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Biomedical subjects

A R Leff

Publications and source records attributed to A R Leff.

169 records · Page 10Linked to original sources
PubMed1981

Selective autonomic stimulation of canine trachealis with dimethylphenylpiperazinium.

The response of canine tracheal muscle to autonomic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was studied isometrically in 39 dogs in vivo. Intra-arterial (ia) DMPP (2.5 X 10(-4) to 2.5 X 10(-2) mg/kg) caused selective dose related contraction [maximum 30.1 +/- 6.5 gram-force (gf)/cm] due to regional stimulation of parasympathetic ganglia. This contraction was blocked by regional administration of atropine 10(-3) mg/kg ia and hexamethonium 5 X 10(-2) mg/kg ia. Nonselective intravenous (iv) administration of DMPP 2.5 X 10(-2) mg/kg caused parasympathetic tracheal contraction [+13.4 +/- 1.64 gf/cm] followed by later sympathetic relaxation [-11.8 +/- 2.3 gf/cm]; 0.5 mg/kg iv atropine abolished contraction but did not affect relaxation. The role of the adrenal gland vs. direct sympathetic innervation in producing tracheal relaxation after sympathetic stimulation was also studied. Tracheal relaxation to 2.5 X 10(-2) mg/kg iv DMPP was -18.2 +/- 4.0 gf/cm before adrenalectomy (ADX) and -4.3 +/- 0.9 gf/cm afterward (P less than 0.001). In contrast, tracheal contraction resulting from alpha-adrenergic stimulation after 2.5 X 10(-2) mg/kg iv DMPP in beta-blocked (BB) dogs was not significantly altered by ADX. At 2.5 X 10(-1) mg/kg iv DMPP, the alpha-adrenergic contractile response was still 70% of the response prior to ADX. We conclude that sympathetic tracheal relaxation in dogs is predominantly mediated by circulating catecholamine from the adrenal gland, but that alpha-adrenergic contraction after BB results predominantly from direct sympathetic innervation and is not greatly augmented by adrenal secretion. We also report a new method for selective stimulation of airway cholinergic nerves in vivo without systemic effects.

Adrenal Glands↗
PubMed1981

Evidence for two subtypes of alpha adrenergic receptors in canine airway smooth muscle.

The contractile response of canine tracheal muscle to i.a. phenylephrine, clonidine and norepinephrine was studied isometrically in situ in 32 dogs after beta adrenergic and ganglionic blockade. Intra-arterial phenylephrine caused dose-related tracheal contraction which was not altered by yohimbine (5 microgram/kg i.a.). Prazosin (4 mg/kg i.v.) caused a 77 +/- 3% decrease in tracheal response to i.a. phenylephrine. Clonidine also caused dose-related tracheal contraction, which was not altered by prazosin (4 mg/kg i.v.) but was 95 +/- 2% blocked by 5 microgram/kg i.a. of yohimbine. Norepinephrine caused tracheal muscle contraction which was greater than both phenylephrine (P less than .05) and yohimbine (P less than .001). Prazosin (4 mg/kg i.v.) caused 53 +/- 6% blockade and yohimbine (5 microgram/kg i.a.) caused 76 +/- 2% blockade of the response to i.a. norepinephrine; prazosin plus yohimbine caused greater than 98% blockade of the response to i.a. norepinephrine. The dose-response curve to i.a. acetylcholine was not altered by treatment with prazosin (4 mg/kg i.v.) plus yohimbine (5 microgram/kg i.a.). These results demonstrate that tracheal contraction induced by sympathomimetic amines is mediated by two subtypes of alpha adrenergic receptors on tracheal muscle, alpha-1 for phenylephrine, alpha-2 for clonidine and both alpha-1 and alpha-2 for norepinephrine.

Airway Resistance↗
PubMed1981

Cholinergic and alpha adrenergic augmentation of histamine-induced contraction of canine airway smooth muscle.

The effect of i.v. methacholine (MC) and norepinephrine (NE) in causing synergistic contraction of airways with histamine was studied in 31 anesthetized dogs. Dose-response studies were performed for individual agonists and then with agonists administered together for the same animal. The additive airway contractile response to i.v. MC and histamine and i.v. NE and histamine was less than that obtained for the same doses of these agonists administered by i.v. injection together in the same syringe. Synergism was observed for 0.005 microgram/kg to 5.0 microgram/kg i.v. of MC and 0.0025 microgram/kg i.v. of histamine, as measured by change in dynamic compliance (P less than 0.1), airway resistance (P less than .001), isometric tracheal smooth muscle tension (P less than .01) and duration of the tracheal contractile response (P less than 0.005). Synergism was also observed for 0.002 microgram/kg to 2.0 microgram/kg of NE and 0.0025 microgram/kg to 2.5 microgram/kg of histamine i.v. for airway resistance and dynamic compliance (P less than .025), isometric tracheal contraction (P less than .05) and duration of tracheal contraction (P less than .01). No augmentation was observed for seven animals receiving NE and MC at any dose nor was the duration of tracheal contraction to these combined agonists greater than additive. The addition of histamine to cholinergic or alpha adrenergic stimulation results in synergistic contraction of airways and augmentation of the duration of contractile response. This effect is specific for histamine, since no augmentation is seen when MC and NE are administered together.

