Toward the formulation of a theory of asthma.
Explore the source record for details and available documents.
Asthma↗
Biomedical subjects
A R Leff
Publications and source records attributed to A R Leff.
Function after amputation, arthrodesis, or arthroplasty for tumors about the knee.
We studied the function of twenty-two patients who had had a malignant skeletal tumor adjacent to the knee. An above-the-knee amputation was done in seven; a resection arthrodesis, in nine; and a replacement arthroplasty, in six. The patients all walked at a similar speed (sixty-one to sixty-six meters per minute), which is slower than normal (eighty meters per minute). They all walked with comparable efficiency at three velocities: the mean consumption of oxygen was 0.210 milliliter per kilogram of body weight per meter at free velocity, 0.215 milliliter per kilogram of body weight per meter when they walked 25 per cent faster, and 0.211 to 0.240 milliliter per kilogram of body weight per meter when they walked 50 per cent faster. The three groups of patients and a normal control group consumed oxygen at similar rates. The patients who had had an amputation were very active, and they were the least worried about damaging the affected limb, but they had difficulty walking on steep, rough, or slippery surfaces. The patients who had had an arthrodesis had a more stable limb and performed the most demanding physical work and recreational activities, but they had difficulty sitting. The patients who had had an arthroplasty led sedentary lives and were the most protective of the limb, but they were the least self-conscious about the limb.
Adolescent↗
Highly sensitive determination of catecholamine and serotonin concentrations in plasma by liquid chromatography-electrochemistry.
Explore the source record for details and available documents.
Animals↗
Distribution of bronchoconstrictor responses in isolated-perfused rat lung.
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)
Acetylcholine↗
Ca2+-dependent facilitated shortening in isotonic contraction of trachealis muscle.
We compared isotonic shortening with isometric force generation as a function of external Ca2+ in 166 tracheal smooth muscle (TSM) strips from 27 mongrel dogs in vitro. Concentration-response curves were generated with muscarinic stimulation (acetylcholine, ACh), alpha-adrenergic receptor activation (norepinephrine after beta-adrenoceptor blockade, NE), serotonin (5-HT), and KCl-substituted Krebs-Henseleit solution. The concentrations of 5-HT causing half-maximal shortening (ECS50, 1.54 +/- 0.14 X 10(-7) M) and half-maximal active isometric tension (ECT50, 1.72 +/- 0.30 X 10(-7) M) were similar (P = NS). Likewise, ECS50 (21.9 +/- 0.7 mM) and ECT50, (22.0 +/- 0.9 mM) were similar for KCl. In contrast, facilitated isotonic shortening (i.e., greater isotonic shortening for comparable degrees of force generation) was elicited with ACh and NE for all levels of force generation between 15 and 85% of maximum and for all concentrations of ACh from 3 X 10(-8) to 3 X 10(-5) M (P less than 0.05 for all points). Facilitated isotonic shortening also was elicited for all concentrations of NE from 10(-8) to 10(-6) M (P less than 0.05 for all points). Removal of Ca2+ from the perfusate substantially reduced the potency of ACh (P less than 0.001) and abolished differences between ECS50 (2.23 +/- 0.28 X 10(-5) M) and ECT50 (2.50 +/- 0.46 X 10(-5) M, P = NS). We demonstrate that for comparable degrees of force generation, muscarinic and alpha-adrenergic receptor activation cause greater isotonic shortening than KCl or 5-HT and that this facilitated shortening is associated with the concentration of external Ca2+.
Acetylcholine↗
PAF-induced contraction of canine trachea mediated by 5-hydroxytryptamine in vivo.
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.
Animals↗
Tachykinins mediate bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs.
We tested the hypothesis that tachykinins mediate hyperpnea-induced bronchoconstriction (HIB) in 28 guinea pigs. Stimulus-response curves to increasing minute ventilation with dry gas were generated in animals depleted of tachykinins by capsaicin pretreatment and in animals pretreated with phosphoramidon, a neutral metalloendopeptidase inhibitor. Sixteen anesthetized guinea pigs received capsaicin (50 mg/kg sc) after aminophylline (10 mg/kg ip) and terbutaline (0.1 mg/kg sc). An additional 12 animals received saline (1 ml sc) instead of capsaicin. One week later, all animals were anesthetized, given propranolol (1 mg/kg iv), and mechanically ventilated (6 ml/kg, 60 breaths/min, 50% O2 in air fully water saturated). Phosphoramidon (0.5 mg iv) was administered to five of the noncapsaicin-treated guinea pigs. Eucapnic dry gas (95% O2-5% CO2) hyperpnea "challenges" were performed by increasing the tidal volume (2-6 ml) and frequency (150 breaths/min) for 5 min. Capsaicin-pretreated animals showed marked attenuation in HIB, with a rightward shift of the stimulus-response curve compared with controls; the estimated tidal volume required to elicit a twofold increase in respiratory system resistance (ES200) was 5.0 ml for capsaicin-pretreated animals vs. 3.7 ml for controls (P less than 0.03). Phosphoramidon-treated animals were more reactive to dry gas hyperpnea compared with control (ES200 = 2.6 ml; P less than 0.0001). Methacholine dose-response curves (10(-11) to 10(-7) mol iv) obtained at the conclusion of the experiments were similar among capsaicin, phosphoramidon, and control groups. These findings implicate tachykinin release as an important mechanism of HIB in guinea pigs.
