and bradykinin appear to involve different mechanisms. Our first goal was to determine whether responses of pial arterioles to bradykinin are impaired in SHRSP. Diameter of pial arterioles (20-60 microns) was measured using intravital microscopy in WKY rats and SHRSP (9-12 months old). Superfusion of bradykinin (3 x 10(-7) M) dilated pial arterioles by 35 +/- 6% (mean +/- SEM) in WKY rats, but only 21 +/- 3% in SHRSP (p less than 0.05 versus WKY rats). Both nitric oxide (5 x 10(-7) M) and nitroglycerin (10(-5) M) produced similar vasodilatation in WKY rats and SHRSP. Our second goal was to determine whether alteration of postreceptor mechanisms contributes to impairment of endothelium-dependent cerebral vasodilatation in SHRSP. Calcium ionophore A23187 (10(-5) M) produced more vasodilatation in WKY rats than in SHRSP (32 +/- 8% versus 9 +/- 4%, p less than 0.05). Responses to A23187 (10(-5) M) were inhibited by indomethacin (46 +/- 13% versus 15 +/- 5%, p less than 0.05) in WKY rats, whereas responses to A23187 (10(-6) M) were potentiated modestly by indomethacin (-3 +/- 2% versus 4 +/- 2%, p less than 0.05) in SHRSP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arterioles; Blood Pressure; Bradykinin; Calcimycin; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronic Disease; Disease Susceptibility; Endothelium, Vascular; Hypertension; Male; Nitroglycerin; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation

Abnormalities in vasomotor tone, including enhanced vasoconstriction at rest and diminished vasodilation in response to various stimuli, develop as a consequence of chronic heart failure. This study was undertaken to evaluate whether a specific local mechanism, namely endothelium-derived relaxing factor (EDRF) activity, might be impaired in an experimental model of chronic heart failure. Segments of thoracic aorta (TA) and pulmonary artery (PA) were isolated from a group of rats that had hemodynamic evidence of heart failure 10 weeks after ligation of the left coronary artery (n = 25) and from a group of sham-operated control rats (n = 18). Both endothelium-dependent and endothelium-independent vascular responses were assessed by exposing arterial segments to increasing concentrations of agonists. All studies were performed in the presence of 10 microM indomethacin to avoid the influence of vasoactive prostanoids. The dose-response curve for EDRF-mediated relaxation to acetylcholine was shifted rightward in rats with heart failure, and the concentrations of acetylcholine required to achieve 50% maximal relaxation (EC50) were increased compared with those of control rats in both TA and PA segments. Additionally, the dose-response curve for relaxation to ADP was shifted rightward with significantly increased EC50 in PA segments from rats with heart failure. In contrast, EDRF-mediated relaxation to the calcium ionophore A23187 was similar in the groups. Endothelium-independent relaxation to nitroglycerin was slightly increased in TA but not PA segments in the heart-failure group. Basal EDRF activity, as assessed by the increase in force after exposure to hemoglobin, was diminished in PA segments from rats with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Aorta, Thoracic; Calcimycin; Cardiac Output, Low; Chronic Disease; Heart; Hemodynamics; Male; Nitric Oxide; Pulmonary Artery; Rats; Rats, Inbred Strains; Vasodilation

To determine whether exposure to chronic hypoxia and subsequent development of pulmonary hypertension induces alterations of endothelium-dependent relaxation in rat pulmonary vascular bed, we studied isolated lung preparations from rats exposed to either room air (controls) or hypoxia (H) during 1 wk (1W-H), 3 wk (3W-H), or 3W-H followed by 48 h recovery to room air (3WH + R). In lungs pretreated with meclofenamate (3 microM), the endothelium-dependent vasodilator responses to acetylcholine (10(-9)-10(-6) M) and ionophore A23187 (10(-9)-10(-7) M) were examined during conditions of increased tone by U46619 (50 pmol/min). Acetylcholine or A23187 produced dose-dependent vasodilation in control lungs, this response was reduced in group 1W-H (P less than 0.02), abolished in group 3W-H (P less than 0.001), and restored in group 3WH + R. In contrast, the endothelium-independent vasodilator agent sodium nitroprusside remained fully active in group 3W-H. The pressor response to 300 pM endothelin was greater in group 3W-H than in controls (6.8 +/- 0.5 mmHg vs. 1.6 +/- 0.2 mmHg, P less than 0.001) but was not potentiated by the endothelium-dependent relaxing factor (EDRF) antagonists: hydroquinone (10(-4) M); methylene blue (10(-4) M); and pyrogallol (3 x 10(-5) M) as it was in controls. It was similar to controls in group 3W-H + R. Our results demonstrate that hypoxia-induced pulmonary hypertension is associated with a loss of EDRF activity in pulmonary vessels, with a rapid recovery on return to a normoxic environment.

