In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine
© Howell et al; licensee BioMed Central Ltd. 2005
Received: 06 October 2004
Accepted: 18 August 2005
Published: 18 August 2005
Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H1 receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models.
In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M2 selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M3 selective antagonist, 4-DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25–35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals.
The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors.
Antihistaminergic drugs are commonly classified into three generations. First generation antihistamines, such as diphenhydramine, effectively block the H1 receptor subtype but their use is limited due to significant central (sedation) and peripheral (tachycardia, xerostomia) antimuscarinic side effects. Second generation antihistamines, such as loratadine, retain a high selectivity for the H1 receptor and have fewer centrally mediated side effects than the first generation compounds because second generation compounds do not readily enter the central nervous system (CNS) . However, two second generation antihistamines, astemizole and terfenadine, cause prolongation of the QT interval resulting in torsades de pointes. This adverse effect prompted the removal of terfenadine from the drug market . The most recent, third generation compounds, include fexofenadine and desloratadine. These compounds are active metabolites of the second generation antihistamines, terfenadine and loratadine, respectively, and generally retain or surpass the H1 receptor selectivity of their parent compounds. For instance, desloratadine displays a higher affinity for the H1 receptor than does loratadine and antagonizes the human H1 receptor in a pseudoirreversible manner [3, 4].
Questions remain concerning the potential for antimuscarinic adverse effects with desloratadine since both in vitro and in vivo experimentation indicates that desloratadine has the ability to block muscarinic receptors. Desloratadine demonstrated in vitro IC50 values of 48 nM and 125 nM against cloned human M1 and M3 muscarinic receptor subtypes, respectively . In vivo muscarinic receptor blockade has been demonstrated in that desloratadine has been shown to inhibit pilocarpine induced salivation in mice and inhibit contractions of isolated rabbit and guinea pig iris smooth muscle [5, 6]. Therefore, these data present the need to more definitively ascertain the potential antimuscarinic activity of desloratadine, in vivo. In the present study, several in vivo models were used to further assess antimuscarinic activity of desloratadine as well as the potential for penetration of the blood-brain barrier.
Oxotremorine-induced tremor with phenylephrine pretreatment
Oxotremorine-induced salivation and lacrimation
Oxotremorine-induced changes in left ventricular contractility
Inhibition of baroreceptor reflex
The ability of desloratadine to significantly alter the baroreceptor reflex was assessed in the conscious rat. Data were expressed as the percent change from corresponding control values of blood pressure and heart rate and subsequently analyzed by linear regression. The mean slope values were then analyzed for significant differences (data not shown). Administration of desloratadine (1.0 mg/kg) prior to stimulation of the baroreceptor reflex resulted in a slope value of -0.708 ± 0.03 (mean ± SE; n = 6) with the corresponding control slope value of -0.795 ± 0.03 (n = 6) which was not a statistically significant difference. Unlike desloratadine, administration of atropine (0.5 mg/kg) prior to stimulation of the baroreceptor reflex resulted in a slope value of -0.548 ± 0.03 (n = 6) with the corresponding control slope value of -0.670 ± 0.02 (n = 6) which was a statistically significant difference (P < 0.05).
The focus of the present experiments was to determine the degree of antimuscarinic effects exerted by desloratadine at M2 and M3 receptors, in vivo. The non-selective muscarinic receptor agonist, oxotremorine , was employed as the challenge agent in the murine and rat models. Relatively selective antagonists at the M2 and M3 receptors, methoctramine [10, 11] and 4-DAMP [12, 13], respectively, were used for comparison. Our results indicate the third generation antihistaminergic agent, desloratadine, possesses a significant degree of antimuscarinic activity, primarily against cardiac M2 and M3 receptor subtypes, using in vivo whole animal preparations. However, the doses at which these activities are demonstrated exceed those normally utilized for therapeutic antihistaminergic effects. In addition, while penetration of the blood-brain barrier by desloratadine is unlikely to occur at therapeutic doses , evidence has been obtained suggesting penetration can be achieved and result in significant central antimuscarinic effects if the blood-brain barrier is compromised by administration of a vasopressor agent.