Aminophylline↗
Effects of vasomotor- and mediator-induced hypotension on bronchomotor tone in swine.
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)
Animals↗
Evidence for platelet-activating factor secretion during immune activation in dogs.
To elucidate the potential physiological significance of platelet-activating factor (PAF) in acute bronchoconstriction, we studied the effect of Ascaris suum antigen on the tachyphylactic response to PAF in 15 natively allergic mongrel dogs in vivo. Active bronchial tension was measured isometrically, and mediator secretion was measured as the arteriovenous difference (AVd) in plasma concentration across the lungs. Administration of PAF into the bronchial artery caused dose-related contraction in five control dogs (maximal active tension = 11.8 +/- 1.68 g/cm) that paralleled the increase in the AVd for serotonin (4,188 +/- 175 pg/ml) but not histamine (maximal AVd less than 6.0 ng/ml). The response to PAF was highly tachyphylactic. In contrast to PAF, 1:10 concentration of intra-arterial antigen caused substantial release of histamine (AVd = 308 +/- 57.1 ng/ml; P less than 0.001 vs. PAF). Diminished responsiveness (2-log shift in threshold and maximal contraction; P less than 0.001) to PAF was demonstrated in five dogs after 1:10 antigen, compatible with endogenous release of PAF during prior immune challenge in the same animals. Administration of Ascaris antigen caused a leftward shift in the dose-response curve to serotonin and only mild tachyphylaxis to the maximal response to histamine. Our data are compatible with physiological participation of PAF in eliciting bronchial smooth muscle contraction during the acute phase of immune activation caused by A. suum antigen.
Animals↗
Epithelial augmentation of trachealis contraction caused by major basic protein of eosinophils.
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.
Animals↗
Effect of PAF on parasympathetic contraction of canine airways.
Platelet-activating factor (PAF) increases the bronchoconstrictor response of mammalian airways to cholinergic agonists and is thus implicated as a potential mediator of airway hyperreactivity. This study further defines the nature of the increase in airway responsiveness induced by PAF. We employed an in situ canine tracheal preparation, which allows differentiation of the effects PAF has on airway smooth muscle contraction from confounding effects it has on inducing airway edema and secretions. We found that PAF, infused regionally into tracheal arteries, increases the responsiveness of the trachealis muscle to parasympathetic stimuli in a dose-dependent manner. This effect occurred within 15 min. To determine whether the increase in trachealis muscle responsiveness resulted from effects localized to the trachea, we compared the effect of PAF on the tracheal segment with effects of the lower airways of the lung. Delivered to the arteries perfusing the tracheal segment, PAF did not increase lung resistance during vagus nerve stimulation. These data indicate that airway hyperresponsiveness elicited by PAF results from regional stimulation and/or release of mediators that augment tracheal contractility and that this effect is distinct from systemic effects elicited by PAF.
Animals↗
Expression of airway contractile properties and acetylcholinesterase activity in swine.
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.
Acetylcholinesterase↗
Beta-adrenergic relaxation of dog trachealis: contractile agonist-specific interaction.
The phenomenon of contractile agonist-dependent relaxation by isoproterenol (ISO) of active tension elicited by acetylcholine (ACh), histamine (HIS), serotonin (5-HT), and potassium chloride-substituted Krebs-Henseleit solution (KCl) was studied in 210 tracheal smooth muscle (TSM) strips from 28 mongrel dogs in vitro. All TSM strips were contracted to similar active tensions [target tension (TT) = 50% of the maximal active tension elicited by 127 mM KCl] with ACh, HIS, 5-HT, or KCl and relaxed with either ISO, forskolin (FSK), N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (db-cAMP), or 3-isobutyl-1-methylxanthine (IMX). The concentrations of ISO causing 50% relaxation from TT (RC50) were ACh (2.9 +/- 1.1 x 10(-6) M) greater than 5-HT (8.4 +/- 1.5 x 10(-8) M) approximately KCl (8.1 +/- 2.1 x 10(-8) M) greater than HIS (1.6 +/- 0.2 x 10(-8) M). FSK and IMX relaxed TSM in the same rank order of potency as ISO. In contrast to the contractile agonist-dependent relaxation elicited by ISO, FSK, and IMX, db-cAMP was nearly equipotent in relaxing similarly contracted strips. These results are consistent with contractile agonist-specific interaction with cAMP production by ISO and FSK. These data demonstrate that the phenomenon of contractile agonist-dependent relaxation by ISO is not related specifically to the beta-adrenoceptor.
