We studied the effect of epithelial removal and intraepithelial administration of human eosinophil granule major basic protein (MBP) on the contraction of underlying canine tracheal smooth muscle in 23 dogs in vivo. A dual in situ tracheal preparation was utilized that allowed sharp excision of epithelium. The response to intra-arterial acetylcholine (ACh) was augmented substantially in five dogs receiving 200 micrograms MBP by intraepithelial instillation. Active tension elicited by 10(-8) mol intra-arterial ACh was 34.0 +/- 2.2 g/cm before and 46.1 +/- 2.6 g/cm 30 min after MBP (P less than 0.002). There was no change in active tension in the control segment in the same dogs after intraepithelial instillation of vehicle only (34.7 +/- 3.2 vs. 34.4 +/- 2.3 g/cm; P = NS). Instillation of MBP directly into the subepithelial tracheal smooth muscle did not alter contraction. To assess whether this augmentation was caused by inhibition of an epithelial-derived relaxant factor, additional studies were performed in nine other dogs in which the epithelium was excised discretely from one of the two tracheal segments. No significant differences in contractile response to ACh or relaxation response to isoproterenol were observed at 2, 15, 30, or 60 min after epithelial excision. We demonstrate that intraepithelial administration of MBP augments the contraction of underlying canine tracheal smooth muscle elicited by ACh. This augmentation is a direct effect of MBP and does not require antagonism of epithelial inhibition.
We studied the effect of maturation on contractile properties of tracheal smooth muscle from seventeen 2-wk-old swine (2ws) and fifteen 10-wk-old swine (10ws) in situ and in vitro. The response to parasympathetic stimulation was studied in situ in isometrically fixed segments. Contraction was elicited at lower frequencies [half-maximal response to electrical stimulation (ES50) = 6.7 +/- 0.05 Hz] in 2ws than in 10ws (ES50 = 9.1 +/- 0.4 Hz; P less than 0.01). Despite substantial differences in morphometrically normalized cross-sectional area in 2ws (0.012 +/- 0.003 cm2) and 10ws (0.028 +/- 0.001 cm2; P less than 0.01), maximal active tension elicited by parasympathetic stimulation was similar (12.4 +/- 3.2 g/cm in 2ws vs. 13.3 +/- 2.3 g/cm in 10ws; P = NS). In separate in vitro studies in 25 tracheal smooth muscle strips from 10 swine, concentration-response curves generated with potassium-substituted Krebs solution (KCl) were similar in 2ws and 10ws. In 58 other strips (10 swine), maximal active force elicited with acetylcholine (ACh) in 2ws was significantly greater than for 10ws (P less than 0.001). Removal of the epithelium had no effect. However, cholinesterase inhibition with 10(-7) M physostigmine augmented the response to ACh in 10ws (P less than 0.02) but not 2ws. We demonstrate increased force generation and sensitivity to vagal stimulation in 2ws vs. 10ws, which corresponds to increased reactivity to ACh in vitro. The relative hyperresponsiveness in 2ws is specific for cholinergic response and is attenuated at least in part by maturation of the activity of acetylcholinesterase enzyme.
To elucidate mechanisms of platelet-activating factor (PAF)-induced contraction, we studied the effect of PAF on 203 canine tracheal smooth muscle (TSM) strips from 45 dogs in vitro in the presence and absence of platelets. PAF (10(-11) to 10(-7) M) alone caused no contraction of TSM even in the presence of airway epithelium. In the presence of 2 x 10(5) platelets/microliter, PAF was an extremely potent contractile agonist (threshold 10(-11) M). This response was inhibited by the PAF antagonist, CV-3988 (10(-6) M), and reversed by the serotonin antagonist, methysergide (EC50 = 3.7 +/- 0.79 x 10(-9) M). Neither atropine nor chlorpheniramine (10(-9) to 10(-6) M) attenuated the response to PAF + platelets. In the presence of platelets, 10(-7) M PAF caused an increase in perfusate concentration of serotonin from 0.93 +/- 0.037 x 10(-8) to 1.7 +/- 0.046 x 10(-8) M (P less than 0.001). Tachyphylaxis, previously demonstrated to be irreversible, was shown to be a platelet-dependent phenomenon; contraction could be repeated in the same TSM after addition of fresh platelets. We demonstrate that PAF-induced contraction of canine TSM is caused by the release of cellular intermediates such as serotonin from platelets. We also demonstrate the site of PAF-induced tachyphylaxis in airway smooth muscle contraction.
We describe our experience managing a 16-year-old girl with systemic lupus erythematosus (SLE) who presented concomitantly with rapidly progressive glomerulonephritis (RPGN) and a thrombotic microangiopathic hemolytic anemia (TMAHA). Her renal biopsy showed evidence of diffuse proliferative glomerulonephritis without glomerular microthrombi. The patient was treated with a combination of intravenous corticosteroids and cyclophosphamide, as well as plasmapheresis, with an excellent response resulting in complete disease remission. The purpose of our report is to make health professionals more aware of TMAHA as a complication of SLE, since the occurrence of TMAHA may confuse the clinical picture, and since its treatment with plasmapheresis is life saving, if performed early.
