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PubMed1990

Characterization of muscarinic acetylcholine receptors in human penile corpus cavernosum: studies on whole tissue and cultured endothelium.

The binding characteristics of the muscarinic acetylcholine receptor antagonist, [3H]quinuclidinyl benzilate, to isolated membranes of human corpus cavernosum and endothelial cells, cultured from this tissue, were investigated. [3H]quinuclidinyl benzilate bound to membranes of human corpus cavernosum and endothelial cells with high affinity and limited capacity. Analysis of the binding data by Scatchard plot revealed the presence of one class of binding sites. The ligand binding specificity was determined by competitive binding assay. The data obtained show that [3H]quinuclidinyl benzilate was displaced by unlabeled competitors in the following order of efficacy in both membrane preparations: quinuclidinyl benzilate greater than scopolamine greater than atropine greater than 4-diphenylacetoxy-N-methyl-piperidine methiodide, M3 antagonist greater than pirenzepine, M1 antagonist greater than oxotremorine greater than (4-hydroxy-2-butynyl)trimethylammonium chloride m-chlorocarbanilate, M1 agonist greater than carbachol greater than hexamethonium. Solubilization of the muscarinic acetylcholine receptors from human corpus cavernosum and endothelial cells, with 1% digitonin and 0.02% cholate and subsequent analysis on sucrose density gradients, demonstrated the presence of a macromolecule specifically bound to [3H]quinuclidinyl benzilate sedimenting at the 6.2 S region of the gradient. These results demonstrate the presence of muscarinic acetylcholine receptors in human corpus cavernosum and in endothelial cells cultured from this tissue.

Binding Sites↗
PubMed1980

Ligand interactions with membrane-bound porcine atrial muscarinic receptor(s).

Ligand interactions with the membrane-bound muscarinic acetylcholine receptor in porcine atria are characterized by using [3H]quinuclidinyl benzilate [Yamamura, H. I., & Snyder, S. H. (1974) Proc. Natl. Acad. Sci. U.S.A. 71, 1725-1729] as a probe for the receptor. Antagonists and local anesthetics appear to displace quinuclidinyl benzilate from a single population of high-affinity sites while agonists appear to interact with two noninterconvertible subpopulations of quinuclidinyl benzilate binding sites. The simplest mechanism that appeared to be consistent with both kinetic and thermodynamic studies of [3H]QNB binding to the receptor required two steps. The first step, in rapid preequilibrium (K = 1.8 X 10(-9) M), was followed by a slow ligand-induced conformational change (k1 = 5.5 X 10(-3) s-1; k-1 = 3.3 X 10(-4) s-1) of the receptor-QNB complex. The overall dissociation constant calculated from the kinetic data (1.09 X 10(-10) M) was in good agreement with that determined from equilibrium measurements (Kov = 1.22 X 10(-10) M). The complex behavior of the dissociation rate constant for [3H]quinuclidinyl benzilate in the presence of competing ligands may indicate that at high concentrations these ligands either bind to a second low-affinity site(s) on the protein, altering the properties of the high-affinity site, or they nonspecifically alter the properties of the membrane, creating a second population of quinuclidinyl benzilate-receptor complexes that dissociate with an observed rate constant equal to 3 X 10(-5) s-1.

Animals↗
PubMed1990

Regional distribution of M1, M2 and non-M1, non-M2 subtypes of muscarinic binding sites in rat brain.