1-Methyl-3-isobutylxanthine↗
Effect of beta-adrenergic blockade and sympathetic stimulation on canine bronchial mast cell response to immune degranulation in vivo.
We examined the effect of beta-adrenoceptor blockade and residual alpha-adrenoceptor effects during sympathetic stimulation on mast cell secretion of histamine in 12 natively allergic mongrel dogs. Bronchial mast cell response was measured as the arteriovenous difference (AVd) in plasma histamine concentration [H] across the bronchus. Plasma [H] was determined simultaneously from the azygos outflow tract and femoral artery as a marker of mast cell response prior to and for 90 s after intra-arterial injection of sham diluent and 1:100 and 1:30 dilutions of Ascaris suum antigen. Sympathetic (alpha-adrenergic) stimulation was elicited with continuous infusion of the nicotinic agonist, dimethylphenylpiperazinium (DMPP) under conditions of muscarinic blockade with atropine and beta-adrenoceptor blockade with propranolol. Plasma epinephrine (EPI) increased from 315 +/- 106 to 34,127 +/- 10,711 pg/ml (p less than 0.02). Control animals receiving sham infusion in place of sympathetic stimulation additionally had neural blockade with hexamethonium and alpha-adrenoceptor blockade with phentolamine. Plasma EPI was 90 +/- 58 pg/ml and did not change significantly during mast cell degranulation. Significant AVd in [H] was elicited after 1:30 A. suum antigen in both control (72.9 +/- 12.5 ng/ml versus 2.8 +/- 10.1 ng/ml at baseline; p = 0.031) and beta-adrenergically blocked (alpha-stimulated) (106.1 +/- 20.1 versus -1.5 +/- 35.9 ng/ml at baseline; p = 0.031) animals. However, alpha-adrenoceptor stimulation did not elicit significantly augmented secretion of [H]. We demonstrate that beta-adrenoceptor blockade blocks completely the inhibition of mast cell secretion caused by sympathetic stimulation with DMPP. However, alpha-adrenoceptor stimulation does not cause significant augmentation of mast cell secretion in the large airways of the dog.
Adrenergic beta-Antagonists↗
Tuberculosis control policies in major metropolitan health departments in the United States. IV. Standards in 1988.
Twenty-eight metropolitan health departments reporting greater than 250 cases annually in 1978 were surveyed to determine the standard of practice in the control of pulmonary tuberculosis and the factors affecting treatment policy. The results were compared to previous surveys in 1978, 1980, and 1984 to determine the impact of policies recommended by the Centers for Disease Control, state health departments, and other agencies. A high degree of uniformity again was demonstrated in chemoprophylaxis and hospitalization policies. However, screening, drug toxicity monitoring, and post-treatment follow-up varied widely among programs. A major trend toward short-course chemotherapy (mean duration of treatment, 20.8 +/- 2.34 months in 1980 versus 7.59 +/- 1.02 months in 1988) accompanied inclusion of pyrazinamide in first-line treatment of 59.4% of all patients in 1988 versus none in 1980. The prevalence of acquired immune deficiency syndrome (AIDS) in association with tuberculosis was estimated to be 7.72% in 1988 versus 2.52% in 1984; nine programs identified AIDS + tuberculosis in greater than 5% of all new cases in 1988 versus only two programs in 1984. Health departments identified the recommendations of the Centers for Disease Control and their respective state health departments as the major source of treatment policy; recommendations of the World Health Organization, American Academy of Pediatrics, and peer-reviewed literature had little effect upon treatment policies. This survey identifies substantial departures from prior treatment policies, some of which are attributed to reduction in available funding, development of shorter-course technology, and recognition of new groups of patients at risk to develop tuberculosis in the major cities in the major cities in the United States.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
Translation of contractile force to constriction in major diameter canine airways in vivo.
