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PubMed1959

Human urinary kinin excretion.

It has been shown that the isolated rat duodenum relaxes in the presence of low concentrations of plasma and urinary kinin. The tissue is at least as sensitive as the rat uterus. Vasopressin and oxytocin, in large doses, also caused relaxation of the duodenum whereas acetylcholine, substance P and 5-hydroxytryptamine caused contraction. It was concluded that if an extract is assayed on the rat uterus and the rat duodenum in parallel using plasma kinin as a standard, and the results agree, this is good evidence that the active principle being estimated is a kinin. This method is therefore both sensitive and specific for kinin estimations, but it will not distinguish between kinins of different origin. The urinary excretion of kinin in 14 healthy adults was found to be fairly constant. The minute output was unaffected by the rate of urine formation, urinary pH, or time of day. There was no increase during sweating or salivation.

Adult↗
PubMed1973

Some initial animal and human pharmacological studies with benapryzine (BRL 1288).

1. The pA2 anti-acetylcholine activity in vitro for benapryzine was 6.55 compared with 9.02 for benzhexol.2. In vivo, the anti-acetylcholine activity of benapryzine relative to benzhexol was 0.038 as assessed by the mydriatic response of mice after subcutaneous administration. The relative activity assessed by the inhibition of pilocarpine-induced salivation was 0.13 after oral administration and 0.056 following subcutaneous administration of the drugs.3. Benapryzine had the same order of activity as benzhexol in inhibiting oxotremorine-induced tremors in mice.4. Benapryzine had anticonvulsant properties but no analgesic activity, whilst in high doses it antagonized the extrapyramidal symptoms induced by perphenazine in rats.5. In patients benapryzine was effective in reducing the symptoms of Parkinson's disease without overt anti-cholinergic effects or central hallucinogenic actions.6. Benapryzine abolished the excess tremor and reduced the rigidity and akinesia induced by physostigmine in Parkinsonian subjects.

Acetylcholine↗
PubMed1980

Pharmacological analysis of salivary and blood flow responses to histamine of the submandibular gland of the dog.

1 The submandibular gland in situ was perfused with blood through the glandular artery at constant pressure in anaesthetized dogs. Drugs were administered intra-arterially. 2 Histamine produced both salivation and an increase in blood flow, each response having an early and a late component. 3 Marked tachyphylaxis to histamine developed in both of the salivary responses but only in the late blood flow response to histamine. 4 The early and late salivary responses were abolished and the late blood flow response was diminished by infusion of tetrodotoxin in doses that abolished the salivary and blood flow responses to electrical stimulation of the chorda-lingual nerve. 5 The whole salivary response to histamine was abolished by infusion of (--)-hyoscyamine in doses that greatly antagonized the salivary and blood flow responses to acetylcholine, whereas the blood flow responses to histamine were scarcely modified. These doses of (--)-hyoscyamine abolished the salivary response to chorda-lingual nerve stimulation but left the blood flow response to it unaffected. 6 The salivary and blood flow responses to histamine were unaffected by infusion of hexamethonium in doses that almost abolished the salivary and blood flow responses to chorda-lingual nerve stimulation. 7 The whole salivary response to histamine was abolished and the late blood response to histamine was partially inhibited by the histamine H1-receptor antagonist, mepyramine, but not by the histamine H2-receptor antagonist, metiamide. 8 The early blood flow response to histamine was antagonized by both mepyramine and metiamide but mepyramine was far more effective than metiamide. 9 These results led to the following conclusions: (1) the whole salivary response and a part of the late blood flow response to histamine are due entirely to excitation of parasympathetic postganglionic neurones; (2) neuronal histamine receptors involved are exclusively of the H1-type; (3) histamine has no direct stimulant action on the glandular cells; (4) the early blood flow response and the remaining part of the late blood flow response to histamine result from the direct action on vascular smooth muscle in the glandular vascular bed; (5) vascular histamine receptors consist of H1- and H2-receptors.

Animals↗
PubMed1982

Comparison of the actions of centrally and peripherally administered clonidine and guanfacine in the rabbit: investigation of the differences.