The distribution of subtypes of the muscarinic receptor in homogenates of the rat brain was investigated by measuring the competitive inhibition of the binding [3H]N-methylscopolamine by pirenzepine and AF-DX 116 (11[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one). In most brain regions, the competitive binding curves for AF-DX 116 and pirenzepine were consistent with a two-site model. The dissociation constant of pirenzepine for its high-affinity site (M1 receptor) was approximately 10(-8) M, whereas the dissociation constant of AF-DX 116 for its high affinity site (M2 receptor) was approximately 10(-7) M. In many regions, particularly those in the forebrain, the sum of the densities of the M1 and M2 binding sites was substantially less than 100% of the total sites, indicating the existence of a third population of sites lacking high affinity for both pirenzepine and AF-DX 116. We have designated these latter sites as non-M1, non-M2 muscarinic receptors. In general, the densities of the M1 and non-M1, non-M2 binding sites were highest in cerebral cortex, corpus striatum and hippocampus, intermediate in thalamus and hypothalamus, and lowest in midbrain, medulla-pons and cerebellum, whereas the M2 binding site had a relatively low, uniform density throughout the brain. The binding capacity of [3H]N-methylquinuclidinyl benzilate was estimated to be 20 to 30% lower than that of [3H]quinuclidinyl benzilate in various regions of the forebrain, but not in more caudal regions of the brain where the two radioligands had approximately the same binding capacities. Treatment of homogenates of the cerebral cortex with benzilylcholine mustard caused a selective loss of the majority of the [3H]N-methylscopolamine binding sites but spared 25% of the sites labeled by [3H]quinuclidinyl benzilate The results of pirenzepine/[3H]quinuclinyl benzilate competitive binding experiments on cerebral cortex treated with benzilylcholine mustard showed that the residual binding sites for [3H] quinuclidinyl benzilate were enriched in M1 muscarinic receptors.

Animals↗
PubMed1982

Two ligands may bind simultaneously to the muscarine receptor.

Competition between 3H-3-quinuclidinyl benzilate (2 and 18 nM) and varying concentrations of antagonists (4-N-methyl piperidinyl benzilate (4-NMPB), atropine, scopolamine and pirenzepine (0-1000 nM) and agonists (acetylcholine, carbamylcholine, oxotremorine and pilocarpine (0.10(-10) to 10(-2) M)) was studied. Inhibition of specific 3H-3-quinuclidinyl benzilate binding was evaluated by Dixon plots which for both competing agonists and antagonists showed deviations from linearity. The best nonlinear least square fit to the Dixon plots was offered by a hyperbola, parabola or a straight line, depending on the ligand used. The data support a model of equilibrium binding which assumes that 3H-3-quinuclidinyl benzilate and one competing ligand molecule may simultaneously bind to the receptor at high concentrations of the competing ligand.

Animals↗
PubMed1990

Muscarinic antagonist binding to intact rat thymocytes.

The presence and properties of muscarinic receptors on intact rat thymocytes have been studied by the use of the muscarinic antagonists [3H]-3-quinuclidinyl benzilate (3H-QNB), [3H]-4-N-methylpiperidinyl benzilate ([3H]-NMBP) and [3H]-N-methylscopolamine (3H-NMS). The course of binding of 3H-QNB reveals a maximum at 5 min, and shows a subsequent decrease of bound radioactivity, suggesting internalization of the receptor 3H-3-QNB complex. This phenomenon has also been studied by the use of another muscarinic antagonist, 3H-NMPB, which has a faster on and off rate than 3H-QNB, and which may be rapidly displaced by an excess of unlabeled muscarinic antagonist, atropine. Bound 3H-NMPB is highly susceptible to atropine displacement only within the first two minutes of incubation with thymocytes at 37 degrees C. The kinetics of binding of the less lipophilic muscarinic antagonist 3H-NMS to thymocytes, show no maximum as a function of incubation time and 3H-NMS is susceptible to displacement by atropine up to 30 min incubation time with the thymocytes. These data suggest that binding of lipophilic benzilate type antagonists (3H-QNB and 3H-NMPB) may be followed by internalization and/or isomerization of the receptor-benzilate antagnist complex while the 3H-NMS-receptor complex is not subject to these processes.

Animals↗
PubMed1983

Muscarinic antagonists induce different receptor conformations in rat adenohypophysis.

We have employed a method based on ligand competition experiments, which is capable of detecting interactions among ligand-occupied binding sites, to study the interactions between rat adenohypophysis muscarinic receptors occupied by several muscarinic antagonists. In this method, one examines the binding of a labeled ligand (the primary ligand) in the absence and presence of a competing ligand. The inhibition of binding of the primary ligand by the competing ligand shows significant deviations from that expected assuming a population of noninteracting, heterogeneous binding sites. The deviations seen in the case of competition between N-methyl-4-piperidyl benzilate (4NMPB) and (-)-N-methyl scopolamine (a benzilate and tropate) are more pronounced than in the case of 4NMPB and (-)-3-quinuclidinyl benzilate (two benzilate derivatives). The occurrence of such deviations suggests the existence of site-site interactions among rat adenohypophysis muscarinic receptors. On the other hand, no deviations were observed in competition experiments in homogenates of rat cortex and medulla-pons. This finding correlates with the linear Scatchard plots (with no indications for site-site interactions or heterogeneity) obtained for the binding of muscarinic antagonists in these brain regions. A mathematical analysis demonstrates that the deviations from the expectations of the site-heterogeneity model observed in the rat adenohypophysis system (which shows similar binding patterns for all ligands employed) can occur only if the primary and competing ligands induce different conformational transitions upon binding to the receptor. It is concluded that different muscarinic antagonists can lead to different isomerization states of the receptor in the system.