Oxotremorine-induced tremor, salivation, and lacrimation in the mouse have been used by others to evaluate the presence of antimuscarinic actions of drugs of interest [13, 15, 16]. The elicitation of tremor by oxotremorine is centrally mediated [17, 18] and blockade of this response gauges penetration of an antimuscarinic agent across the blood-brain barrier. Thus, blockade of oxotremorine-induced tremor is indirectly indicative of the potential for an antimuscarinic agent to exert central actions, such as sedation, following peripheral administration. In the presence of an intact blood-brain barrier, desloratadine did not exert significant blockade of oxotremorine-induced tremor, except at the highest dose tested (5.0 mg/kg) which caused roughly 30% reduction in tremor severity. In contrast, following treatment with the vasopressor agent, phenylephrine, to open the blood-brain barrier, a previously ineffective dose of desloratadine (1.0 mg/kg) caused a 60% reduction in tremor severity. These data suggest that while desloratadine is unlikely to exert central antimuscarinic effects at therapeutic dosages (5.0 mg recommended dose) in normal adults, considerably greater CNS penetration may occur when the blood-brain barrier is compromised. The significance of this when desloratadine is combined with a vasopressor decongestant or when infection may compromise the blood-brain barrier [19, 20] remains for further study. The present results showing blockade by pretreatment with either methoctramine or 4-DAMP, indicate that oxotremorine-induced tremor is mediated by both M2 and M3 receptors in the mouse as has been previously demonstrated by others [13, 21].
Both oxotremorine-induced lacrimation  and salivation  have been shown to be mediated selectively through the M3 receptor subtype, a mediation confirmed by the present study. Thus, while methoctramine pretreatment had no effect on either variable, 4-DAMP pretreatment was capable of reducing both lacrimation and salivation by 60–80% below control responses. In direct contrast, desloratadine inhibited neither lacrimation nor salivation at doses as high as 5 mg/kg.
The pithed, atenolol-treated rat provides a useful acute model with which to examine antimuscarinic drug action on the circulatory system in the absence of both basal and phasic sympathetic nervous system influences. The administration of oxotremorine, in this model elicits dose-dependent bradycardia, and biphasic effects on cardiac inotropy. Oxotremorine causes an initial decline in contractility, as determined by ventricular dP/dt, followed by a more prolonged positive inotropic phase. This biphasic inotropic response to a muscarinic agonist has been previously reported for acetylcholine, bethanechol, and carbachol in a variety of experimental species [24–27].
The rat heart contains multiple muscarinic receptors, including the M1 , M2 , and M3  subtypes. Of these, the M2 subtype predominates based on reverse-transcriptase polymerase chain reaction (rt-PCR) data indicating the M2 subtype constitutes more than 90% of the total muscarinic receptor mRNA, therefore, supporting its role as the major mediator of muscarinic influence over the functional state of the myocardium . However, Krejci and Tucek also demonstrated the presence of mRNA for M1 and M3 subtypes, each constituting less than 1% and 3%, respectively, of the total muscarinic receptor mRNA in the rat heart . M2 receptor agonists elicit bradycardia and a negative inotropic response through inhibition of cardiac adenylyl cyclase and/or an increase in potassium conductance via the muscarinic potassium channel [31, 32]. In contrast, effects mediated through the M1 and/or M3 receptors may lead to increased contractile strength, through enhanced activity of phospholipase C and subsequent downstream events leading to increased intracellular free calcium availability [29, 33]. Wang et al.  have recently reviewed the existence of multiple muscarinic receptors in the mammalian myocardium and have emphasized the presence of and physiological functions exerted by M3 receptors. A lesser body of data supports functional actions of the M1 subtype.
Desloratadine, at a dose of 1.0 mg/kg, effectively antagonized bradycardia and both negative and positive inotropic responses elicited by oxotremorine. Assuming adequate selectivity between cardiac muscarinic receptor subtypes, our data suggest the ability of methoctramine to blunt oxotremorine-induced negative inotropic event and the ability of 4-DAMP to blunt oxotremorine-induced positive inotropic event to be indicative of M2 and M3 receptor mediation of these phenomena, respectively. In contrast, however, both methoctramine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg) blunted oxotremorine-induced bradycardia. Therefore, the possibility exists that oxotremorine-induced bradycardia is mediated by both M2 and M3 receptor subtypes.