1 Guanfacine was administered intravenously to rabbits and produced a dose-dependent lowering of blood pressure. 2 Clonidine and guanfacine, administered to rabbits intravenously (30 micrograms/kg and 300 micrograms/kg respectively) and intracisternally (3 micrograms/kg and 12 micrograms/kg respectively) caused a similar degree of hypotension, apparently of central origin. 3 Saliva flow in vivo was estimated. Clonidine (30 micrograms/kg, i.v.) caused a significant decrease in salivation (P less than 0.05) for the first 50 min after injection. Guanfacine caused a significant fall (P less than 0.05) only at 50 and 180 min after injection. 4 Apparent partition coefficients for an octanol/buffer system at pH 7.4 for clonidine and guanfacine were 5.4 and 21.2 respectively. 5 Measurement of guanfacine levels concurrently in both plasma and brain showed that guanfacine had higher brain than plasma levels and that the brain levels were fairly constant over the 3 h measured. Brain:plasma ratios were 2.1:1, 5.3:1 and 13.6:1 after 15, 90 and 180 min respectively. 6 These results suggest that the long duration of action of guanfacine is due to its persistence at its central site of action.

Animals↗
PubMed2007

Oral submucous fibrosis: study of 1000 cases from central India.

BACKGROUND: Very few reports have been published on the gender specificity of oral submucous fibrosis (OSF) in relation to habit patterns and the severity of disease in the world literature. The purpose of the study was to ascertain the gender specificity for different habits and severity of OSF. METHODS: A hospital-based cross-sectional study on various habit patterns associated with OSF was performed in Nagpur over a 5-year period. A total of 1000 OSF cases from 266,418 out patients comprised the study sample. RESULTS: The male-to-female ratio of OSF was 4.9:1. Occurrence of OSF was at a significant younger age group (<30 years) among men when compared with women (OR = 4.62, 3.22-6.63, P = 0.0001). Reduced mouth opening, altered salivation and altered taste sensation were found to be significantly more prevalent in women when compared with men. Exclusive areca nut chewing habit was significantly more prevalent in women (OR = 44.5, 25.4-79.8, P = 0.0001). Whereas significant increase for Gutkha (Areca quid with tobacco) (OR = 2.33, 1.56-3.54, P = 0.0001) and kharra/Mawa (crude combination of areca nut and tobacco) (OR = 6.8, 4.36-11.06, P = 0.0001) chewing was found in men when compared with women. CONCLUSIONS: There is a marked difference in literacy, socioeconomic status, areca nut chewing habits, symptoms and disease severity in women when compared with men in the central Indian population.

Adolescent↗
PubMed2005

A synergistic chlorhexidine/chitosan combination for improved antiplaque strategies.

BACKGROUND: The minor efficacy of chlorhexidine (CHX) on other cariogenic bacteria than mutans streptococci such as Streptococcus sanguinis may contribute to uneffective antiplaque strategies. METHODS AND RESULTS: In addition to CHX (0.1%) as positive control and saline as negative control, two chitosan derivatives (0.2%) and their CHX combinations were applied to planktonic and attached sanguinis streptococci for 2 min. In a preclinical biofilm model, the bacteria suspended in human sterile saliva were allowed to attach to human enamel slides for 60 min under flow conditions mimicking human salivation. The efficacy of the test agents on streptococci was screened by the following parameters: vitality status, colony-forming units (CFU)/ml and cell density on enamel. The first combination reduced the bacterial vitality to approximately 0% and yielded a strong CFU reduction of 2-3 log(10) units, much stronger than CHX alone. Furthermore, the first chitosan derivative showed a significant decrease of the surface coverage with these treated streptococci after attachment to enamel. CONCLUSIONS: Based on these results, a new CHX formulation would be beneficial unifying the bioadhesive properties of chitosan with the antibacterial activity of CHX synergistically resulting in a superior antiplaque effect than CHX alone.

Anti-Infective Agents, Local↗
PubMed1997

Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine.