Allosteric Regulation↗
PubMed2005

Topography of 3H-DHA, 3H-QNB, 3H-dopamine, and 3H-DAGO binding sites distribution in the central part of the sinoatrial node in rat heart.

The topography of distribution of 3H-dihydroalprenolol, 3H-quinucledinyl benzilate, 3H-dopamine, and 3H-DAGO binding sites in the central part of the sinoatrial node in rat heart was studied by autoradiography after electrophysiological identification of the dominant pacemaker region location. Receptor asymmetry between the lateral and median regions of the central part of the sinoatrial node was shown. The dominant pacemaker region lay in the lateral area of the sinoatrial node; the number of binding sites for all four ligands was minimum in it. The number of binding sites gradually increased in the cranial and caudal directions from the dominant pacemaker region along the sinoatrial node artery (more smoothly in the caudal direction). The relative densities of bindings sites for 3H-dihydroalprenolol and 3H-dopamine were higher in the lateral region compared to the perinodal working myocardium, while the densities for 3H-quinucledinyl benzilate and 3H-DAGO were virtually the same. The distribution of binding sites along the artery in the median region of the sinoatrial node was even for 3H-quinucledinyl benzilate and 3H-DAGO. For 3H-DAGO these parameters were close to those in the perinodal atrial myocardium, for 3H-quinucledinyl benzilate somewhat lower. Curves presenting the distribution of binding site densities for 3H-dihydroalprenolol and 3H-dopamine in the median region of the sinoatrial node were similar, with a pronounced peak in the region contralateral to the dominant pacemaker region, and significantly higher binding parameters compared to those for the perinodal atrial myocardium. The difference consisted in higher density of 3H-dopamine binding sites in the median region of the sinoatrial node in comparison with the lateral region. Binding activity was maximum in the wall of the sinoatrial node artery. The distribution of binding sites for ligands to the main autonomic nervous system neurotransmitters in the rat heart sinoatrial node is heterogeneous.

Animals↗
PubMed1986

Competitive interaction of pirenzepine with rat brain muscarinic acetylcholine receptors.

In the present work, we studied the details of the interaction of the nonclassical muscarinic receptor antagonist pirenzepine with [3H]quinuclidinyl benzilate binding sites in rat brain homogenates. Pirenzepine showed biphasic competition curves with a Hill coefficient lower than unity, and these curves were better described according to a two-site receptor model. The affinities and the relative preponderance of these sites were constant at different ligand concentrations, in accordance with a competitive type of interaction. Similarly, pirenzepine did not influence the rate of dissociation of the [3H]quinuclidinyl benzilate-receptor complex, even at relatively high concentrations. However, although low concentrations of pirenzepine decreased the affinity of [3H]quinuclidinyl benzilate for the receptor without affecting the density of the binding sites, higher concentrations of the antagonist decreased the receptor number in a reversible fashion. Schild plots of these data indicated an apparent deviation from simple competition in this experimental design, an observation which can be attributed to the selectivity of pirenzepine for different receptor subtypes. Furthermore, pirenzepine, at concentrations high enough to saturate both its high- and low-affinity sites protected [3H]quinuclidinyl benzilate binding sites in the brain against irreversible alkylation by propylbenzilylcholine mustard. Therefore, our data support a competitive nature of interaction of pirenzepine with rat brain muscarinic receptors.

Animals↗
PubMed1991

Muscarinic acetylcholine receptors are expressed and enriched in growth cone membranes isolated from fetal and neonatal rat forebrain: pharmacological demonstration and characterization.