The context in which the present results are taken is worthy of discussion. Both in vitro receptor binding data [35–37] and results from prior in vivo studies [5, 6, 37] demonstrate a considerably greater affinity of desloratadine for histaminergic than muscarinic receptors (for reviews see, [38, 39]). Desloratadine has been found to exhibit a peak plasma concentration of approximately 28 ng/ml in healthy volunteers following a therapeutic antihistaminic dose of its parent compound, loratadine . Single oral doses of desloratadine of 5, 7.5, 10, and 20 mg yielded peak plasma concentrations of 2.18, 3.03, 3.80, and 8.08 ng/L in human volunteers . In mice, desloratadine exhibits an ED50 of 0.15 mg/kg in reduction of histamine induced paw edema . Cardelus et al.  noted local antimuscarinic effects following topical ocular administration of 1–10 mg/ml of desloratadine. However, it is unlikely that systemic concentrations of desloratadine would rise to levels approaching those in the present study following normal therapeutic dosages of desloratadine, a fact which has been emphasized by others . Thus, the antimuscarinic actions of desloratadine demonstrated in the present study would, most probably, be of significance only in overdose situations.
Our findings indicate that, at doses greater than those recommended for antihistaminergic therapy, desloratadine causes significant blockade of cardiac M2 and possibly cardiac M3 receptors, in vivo. This was demonstrated by significant inhibition of oxotremorine-mediated positive and negative inotropic events and bradycardia by desloratadine in the pithed rat. In contrast, desloratadine does not significantly antagonize the M3 receptor subtype responsible for salivation and lacrimation as demonstrated by the compound's inability to inhibit oxotremorine-mediated salivation and lacrimation in the conscious mouse and lacrimation in the anesthetized mouse. Also, under normal physiological conditions, desloratadine does not effectively cross the blood-brain barrier. However, upon disruption of this barrier, desloratadine has the potential for CNS penetration and muscarinic receptor blockade.
Drugs and solutions
Test agents included atropine sulfate, atropine methyl nitrate, diphenhydramine hydrochloride, methoctramine hydrochloride, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), and desloratadine. All were reconstituted in 1% DMSO / PBS, aliquoted into separate vials, and stored at -20°C until used. With the exception of desloratadine and 4-DAMP, all test agent concentrations were calculated using the salt weights. Atropine sulfate, atropine methyl nitrate, diphenhydramine hydrochloride, DMSO, oxotremorine sesquifumarate, atenolol, halothane, and urethane were all purchased from Sigma Chemical Co. (St. Louis, MO, USA). Other purchased agents were isoflurane (Abbott Laboratories; North Chicago, IL, USA), methoctramine hydrochloride (ICN Biochemicals, Inc.; Aurora, OH, USA), and 4-DAMP (Tocris; Ellisville, MO, USA). Desloratadine was provided by Aventis Pharmaceuticals (Bridgewater, NJ, USA).
Male Sprague Dawley rats (275–325 g) and male ICR mice (25–35 g) were purchased from Harlan Sprague Dawley and housed in plastic group shoebox cages in an AAALAC-approved Laboratory Animal Facility. Animals were housed under a twelve hour light-dark cycle with food and water ad libitum. Food was withheld twelve hours prior to experimentation or surgical procedures. All animal use protocols were approved by the University of Mississippi Medical Center Institutional Animal Care and Use Committee.
Inhibition of oxotremorine-induced tremor, salivation, and lacrimation
A murine model was used to test the ability of desloratadine to antagonize muscarinic actions induced by administration of the muscarinic agonist, oxotremorine . On the afternoon of an experiment, each mouse was weighed and placed in a clear shoebox cage for observation 15 minutes prior to any drug administration. Test agents for this experiment were vehicle, atropine sulfate (0.5 mg/kg), atropine methyl nitrate (0.5 mg/kg), diphenhydramine hydrochloride (1.0 mg/kg), methoctramine hydrochloride (0.5 mg/kg), 4-DAMP (1.0 mg/kg), and desloratadine (5.0, 1.0, 0.1, and 0.01 mg/kg). Each mouse was given a single intraperitoneal (i.p.) injection in a volume of 1 μl/g of one of the test agents. Fifteen minutes later, each mouse received a single subcutaneous (s.c.) injection of oxotremorine sesquifumarate (0.5 mg/kg), a non-selective muscarinic agonist, at the nape of the neck. At 5, 10, and 15 minutes following oxotremorine injection, each mouse was assessed for the degree of tremor and for the presence or absence of salivation and lacrimation. A modified five-point grading scale was used to evaluate tremor: 0 = no observable tremor; 0.5 = limb tremor observable when mouse is held by the tail with all feet off the cage bottom for 15 seconds; 1 = intermittent tremor, with bouts lasting from 3–5 seconds; 2 = intermittent tremor, with bouts lasting more than 5 seconds; or continuous, fine tremor noticeable on tail and ears; 3 = severe, continuous, whole-body tremor. Salivation and lacrimation were separately evaluated on a two-point scale: 0 = no observable salivation/lacrimation; 1 = salivation/lacrimation present. All responses were assessed by each of two observers with no knowledge of the pretreatment given each mouse. The grade for each mouse reflects the sum of the three consecutive observations as either Total Tremor, Total Salivation, or Total Lacrimation Score.