PNU-200577 (labcode DD 01 [(R)-N, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine ) is a major pharmacologically active metabolite of tolterodine, a new muscarinic receptor antagonist intended for the treatment of an overactive bladder. In vitro, PNU-200577 produced a competitive and concentration-dependent inhibition of carbachol-induced contraction of guinea-pig isolated urinary bladder strips (KB = 0.84 nM; pA2 = 9.14). In vivo, PNU-200577 was significantly more potent at inhibiting acetylcholine-induced urinary bladder contraction than electrically induced salivation in the anaesthetised cat (ID50 15 and 40 nmol.kg-1, respectively; P < 0.01). In radioligand binding studies carried out in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic m1-m5 receptors, PNU-200577 was not selective for any muscarinic receptor subtype. Thus, PNU-200577 is similar to tolterodine in terms of antimuscarinic potency, functional selectivity for the urinary bladder in vivo and absence of selectivity for muscarinic receptor subtypes in vitro. The results of this study clearly indicate that PNU-200577 contributes to the therapeutic action of tolterodine, in view of its high antimuscarinic potency, similar serum concentration and lower degree of protein binding.

Acetylcholine↗
PubMed1995

Comparison of the effect of the linseed extract Salinum and a methyl cellulose preparation on the symptoms of dry mouth.

The effect of a linseed extract Salinum and a sodium carboxymethyl cellulose preparation called MAS-84 was compared with regard to its effect on the symptoms of dry mouth. Twenty patients with xerostomia, who had been treated for cancer in the head and neck by radiation were recruited from the clinic for maxillofacial surgery, Malmo University Hospital. Following radiation treatment the salivation was severely reduced. The symptoms of a general feeling of a dry mouth, difficulties in chewing and swallowing, taste disturbances, problems with speech and mouth burning were registered on a subjective verbal rating scale. In addition plaque index and gingival bleeding were determined. The study design was crossover and performed single blind. The experimental period was 7 weeks. The patients were randomly divided into 2 groups. One group used Salinum and the other MAS-84 for 3 weeks. The fourth week was a wash out period and for the next three weeks the patients shifted preparation. Each of the preparations was used ad libitum. Registrations of the various parameters were undertaken on days 0, 7 and 21 of the respective period. At the initial examination all patients reported considerable disturbances from mouth-dryness. These symptoms were reduced in 15 patients during the Salinum period and in 9 during the MAS-84 period. The relief was significantly more pronounced during the use of Salinum compared to that during the use of the methyl cellulose preparation. On day 21 plaque and gingival bleeding were significantly reduced during the Salinum period but not during the MAS-84 period. The results of the present study confirm those of a previous pilot study and indicate that the linseed mucilage significantly reduced the symptoms of dry mouth. This effect increased with increasing time of saliva substitute use. The linseed mucilage Salinum appeared to be a suitable saliva replacement in mouth dry patients.

Aged↗
PubMed1991

Parotid secretion of fluid, amylase and kallikrein during reflex stimulation under normal conditions and after acute administration of autonomic blocking agents in man.

The purpose of this work was to study the effect of graded mechanical and gustatory stimulation on the secretion of the acinar products fluid and amylase and the ductal product kallikrein from the human parotid gland (n = 9). The involvement of parasympathetic and sympathetic nerves in the salivary reflexes was subsequently examined using receptor blocking agents (n = 4). Chewing elevated the secretion of all products as compared to rest (P less than 0.013). When increasing the length of the chewing object, secretion of fluid (P less than 0.013), but not enzymes, further increased. The shift from mechanical to gustatory stimulation with 0.5% citric acid enhanced significantly the secretion of amylase and kallikrein (P less than 0.009), while application of 5.0% citric acid increased the secretion of both acinar products (P less than 0.009) more than kallikrein. A differentiated reflex control of salivation both with regard to input and output was thereby indicated. The muscarinic-cholinergic antagonist oxyphencyclimin reduced median fluid secretion between 54 and 76% depending on the stimuli. During citric acid stimulation, but not during chewing, fluid secretion was reduced about 40% by the beta 1-adrenergic antagonist metoprolol, and about 20% by the alpha 1-adrenergic antagonist prazosin. Median amylase secretion was reduced 30% during chewing and 75% during gustatory stimulation by metoprolol. It was concluded that the masticatory-salivary reflex mainly activated parasympathetic pathways producing saliva of low protein content.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Xerostomic complaints induced by an anti-sialogogue in healthy young vs. older adults.