Nerve growth cones, the motile tips of growing neurites, are closely related to the exact pathway finding, and their roles for synaptogenesis have been proposed to be modified by some neurotransmitters. In the present study, to clarify the expression and the ontogeny of muscarinic acetylcholine receptors in growth cones, growth cone membranes from fetal and neonatal rat forebrain were isolated, and muscarinic receptors in growth cone membrane were pharmacologically characterized, by using the [3H]quinuclidinyl benzilate as a labeled ligand. The specific binding sites for [3H]quinuclidinyl benzilate had already been detected in growth cone membrane on embryonic day (E)17 (Bmax = 557 fmol/mg protein: KD = 19.7 pM) and gradually increased in amount without significant changes in the KD values from E17 to postnatal day (P)5. [3H]Quinuclidinyl benzilate binding sites in growth cone membrane were several times higher than that in the P2-fraction-derived membranes, and in perinuclear membranes. Competitive inhibition studies showed that the proportion of high-affinity sites for pirenzepine (M1-subtype) to total [3H]quinuclidinyl benzilate binding sites in growth cone membrane was significantly lower than that in adult synaptic plasma membranes. In contrast, the proportion of high-affinity sites for AF-DX 116 (M2-subtype) was significantly higher than that in adult synaptic plasma membranes (E17 growth cone membrane: M1, 29.5%; M2, 56.9%; adult synaptic plasma membrane: M1, 63.6%, M2, 5.9%). Electron micrographic examination revealed that there were no significant morphological differences among growth cone particle fractions at the developmental stages which we examined, and that mature synaptic elements did not contaminate the growth cone particle fractions. Biochemical examination by electrophoresis and the phosphorylation study of the growth cone particle fractions showed that the protein composition and the phosphoprotein pattern did not change markedly during these stages. Our results suggest that muscarinic receptors were expressed and more concentrated in growth cone membrane than in other membrane portions from perinatal rat forebrain, and that they may play some role in the axonal guidance in growth cone via receptor subtype-specific signal transduction mechanisms.

Animals↗
PubMed1988

On the cellular localization of cerebellar muscarinic receptors: an autoradiographic analysis of weaver, reeler, Purkinje cell degeneration and staggerer mice.

Light microscopic autoradiography of [3H]quinuclidinyl benzilate binding sites was used to study the distribution of muscarinic cholinergic receptors in mouse mutants which have abnormalities affecting specific cerebellar cell types. In the normal C57BL/6J mouse, binding sites were distributed throughout the cerebellar cortex, with the highest levels in the granule cell layer and deep cerebellar nuclei. Normal binding site density was observed in the cerebellum of the weaver mutant in which the majority of granule cells had degenerated. The density of [3H]quinuclidinyl benzilate binding sites was elevated in the cortex of the reeler, despite a reduction in the number of granule cells. The concentration of binding sites was also high over the Purkinje cell masses where granule cells were largely absent. No significant reduction in cortical [3H]quinuclidinyl benzilate binding site density was detected in the Purkinje cell degeneration mutant, in which essentially all Purkinje cells had degenerated. In contrast, receptor binding in the deep cerebellar nuclei of this mutant was significantly increased. A substantial increase in labeling was observed in the cortex and deep nuclei of the staggerer cerebellum in which a large fraction of Golgi II cells, Purkinje cells, granule cells and mossy fibers have degenerated. We discuss the possibility that the persistence of [3H]quinuclidinyl benzilate binding sites in all four mutants may imply a non-neuronal localization for a large proportion of muscarinic receptors in the mouse cerebellar cortex.

Animals↗
PubMed1995

Competitive and allosteric binding of 2 alpha-DHET and its optical isomers to rat cardiac muscarinic receptors.

The possibility of both competitive and allosteric interactions of 2 alpha-(2',2'-disubstituted-hydroxy-ethoxy)tropane (2 alpha-DHET) and its four optical isomers with rat cardiac muscarinic receptors was studied. 2 alpha-DHET and its optical isomers competitively inhibited the binding of [3H] quinuclidinyl benzilate to rat cardiac muscarinic receptors and allosterically decelerated the dissociation of bound [3H] quinuclidinyl benzilate in a concentration-dependent manner. The rank order of potencies to displace [3H] quinuclidinyl benzilate binding was 1R-2 alpha-2'R > 1S-2 alpha-2'R > 2 alpha-DHET > 1S-2 alpha-2'S > 1R-2 alpha-2'S, while their potencies to decelerate the dissociation of bound [3H] quinuclidinyl benzilate were not significantly different. The allosteric potencies were found not to be correlated with their binding potencies.