Inhibition of oxotremorine-induced salivation
A second paradigm, using mice (25–35 g), anesthetized with ethyl carbamate (urethane, 1.5 g/kg, i.p., 1 g/ml) was used to independently evaluate putative M3 receptor blockade inhibition of oxotremorine-induced salivation. This was modified after similar methods described for use in the rat by Lavy and Mulder . All mice were denied access to food, but not to water, for 16 hours prior to anesthetization. Test agents for this experiment were vehicle, atropine sulfate (0.5 mg/kg), diphenhydramine hydrochloride (1.0 mg/kg), methoctramine hydrochloride (0.5 mg/kg), 4-DAMP (1.0 mg/kg; free base) and desloratadine (1.0 mg/kg; free base). A single i.p. injection of one of the test agents or vehicle was administered in a volume of 1.0 μl/g five minutes following injection of urethane. Each mouse was then placed prone and head-down on a plexiglass plate inclined at 10° and covered with a sheet of Whatman no. 3 MM filter paper. Fifteen minutes after test agent administration, a 0.5 mg/kg (i.p.) dose of oxotremorine was given in a volume of 1.0 μl/g body weight. Each mouse was moved up the incline every five minutes for thirty minutes. Saliva production was quantitated at the end of each five-minute collection period by measurement of the circumference of the moist area of filter paper immediately beneath each mouse's mouth. The sum of values from the six collection periods was recorded as Total Salivation Score (TSS).
Inhibition of oxotremorine-induced tremor with phenylephrine pretreatment
Mice (30–35 g) were treated with a single i.p. injection of phenylephrine hydrochloride (10 μg/kg; 10 μL/g) to elevate systemic blood pressure and open the blood-brain barrier [7, 8]. Each mouse was then placed in an individual shoebox cage for observation. Five minutes after this, each mouse was given a second i.p. injection of either vehicle or desloratadine (free base) at a dose of 1.0 mg/kg. Fifteen minutes later, each mouse received a single s.c. injection of oxotremorine (0.5 mg/kg) at the nape of the neck. At 5, 10, and 15 minutes post oxotremorine injection, mice were observed for severity of tremor. The sum of the scores for the three time points is presented as Total Tremor Score.
Inhibition of oxotremorine-induced changes in cardiac function
The influence of oxotremorine over cardiac function in a pithed rat model was employed to evaluate muscarinic receptor antagonistic properties of desloratadine . Male rats (275–325 g) were acutely anesthetized with 2–4% isoflurane in medical grade oxygen. Polyethylene arterial (PE-50) and venous (PE-10) catheters and a tracheal cannula (PE-240) were surgically implanted to permit monitoring of arterial blood pressure and chronotropy, i.v. drug administration, and maintenance of respiration by means of a Harvard rodent respirator, respectively. A catheter (PE-50) was passed via the right carotid artery into the left cardiac ventricle for measurement of left ventricular dP/dt as an index of inotropy. Responses were obtained using either a Grass Model 7P20G differentiator and recorded on a Grass Model 7D polygraph (Grass Instrument Co.; Quincy, MASS, USA) or with PowerLab/16 SP data acquisition system using Chart for Windows v4.0 recording software (ADInstruments; Colorado Springs, CO, USA). Each rat was then pithed by insertion of a blunt stainless steel rod, 2 millimeters in diameter, through the orbit of the eye and passed through the brain and spinal column, thus destroying the central nervous system (CNS) from forebrain to the terminus of the spinal cord. Atenolol (10 mg/kg, 1.0 ml/kg, i.v.) was administered to obviate peripheral catecholamine-induced increases in cardiac function. After a 15 minute stabilization period, doses of oxotremorine (0.00125, 0.0025, 0.005, 0.01, 0.02, 0.1 mg/kg), were administered randomly and flushed with 0.1 ml of heparinized 0.9% saline. Subsequently, a single i.v. injection of one of three test agents was administered over a two minute period. The test agents were desloratadine (1.0 mg/kg, 1.0 ml/kg, i.v.), the selective M3 muscarinic receptor antagonist, 4-DAMP (1.0 mg/kg, 1.0 ml/kg, i.v.), or the selective M2 muscarinic receptor antagonist, methoctramine (0.5 mg/kg, 1.0 ml/kg, i.v.). All doses of oxotremorine were then repeated in the order they were given prior to administration of the test compound. Maximal changes in chronotropy and inotropy were measured with each injection. Values are expressed as percent of the control value taken immediately before injection of each dose of oxotremorine.