Topics: Acetylcholine; Animals; Blood Pressure; Calcimycin; Chronic Disease; Endothelins; Endothelium, Vascular; Hypertension, Pulmonary; Hypoxia; Male; Nitric Oxide; Nitroprusside; Pulmonary Circulation; Rats; Rats, Inbred Strains

We have undertaken a prospective analysis of the diagnostic significance of three different criteria of human sperm function including the conventional semen profile, measurements of hamster-oocyte fusion, and determinations of reactive oxygen species generation in 139 couples. The latter, who were characterized by a lack of detectable abnormalities in the female partner, were followed up for a maximum of 4 years to determine the incidence of spontaneous pregnancy in the absence of therapeutic intervention. Assessments of monthly fecundity with life table analysis techniques revealed a highly significant, positive relationship between fertility and hamster-oocyte fusion rates that were measured in the presence of the ionophore, A23187. Conversely, reactive oxygen species generation was shown to be negatively associated with both the outcome of the sperm-oocyte fusion assay and fertility in vivo. The clinical significance of these diagnostic techniques was emphasized by the fact that within the same data set, the conventional semen profile was of no significant diagnostic value.

Topics: Animals; Calcimycin; Chronic Disease; Cricetinae; Female; Follow-Up Studies; Humans; Infertility, Male; Luminescent Measurements; Male; Oxygen Consumption; Pregnancy; Prognosis; Prospective Studies; Semen; Sperm-Ovum Interactions

The course of the rabbit aortic wall reactivity changes due to hypercholesterolemia involved, in the first place, the inhibition of the endothelium relaxing influence on the smooth muscle contractile activity and an increase in the muscle sensitivity to neurogenic and humoral tonic influences. Later, a sharp inhibition of the vessel's wall functional activity occurred due to a mechanical factor: the development of connective tissue which prevents active vascular reactions. Nevertheless, endothelial and smooth muscle cells functional activity was high enough. The main cause of the vascular reactivity disturbances involved structural changes in the vessel wall whilst the direct influence of high blood cholesterol was much less obvious.

Topics: Acetylcholine; Animals; Aorta; Calcimycin; Chronic Disease; Diet, Atherogenic; Endothelium, Vascular; Hypercholesterolemia; Muscle Contraction; Muscle, Smooth, Vascular; Nitroglycerin; Norepinephrine; Phenylephrine; Rabbits

The metabolism of endogenous arachidonic acid by human polymorphonuclear leukocytes (PMNL) isolated from peripheral blood has been studied in 19 patients with chronic plaque psoriasis and 19 healthy controls. Using calcium ionophore A23187 as a stimulus, the PMNL synthesized leukotriene B4 (LTB4), 6-trans-leukotriene B4, 12-epi-6-trans-LTB4, and 5-hydroxy-6,8,11,14-eicosatetraenoic acid. There was no significant difference in the amounts of the products formed between the psoriatic and control groups. The elevated levels of LTB4 that have been described in psoriatic skin may therefore be due to the PMNL infiltrate or to enhanced synthesis by another cell type. The reported increase in activity of the circulating PMNL in psoriasis does not appear to be due to increased 5-lipoxygenase activity in these cells.

Topics: Adult; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Calcimycin; Chromatography, High Pressure Liquid; Chronic Disease; Female; Humans; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Neutrophils; Psoriasis