We studied the effects of bronchoconstrictor stimuli administered selectively through isolated-perfused preparations of the bronchial and pulmonary circulations of 80 Sprague-Dawley rats. Dose-related contraction was elicited with infusion of acetylcholine (ACh), histamine, and serotonin (5-HT). Bolus infusion of 10(-5) mol ACh caused a 3.5-fold increase in pulmonary resistance (RL) after infusion into the pulmonary circulation (PC) and a 2.5-fold increase in the bronchial circulation (BC) (P less than 0.05 vs. control) that was blocked selectively in each circulation with atropine. Administration of 10(-5) mol 5-HT into the BC caused only a 45% increase in RL; the same dose of 5-HT caused a 5.1-fold increase in RL in the PC. A biphasic (increase at lower doses/decrease at higher doses) change in RL was elicited by histamine that was converted to dose-related constriction after H2-receptor blockade with cimetidine in both BC and PC. Response to exogenous ACh remained viable for greater than 5 h. Infusion of the mast cell degranulating agent, compound 48/80 (48/80), caused increase in RL that corresponded to quantitative recovery of histamine in the perfusates of both BC and PC. Histamine concentration in the perfusate increased from 47.2 +/- 31.8 (base line) to 624 +/- 60.1 ng/ml (2-fold increase in RL) in the BC and from 38.3 +/- 17.7 (base line) to 294.4 +/- 38.1 ng/ml (50% increase in RL) in the PC (P less than 0.001 vs. baseline concentration) after a 0.1-mg/ml dose of 48/80.(ABSTRACT TRUNCATED AT 250 WORDS)
The comparative effects of contractile agonists and physiological stimulation of the tracheal and bronchial smooth muscle (BSM) response were studied isometrically in situ in five Basenji-greyhound (BG) and six mongrel dogs. Frequency-response curves generated by bilateral stimulation of the vagus nerves (0-20 Hz, 15-20 V, 2-ms duration) elicited greater maximal contraction in mongrel trachea (36.8 +/- 8.1 vs. 26.9 +/- 4.0 g/cm; P less than 0.02) and exhibited greater responsiveness in mongrel BSM (half-maximal response to electrical stimulation 3.0 +/- 1.1 vs. 7.0 +/- 0.5 Hz; P less than 0.05) compared with BG dogs. However, muscarinic sensitivity to intravenous methacholine (MCh) was substantially greater in BG dogs; MCh caused contraction greater than 1.5 g/cm at a mean dose of 3.0 X 10(-10) mol/kg for BG dogs compared with 5.1 X 10(-9) mol/kg for mongrel controls (P less than 0.03, Mann-Whitney rank-sum test). In contrast to the muscarinic response, the contractile response elicited by intravenous norepinephrine after beta-adrenergic blockade was similar in trachea and bronchus for both mongrel and BG dogs. Our data confirm previous in vitro demonstration of tracheal hyporesponsiveness in BG dogs and demonstrate that the contraction resulting from efferent parasympathetic stimulation is less in the BG than mongrel dogs. However, postsynaptic muscarinic responsiveness of BG BSM is substantially increased. We conclude that a component of airway responsiveness in BG dogs depends directly on contractile forces generated postsynaptically that are nongeometry dependent, postjunctional, and agonist specific.
We studied the sympathetic neural response on airways to hypotensive stimuli in 19 swine in vivo. The effects of pharmacologically induced hypotension with nitroprusside (NTP) and hypotension elicited by intravenous compound 48/80 (48/80), a mast cell degranulating agent, were compared after equivalent reductions in mean arterial blood pressure (MAP). Reduction of the MAP to 60% of base line with NTP in six swine caused an increase in plasma epinephrine (E) from 60 +/- 28 to 705 +/- 276 pg/ml (P = 0.032) and plasma norepinephrine (NE) from 270 +/- 46 to 796 +/- 131 pg/ml (P = 0.032). Comparable reduction in MAP elicited with 48/80 in six other swine caused a substantially greater increase in both plasma E (9,581 +/- 4,147 pg/ml; P = 0.012 vs. NTP group) and plasma NE (2,239 +/- 637 pg/ml; P = 0.041 vs. NTP group). Catecholamine secretion attenuated mediator-induced changes in lung resistance (RL). In animals receiving 48/80, RL increased from 2.97 +/- 0.31 to 7.44 +/- 0.56 cmH2O.l-1.s. In animals having ganglionic blockade with 7.5 mg/kg iv hexamethonium and beta-adrenergic blockade with propranolol (4.0 mg/kg iv followed by 40 micrograms/kg-1.min-1), comparable doses of 48/80 caused an increase in RL to 18.6 +/- 4.55 cmH2O.l-1.s (P less than 0.04 vs. swine receiving neither hexamethonium nor propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
We studied the secretory correlates of tracheal smooth muscle contraction caused by platelet-activating factor (PAF) in nine mongrel dogs in vivo. In five dogs, dose-response curves were generated by rapid intra-arterial injection of 10(-10) to 10(-6) mol PAF into the isolated tracheal circulation; tracheal contractile response was measured isometrically in situ. To examine the mechanism by which PAF elicits contraction of canine trachealis, concentrations of serotonin (5-HT) and histamine were assayed in the venous effluent as the arteriovenous difference (AVd) in mediator concentration across the airway for each level of contraction. PAF caused dose-related active tracheal tension to a maximum of 37.2 +/- 5.4 g/cm (10(-6) mol PAF). The AVd in 5-HT increased linearly from 0.20 +/- 0.05 (10(-9) mol PAF) to 3.5 +/- 0.3 ng/ml (10(-6) mol PAF) (P less than 0.005). In contrast, the AVd in histamine was insignificant and did not change with increasing doses of PAF. A positive correlation was obtained between the AVd in 5-HT and active tracheal tension (r = 0.92, P less than 0.001); there was no correlation between AVd in histamine and active tension (r = -0.16). PAF-induced parasympathetic activation was not mediated by 5-HT; contraction elicited by exogenous 5-HT was not affected by muscarinic blockade. We conclude that nonparasympathetically mediated contraction elicited acutely by PAF in dogs results at least in part from secondary release of serotonin and is not mediated by histamine.
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