Inhibition of baroreceptor reflex
Rats (300–325 g) were used to determine the ability of desloratadine to block the vagally-mediated bradycardic component of the baroreceptor reflex. Catheters were inserted into the femoral artery (PE-50) and femoral vein (PE-10) and exteriorized between the animal's shoulders. Animals were allowed to recover for a minimum of three days. The experiment lasted two days per animal. Before the baroreceptor reflex of each animal was measured, the animal was allowed an acclimation period. The first day consisted of control baroreceptor reflex measurement. On the second day, either desloratadine (1.0 mg/kg, i.v.) or atropine (0.5 mg/kg, i.v.) was given prior to baroreceptor challenge. After an acclimation period, baroreceptor reflex measurement was repeated. The baroreceptor reflex was initiated by increasing doses of both phenylephrine and sodium nitroprusside to increase or decrease blood pressure, respectively. Dosing was discontinued when a maximal change of 50 mmHg was achieved. Blood pressure was recorded with Powerlab Data Acquisition system via a transducer attached to the arterial line. The linear regression feature in Origin 6.0 (OriginLab Corp.; Northhampton, MA) analyzed data and the slopes compared with SigmaStat 2.0 (Jandel Scientific Software; San Rafael, CA).
Data obtained from the murine models of oxotremorine-induced salivation, lacrimation, and tremor were analyzed using a one-way repeated measures ANOVA with a Dunn's post hoc test. Data obtained from animals pretreated with either phenylephrine or vehicle was analyzed via the paired t-test. Inhibition of oxotremorine-induced alterations in cardiac function before and after either desloratadine, methoctramine, or 4-DAMP administration was analyzed via the paired t-test with changes in cardiac function at each dose of oxotremorine being compared. In all statistical comparisons, P ≤ 0.05 was deemed statistically significant.
This work was supported by a grant from Aventis Pharmaceuticals and in part by an award from the Howard Hughes Medical Institute.
- Kay GG, Harris AG: Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation. Clin Exp Allergy. 1999, 29 Suppl 3: 147-150. 10.1046/j.1365-2222.1999.0290S3147.x.View ArticlePubMedGoogle Scholar
- DuBuske LM: Second-generation antihistamines: the risk of ventricular arrhythmias. Clin Ther. 1999, 21: 281-295. 10.1016/S0149-2918(00)88286-7.View ArticlePubMedGoogle Scholar
- Anthes JC, Gilchrest H, Richard C, Eckel S, Hesk D, West REJ, Williams SM, Greenfeder S, Billah M, Kreutner W, Egan RE: Biochemical characterization of desloratadine, a potent antagonist of the human histamine H(1) receptor. Eur J Pharmacol. 2002, 449: 229-237. 10.1016/S0014-2999(02)02049-6.View ArticlePubMedGoogle Scholar
- Handley DA, McCullough JR, Fang Y, Wright SE, Smith ER: Descarboethoxyloratadine, a metabolite of loratadine, is a superior antihistamine. Ann Allergy Asthma Immunol. 1997, 78: P164-Google Scholar
- Cardelus I, Puig J, Bou J, Jauregui J, Llenas J, Fernandez AG, Palacios JM: Xerostomia and mydriasis, two muscarinic peripheral side effects associated with descarboethoxyloratadine, the main metabolite of loratadine. Br J Pharmacol. 1998, 123: 267P-Google Scholar
- Cardelus I, Anton F, Beleta J, Palacios JM: Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle. Eur J Pharmacol. 1999, 374: 249-254. 10.1016/S0014-2999(99)00310-6.View ArticlePubMedGoogle Scholar
- Mayhan WG: Disruption of blood-brain barrier during acute hypertension in adult and aged rats. Am J Physiol. 1990, 258: H1735-H1738.PubMedGoogle Scholar