Airway Resistance↗
PubMed1980

Physiological and pharmacological properties of canine trachealis muscle in vivo.

In 23 dogs anesthetized with chloralose and urethan, we developed a preparation that premitted measurement of isometric tension in segments of the tracheal posterior membrane in situ. Length-tension studies showed an optimal length for contraction in each of 5 segments; in all 5 segments, length was optimal when resting tension was 22-35 g/cm. In 8 other segments, stimuli were delivered by systemic intravenous injections, by electrical stimulation of nerves, or by selective injections into the tracheal circulation; the time between delivery of repeated stimuli required for reproducible responses differed for each form of stimulation. Hypoxemia increased tension by 23.1 +/- 5.5 (SE) g/cm in 10 out of 10 other segments; these increases were the results of reflexes, not direct effects. Because the innervation and vascular supply of these segments were largely intact, we concluded that this preparation permits the study of neurohumoral mechanisms which modulate smooth muscle contraction in a prototypic central airway in vivo.

Acetylcholine↗
PubMedDate not supplied

Upregulated surface expression of intracellularly sequestered Igepsilon receptors (FcepsilonRII/CD23) following activation in human peripheral blood eosinophils.

We investigated the regulation, secretion, and surface expression of the low-affinity FcepsilonRII receptor (CD23) in eosinophils isolated from human blood using multiple monoclonal antibodies (mAbs) directed at different epitopes of human CD23. Substantial surface expression of CD23 was not demonstrated in the resting state. Mean fluorescence intensity (MFI) measured by flow cytometry was 7. 1 +/- 0.8 for 9P25 mAb (p = NS) and 15.7 +/- 3.8 for BU38 mAb (p <. 04) versus 5.3 +/- 1.0 for IgG1 isotype control Ab. By contrast, MFI using BU38 mAb was 154 +/- 18 for JY-B lymphocytes (p <.0001 versus eosinophils). Despite weak surface expression, eosinophil permeabilization demonstrated substantial intracellular expression of CD23; MFI was 33.6 +/- 5.2 for 9P25 mAb versus 4.4 +/- 0.43 for IgG control (p <.001). Western blot analysis using both positive and negative controls demonstrated immunological identity with CD23 on JY-B lymphocytes. Activation of eosinophils caused rapid translocation of CD23 to the surface membrane (160 +/- 33 MFI; p <. 005), which was maximal within 30 sec. Secretory CD23 was detected within the perfusate also at 30 sec and was fully reinternalized at 10 min. This is the first demonstration of the presence of intracellular CD23 in human eosinophils. Our data indicate that eosinophils rarely express CD23 on their surface but are capable of transient high-level expression and secretion with rapid reuptake of intracellular stores of CD23.

Cells, Cultured↗
PubMedDate not supplied

Selectivity of the intrinsic sympathomimetic activity of the beta-adrenergic blocking drug bucindolol.

We studied the comparative effects of beta-adrenergic blockade with propranolol (PROP) and bucindolol (BUC), a beta-adrenergic agonist having both alpha-adrenergic blocking properties and intrinsic sympathomimetic activity (ISA) on airway and cardiovascular responses, in 38 mongrel dogs in situ. Intravenous infusion of 0.6 mg/kg + 6 micrograms/kg/min BUC and 2.0 mg/kg + 20 micrograms/kg/min PROP caused identical shifts in the isoproterenol (ISO) EC50 for chronotropic and hypotensive arterial blood pressure responses. After PROP administration, resting heart rate (HR) decreased from 188 +/- 15 to 142 +/- 12 beats/min (p less than 0.02); BUC caused no decrease in HR. In contrast, the effects of BUC and PROP on mean arterial blood pressure response to ISO were similar. No change in bronchomotor tone was observed after bolus injection of either BUC or PROP. Beta-Adrenergic relaxation to ISO and alpha-adrenergic contraction to norepinephrine (NE) were studied simultaneously in tracheal and bronchial airways using chronotropically equivalent beta-adrenoceptor blocking doses of PROP and BUC. Comparable inhibition of ISO-induced airway relaxation after contraction with 120 micrograms/kg/min i.v. serotonin was demonstrated in both PROP (n = 5) and BUC (n = 5) groups (p less than 0.01 for doses greater than 5 X 10(-11) mol/kg). Similarly, both BUC (n = 5) and PROP (n = 5) blocked beta-adrenergic relaxation and caused identical alpha-adrenergic airway contraction to intravenous NE. We conclude that the ISA of the beta-adrenergic blocking drug BUC can be demonstrated on the spontaneous rate of the heart but not on the activity of bronchial smooth muscle. BUC neither augments ISO-induced relaxation nor inhibits NE-induced contraction of airways after effective chronotropic blockade.

Adrenergic beta-Antagonists↗