We studied the relationship between force generation and airway narrowing in the major diameter bronchi (Generations 1 to 5) in 14 mongrel dogs using tantalum bronchography in vivo. A characteristic tension-radius curve was described for each airway having two phases (different elastances). Substantial heterogeneity was demonstrated in the passive characteristics of these airways; compliance increased progressively with advancing airway generation. Changes in airway caliber elicited with intravenous infusion of methacholine (MCh) were used to calculate active force translated to airway wall tensions, and radius-tension (approximately equal to length-tension) curves were calculated for each airway after correcting for wall thickness. The resting smooth muscle length at which maximal active tension (ATmax) was elicited for each generation (expressed as percent of the initial radius; %Ri) was similar for all generations (147 +/- 7.32% for Generation 2 to 160 +/- 8.82 for Generation 5). However, ATmax decreased with advancing airway generation from 6.58 +/- 1.51 dyne/cm (Generation 2, extraparenchymal) to 1.60 +/- 0.13 dyne/cm (Generation 5, intraparenchymal; p less than 0.001). Relative change in airway diameter nonetheless was greater in smaller airways (28.2 +/- 5.1% in Generation 5) than in larger airways (15.8 +/- 3.5% in Generation 2; p less than 0.001). These data indicate that increased narrowing of more distal airways in the dog results predominantly from mechanical advantage related to smaller Ri and/or greater compressibility rather than to greater force translation from airway smooth muscle contraction, as suggested by prior investigations.
Animals↗
Comparative distribution of cholinomimetic and parasympathetic contractile responses in the major diameter airways of dogs.
The distribution of cholinomimetic and parasympathetic contractile responses in the major diameter airways and the simultaneous change in lung resistance was examined in 10 mongrel dogs in vivo. The airways of animals anesthetized with chloralose-urethane were insufflated with tantalum, and responses in airway generations 0 (trachea) through 5 were assessed as the change in airway diameter (dDaw) at functional residual capacity (FRC). All animals had beta-adrenergic blockade with propranolol to block reflex sympathetic effects resulting from hypotension. Sequential dose-response curves to 10(-10) to 10(-7) mol/kg iv methacholine (MCh; n = 5) were elicited; in separate studies, stimulus-response curves were generated (1-20 Hz; n = 5) at 7 min intervals. Tantalum bronchograms were obtained at each point on the stimulus/dose-response curve for each animal. Maximal parasympathetic stimulation caused a 28.8 +/- 4.35% dDaw in trachea, a 37.2 +/- 2.33% dDaw in generation 1 airways and a 42.4 +/- 3.63% dDaw in generation 5 airways. In contrast, cholinomimetic stimulation caused substantially less narrowing of trachea (dDaw = 8.04 +/- 2.60%; P less than 0.001 vs cholinomimetic stimulation) and generation 1 airways (21.6 +/- 2.06%; P less than 0.001) and substantially less change in airway resistance (981 +/- 107% for MCh vs 1634 +/- 173% P less than 0.01) when diameter changes in generation 5 airways were comparable (45.6 +/- 7.38% vs 42.4 +/- 3.63%; P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Antagonism of relaxation to isoproterenol caused by agonist interactions.
The interaction of contractile agonists on the relaxation elicited with isoproterenol (ISO) was studied in 112 tracheal smooth muscle (TSM) strips from 20 dogs in vitro. Strips were contracted to the same active target tension (TT) with acetylcholine (ACh), histamine (HIS), serotonin (5-hydroxytryptamine, 5-HT), potassium chloride (KCl), or the combinations of ACh + HIS, ACh + 5-HT, HIS + KCl, HIS + 5-HT (50% TT from each agonist). Although a less potent agonist, adding HIS to cause 50% of the TT reduced the concentration of ACh to elicit the remaining 50% TT and substantially altered relaxation by ISO compared with HIS alone [concentration required to achieve 50% relaxation (RC50) = 9.2 +/- 2.4 X 10(-8) vs. 9.0 +/- 4.4 X 10(-9) M to HIS alone; P less than 0.003]. Relaxation for TSM strips contracted with ACh + HIS was comparable to that elicited from the same TT with ACh alone, although concentrations required in combination were lower than for either agonist alone. Trachealis strips contracted equivalently with KCl + HIS also had augmented contraction and attenuated relaxation (RC50 = 3.7 +/- 0.8 X 10(-8) M; P less than 0.015 vs. HIS alone). However, combinations of 5-HT + ACh and 5-HT + HIS did not alter relaxation to ISO from that elicited by the weaker agonist alone. We demonstrate that TSM relaxation depends on the combination of agonists eliciting contraction and may be inhibited substantially by interactions among contractile agonists.
Acetylcholine↗