- Kramer JM, Aragones A, Waldrop TG: Reflex cardiovascular responses originating in exercising muscles of mice. J Appl Physiol. 2001, 90: 579-585.PubMedGoogle Scholar
- Ringdahl B, Jenden DJ: Pharmacological properties of oxotremorine and its analogs. Life Sci. 1983, 32: 2401-2413. 10.1016/0024-3205(83)90365-X.View ArticlePubMedGoogle Scholar
- Giraldo E, Micheletti R, Montagna E, Giachetti A, Vigano MA, Ladinsky H, Melchiorre C: Binding and functional characterization of the cardioselective muscarinic antagonist methoctramine. J Pharmacol Exp Ther. 1988, 244: 1016-1020.PubMedGoogle Scholar
- Wess J, Angeli P, Melchiorre C, Moser U, Mutschler E, Lambrecht G: Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo. Naunyn Schmiedebergs Arch Pharmacol. 1988, 338: 246-249. 10.1007/BF00173395.View ArticlePubMedGoogle Scholar
- Moriya H, Takagi Y, Nakanishi T, Hayashi M, Tani T, Hirotsu I: Affinity profiles of various muscarinic antagonists for cloned human muscarinic acetylcholine receptor (mAChR) subtypes and mAChRs in rat heart and submandibular gland. Life Sci. 1999, 64: 2351-2358. 10.1016/S0024-3205(99)00188-5.View ArticlePubMedGoogle Scholar
- Sanchez C, Lembol HL: The involvement of muscarinic receptor subtypes in the mediation of hypothermia, tremor, and salivation in male mice. Pharmacol Toxicol. 1994, 74: 35-39.View ArticlePubMedGoogle Scholar
- Clissold SP, Sorkin EM, Goa KL: Loratadine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1989, 37: 42-57.View ArticlePubMedGoogle Scholar
- Watanabe T, Kakefuda A, Tanaka A, Takizawa K, Hirano S, Shibata H, Yamagiwa Y, Yanagisawa I: Synthesis and biological evaluation of phenylacetyl derivatives having low central nervous system permeability as potent and selective M2 muscarinic receptor antagonists. Chem Pharm Bull (Tokyo). 1998, 46: 53-68.View ArticleGoogle Scholar
- Lavy UI, Mulder D: Salivary inhibition in mice and rabbits by a number of anticholinergics. A methodological investigation. Arch Int Pharmacodyn Ther. 1969, 178: 437-445.PubMedGoogle Scholar
- Espinola EB, Oliveira MG, Carlini EA: Differences in central and peripheral responses to oxotremorine in young and aged rats. Pharmacol Biochem Behav. 1999, 62: 419-423. 10.1016/S0091-3057(98)00192-0.View ArticlePubMedGoogle Scholar
- Sanchez C, Meier E: Central and peripheral mediation of hypothermia, tremor and salivation induced by muscarinic agonists in mice. Pharmacol Toxicol. 1993, 72: 262-267.View ArticlePubMedGoogle Scholar
- Boje KM: Inhibition of nitric oxide synthase attenuates blood-brain barrier disruption during experimental meningitis. Brain Res. 1996, 720: 75-83. 10.1016/0006-8993(96)00142-4.View ArticlePubMedGoogle Scholar
- Mayhan WG: Effect of lipopolysaccharide on the permeability and reactivity of the cerebral microcirculation: role of inducible nitric oxide synthase. Brain Res. 1998, 792: 353-357. 10.1016/S0006-8993(98)00259-5.View ArticlePubMedGoogle Scholar
- Bymaster FP, Carter PA, Zhang L, Falcone JF, Stengel PW, Cohen ML, Shannon HE, Gomeza J, Wess J, Felder CC: Investigations into the physiological role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice. Life Sci. 2001, 68: 2473-2479. 10.1016/S0024-3205(01)01041-4.View ArticlePubMedGoogle Scholar
- Nakamura M, Tada Y, Akaishi T, Nakata K: M3 muscarinic receptor mediates regulation of protein secretion in rabbit lacrimal gland. Curr Eye Res. 1997, 16: 614-619. 10.1076/ceyr.16.6.614.5077.View ArticlePubMedGoogle Scholar