Allosteric Site↗
PubMed1982

Muscarinic acetylcholine receptors of the small intestine and pancreas of the rat: distribution and the effect of vagotomy.

1. The distribution of muscarinic cholinergic receptors (mAChR), detected by atropine-inhibitable binding of [3H] quinuclidinyl benzilate, was examined in membrane fractions of pancreas, small intestinal muscle, mucosa, villi and crypts of sham-operated and vagotomized rats. 2. Specific (atropine inhibitable) [3H] quinuclidinyl benzilate binding was greater to the ileal mucosa than to jejunal mucosa or to duodenal mucosa, but binding crypt and villus fractions was not significantly different. This distribution of specific [3H] quinuclidinyl benzilate binding suggests that cholinergic mucosal innervation is more important in the ileum than the jejunum. 3. Vagotomy produced a decrease in the amount of specific [3H] quinuclidinyl benzilate binding to duodenal mucosa only, suggesting that parasympathetic denervation of the small intestine does not cause mucosal hypersensitivity to acetylcholine by an increase in mAChR.

Acetylcholine↗
PubMed1987

Pharmacologic characterization and functional role of muscarinic autoreceptors in the rabbit striatum.

The objectives of the present studies were 1) to pharmacologically characterize the muscarinic autoreceptors in the striatum and 2) to examine their role in the regulation of physiologic acetylcholine (ACh) release. Schild plots were generated for atropine and pirenzepine against oxotremorine-induced inhibition of [3H]ACh release. Atropine, a nonselective antagonist, yielded a pA2 of 8.92. The pA2 for pirenzepine, a purported M1-selective antagonist, was 7.14. Both Schild plots had slopes not significantly different from one. Four agonists [oxotremorine, carbachol (CARB), McN-A-343 and pilocarpine] were tested for their effectiveness in inhibiting [3H]ACh release. McN-A-343 and pilocarpine have been reported to be selective for M1 receptors. Oxotremorine and carbachol were effective and potent inhibitors of [3H] ACh release, whereas McN-A-343 and pilocarpine were weak. Although the existence of muscarinic receptor subtypes remains an open question, these data are consistent with the "low" pirenzepine affinity (M2) subtype. Chronic treatments (14 days) with several agents were carried out (in vivo) to assess the role of muscarinic autoreceptors in the regulation of physiologic ACh release. Scatchard analyses of binding studies with [3H]quinuclidinyl benzilate were also performed to assess changes in the muscarinic receptor population in the striatum. Chronic treatment with scopolamine caused a 100% increase in the Bmax for [3H]quinuclidinyl benzilate binding but had no effect on the sensitivity of [3H]ACh release to inhibition by CARB. Fourteen-day treatment with physostigmine (3 mg/kg) produced a decrease in the sensitivity of [3H]ACh release to CARB plus a 42% decrease in Bmax and a 48% decrease in Kd for [3H]quinuclidinyl benzilate binding. Chronic haloperidol treatment caused an increase in the sensitivity of [3H]ACh release to CARB accompanied by a 46% increase in Bmax for 3H quinuclidinyl benzilate binding. These data suggest that muscarinic autoreceptors in the striatum do not regulate physiologic ACh release in the presence of intact acetylcholinesterase and that the interaction of dopaminergic and cholinergic neurons in the striatum may not be simple trans-synaptic inhibition.

Acetylcholine↗
PubMed1985

Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates.

The binding properties of (-)-[3H]quinuclidinyl benzilate and [3H] N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-[3H]quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of [3H]N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when [3H]N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-[3H] quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

Animals↗
PubMed1979

Isomerization of the muscarinic receptor . antagonist complex.

The mechanism of binding of two antagonists, 3-quinuclidinyl benzilate and N-methyl-4-piperidinyl benzilate, to the muscarinic receptor was studied. The pseudo-first order rate constant of association showed a hyperbolic dependence on the concentration of the antagonist(s) indicating that the interaction involves two equilibria. The first binding equilibrium is reached rapidly and is characterized by dissociation constants 2.7 +/- 0.4 nM and 6.7 +/- 2.5 nM in phosphate buffer (0.05 M, pH = 7.4) for 3-quinuclidinyl benzilate and N-methyl-4-piperidinyl benzilate, respectively. The first binding equilibrium is followed by a slower isomerization step of the receptor . antagonist complex. The equilibrium constants for the isomerization step of the complex for both ligands were about 0.15. The overall constant of binding obtained as the product of the above constants shows good agreement with the results of equilibrium binding studies.