- Schiavone A, Brambilla A: Muscarinic M3 receptors mediate secretion from sweat glands in the rat. Pharmacol Res. 1991, 23: 233-239.View ArticlePubMedGoogle Scholar
- Du XY, Schoemaker RG, Bos E, Saxena PR: Characterization of the positive and negative inotropic effects of acetylcholine in the human myocardium. Eur J Pharmacol. 1995, 284: 119-127. 10.1016/0014-2999(95)00384-W.View ArticlePubMedGoogle Scholar
- Eglen RM, Montgomery WW, Whiting RL: Negative and positive inotropic responses to muscarinic agonists in guinea pig and rat atria in vitro. J Pharmacol Exp Ther. 1988, 247: 911-917.PubMedGoogle Scholar
- Nishimaru K, Tanaka Y, Tanaka H, Shigenobu K: Positive and negative inotropic effects of muscarinic receptor stimulation in mouse left atria. Life Sci. 2000, 66: 607-615. 10.1016/S0024-3205(99)00633-5.View ArticlePubMedGoogle Scholar
- Yang JM, Chung KT, Yang SN: Muscarinic activation causes biphasic inotropic response and decreases cellular Na+ activity in canine cardiac Purkinje fibers. J Biomed Sci. 1999, 6: 176-182. 10.1159/000025385.PubMedGoogle Scholar
- Sharma VK, Colecraft HM, Wang DX, Levey AI, Grigorenko EV, Yeh HH, Sheu SS: Molecular and functional identification of m1 muscarinic acetylcholine receptors in rat ventricular myocytes. Circ Res. 1996, 79: 86-93.View ArticlePubMedGoogle Scholar
- Ponicke K, Heinroth-Hoffmann I, Brodde OE: Demonstration of functional M3-muscarinic receptors in ventricular cardiomyocytes of adult rats. Br J Pharmacol. 2003, 138: 156-160. 10.1038/sj.bjp.0704997.PubMed CentralView ArticlePubMedGoogle Scholar
- Krejci A, Tucek S: Quantitation of mRNAs for M(1) to M(5) subtypes of muscarinic receptors in rat heart and brain cortex. Mol Pharmacol. 2002, 61: 1267-1272. 10.1124/mol.61.6.1267.View ArticlePubMedGoogle Scholar
- Dhein S, van Koppen CJ, Brodde OE: Muscarinic receptors in the mammalian heart. Pharmacol Res. 2001, 44: 161-182. 10.1006/phrs.2001.0835.View ArticlePubMedGoogle Scholar
- McMorn SO, Harrison SM, Zang WJ, Yu XJ, Boyett MR: A direct negative inotropic effect of acetylcholine on rat ventricular myocytes. Am J Physiol. 1993, 265: H1393-H1400.PubMedGoogle Scholar
- Gallo MP, Alloatti G, Eva C, Oberto A, Levi RC: M1 muscarinic receptors increase calcium current and phosphoinositide turnover in guinea-pig ventricular cardiocytes. J Physiol. 1993, 471: 41-60.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang Z, Shi H, Wang H: Functional M3 muscarinic acetylcholine receptors in mammalian hearts. Br J Pharmacol. 2004, 142: 395-408. 10.1038/sj.bjp.0705787.PubMed CentralView ArticlePubMedGoogle Scholar
- Haria M, Fitton A, Peters DH: Loratadine. A reappraisal of its pharmacological properties and therapeutic use in allergic disorders. Drugs. 1994, 48: 617-637.View ArticlePubMedGoogle Scholar
- Gupta S, Banfield C, Affrime M, Marco A, Cayen M, Herron J, Padhi D: Desloratadine demonstrates dose proportionality in healthy adults after single doses. Clin Pharmacokinet. 2002, 41 Suppl 1: 1-6.View ArticlePubMedGoogle Scholar
- Kreutner W, Hey JA, Anthes J, Barnett A, Young S, Tozzi S: Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects. Arzneimittelforschung. 2000, 50: 345-352.PubMedGoogle Scholar
- Geha RS, Meltzer EO: Desloratadine: A new, nonsedating, oral antihistamine. J Allergy Clin Immunol. 2001, 107: 751-762. 10.1067/mai.2001.114239.View ArticlePubMedGoogle Scholar
- Henz BM: The pharmacologic profile of desloratadine: a review. Allergy. 2001, 56 Suppl 65: 7-13. 10.1034/j.1398-9995.2001.00101.x.View ArticlePubMedGoogle Scholar
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