Animals↗
PubMed2001

The role of species-dependent metabolism in the regional brain retention of 18F-labeled muscarinic acetylcholine receptor ligands.

We have developed PET radioligands for the muscarinic acetylcholine receptor designed to be sensitive to endogenous acetylcholine changes. These radioligands were based on the piperidyl and pyrrolidyl benzilate scaffold and include (R)-N-(2-[18F]fluoroethyl)-3-piperidyl benzilate (1b), (R)-N-(2-[18F]fluoroethyl)-3-pyrrolidyl benzilate (2b), and N-(2-[18F]fluoroethyl)-4-piperidyl benzilate (3b). In the mouse, intravenous injection of 2b produced a heterogeneous receptor-mediated regional retention of radioactivity, whereas in the rat a homogeneous brain distribution was observed. Analyses of blood and brain extracts showed a radiolabeled metabolite for 2b which was formed to a much greater extent in mice than rats. This metabolite may have a higher receptor binding affinity than authentic 2b, and thus be responsible for the apparent receptor-mediated binding in the mouse brain. Our findings emphasize the importance of metabolite analysis in multiple species when developing novel radiopharmaceuticals for in vivo use.

Animals↗
PubMed2007

Quantitative evaluation of the mechanism of electroreduction of benzoyl cyanides.

The mechanism of reduction of benzoyl cyanide, 6, p-methoxybenzoyl cyanide, 7, and p-chlorobenzoyl cyanide, 8, has been studied in acetonitrile (6 and 7), N,N-dimethylformamide (6), and acetonitrile containing water (all three compounds). The reaction proceeds by initial reduction to form the anion radical followed by dimerization to produce an intermediate dianion, the dianion of the dicyanohydrin of benzil. The latter loses cyanide to give the anion of the monocyanohydrin of benzil, which undergoes two parallel reactions: expulsion of cyanide to give the corresponding benzil and rearrangement to the monoanion of mandelonitrile benzoate. The addition of water brings about an increase in the dimerization rate constant and an associated increase in the amount of benzil that is produced. The standard potentials for the initial reduction step have been evaluated, and their dependence on the substituent is discussed. The dimerization rate constants have also been evaluated.

Journal Article↗
PubMed2002

Control of particle size by coagulation of novel condensation aerosols in reservoir chambers.

The coagulation growth behavior of capillary aerosol generator (CAG) condensation aerosols was investigated in a series of reservoir chambers. Aerosols consisted of a condensed system of 0.7% w/w benzil (model drug) in propylene glycol (vehicle). These were generated into 250-, 500-, 1,000-, and 2,000-mL reservoirs in both flowing air-stream and static air experiments. Changes in drug and total aerosol particle size were measured by a MOUDI cascade impactor. In both series of experiments the CAG aerosols grew in size. Growth in flowing air-stream experiments was attributed to the amount of accumulation aerosols experienced in reservoirs during sampling and increased with increasing reservoir volume. Mean (SD) MMAD's for the total mass distribution measured for the 250- and 2,000-mL reservoirs were 0.70 (0.02) and 0.87 (0.03) microm, respectively. For the benzil mass distribution, they were 0.64 (0.02) and 0.87 (0.06) microm, respectively. Growth in static air experiments was dependent on the volume aerosol boluses were restricted to and increased with decreasing reservoir volume. Mean (SD) initial MMAD's for the benzil mass distribution for the 250- and 2,000-mL reservoirs were 1.44 (0.03) and 1.24 (0.08) microm, respectively. Holding aerosols for up to 60 sec further increased their size. Mean (SD) MMAD's for benzil after holding for 60 sec in these reservoirs were 2.28 (0.04) and 1.67 (0.09) microm, respectively. The coagulation behavior and therefore particle size of CAG aerosols may be modified and controlled by reservoir chambers for drug targeting within the respiratory tract.

Aerosols↗