Complaints of xerostomia and salivary hypofunction are common in older adults. However, recent studies reported that dehydration-induced salivary hypofunction caused fewer xerostomic complaints in older compared with young adults. This may predispose older adults to developing oral problems that will subsequently not receive attention from health care providers. Since many medications are known to inhibit salivation, this study attempted to determine if an anticholinergic drug (glycopyrrolate) had a differential effect on xerostomic complaints in young vs. older adults. Eighteen young (age 20-38 yrs) and 18 older (age 60-77 yrs) healthy adults were given a 4.0 micrograms/kg dose of i.v. glycopyrrolate. For 6 hrs after drug administration, stimulated parotid salivary flow was collected, and an eight-item Visual Analogue Scale (VAS) subjective xerostomia test was given. At several time points post-i.v. glycopyrrolate, salivary flow rates were consistently lower in older compared with young adults. For some measures of xerostomic complaint (time to first complaint; time to maximum complaint; mean maximum complaint), there were no age-related differences for all VAS items. However, a trend for increased xerostomic complaints in older adults was demonstrated (time to recovery; total duration of complaint; number xerostomic at 6 hrs). These findings suggest that, given equal doses of an anti-sialogogue, salivary hypofunction is greater in healthy older adults, while increased complaints of xerostomia are not as consistent.

Adult↗
PubMed1989

Salivatory effects induced by pirenzepine, atropine, metacine and hexamethonium in preganglionar chronically denervated human parotid gland.

Both classical (atropine) and non-traditional (pirenzepine, metacine) antagonists of the muscarinic cholinoreceptors induce, rather than block, an intense and prolonged salivary response in chronically denervated human parotid glands and thus are capable of discriminating between neuronal and aneuronal receptors. Hexamethonium (benzohexonium) a ganglion-blocking agent (0.4 mL, 2.5%) completely inhibits this paradoxical salivation to atropine, benzilylcholine (metacine) and pirenzepine in the chronic preganglionically denervated human parotid gland. The authors discuss the essence of the revealed paradoxical phenomena.

Adult↗
PubMed1993

Dependency of salivary excretion of mexiletine on the plasma concentration in rats.

The effect of steady-state plasma concentrations on the salivary excretion of mexiletine was investigated following simultaneous bolus intravenous injection of the loading dose (2.7 or 16.1 mg kg-1) and constant-rate intravenous infusion of the maintenance dose (15 or 102 micrograms min-1 kg-1) in male Wistar rats. Parotid and mandibular saliva was collected separately by stimulating salivation with a constant-rate infusion of pilocarpine (50 micrograms kg-1 min-1) in each rat. The low and high steady-state levels of mexiletine in blood plasma were attained at 0.259 +/- 0.123 and 1.616 +/- 0.475 micrograms mL-1, respectively, within the first 1-2 h after drug administration. Similarly, the two different steady-states in both parotid and mandibular saliva were attained. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva at any steady-state (P < 0.001 or 0.01). In parotid saliva, the high steady-state produced greater saliva to plasma drug concentration ratios (S/P ratio, 0.475 +/- 0.160) than that (0.386 +/- 0.131) at the low steady-state (P < 0.05). The S/P ratio for mandibular saliva at the high (0.204 +/- 0.060) steady-state was also greater than that at the low (0.158 +/- 0.050) steady-state (P < 0.01). These changes in the S/P ratio could not be explained by the pH for either parotid or mandibular saliva, but partially by the change in the unbound fraction of the drug which tended to be consistent with that in the ratio for both salivary glands. These findings suggest that the salivary excretion of mexiletine may be dependent on the plasma unbound concentration in rats.

Animals↗
PubMed1977

Is the lemon test an index of arousal level?

On the basis of numerous studies, it was predicted that salivary output to lemon juice would increase in a noisy relative to a quiet environment. Following the accepted procedure (Corcoran, 1964) salivary output to lemon juice was measured under quiet conditions; then experimental subjects selected a level of noise 'just too loud for comfort' and the salivary index was reassessed. Controls were treated identically except that both measures were conducted in the quiet. It was found that salivation increased in noise, and the weight of saliva produced correlated with the level of noise chosen.

Acoustic Stimulation↗
PubMed1967

Temperature effects produced in dogs and monkeys by injections of monoamines and related substances into the third ventricle.

1. In dogs the effects on rectal temperature of noradrenaline, adrenaline, 5-hydroxytryptamine (5-HT) and of the monoamine oxidase inhibitor tranylcypromine were studied following their injection into the third ventricle through a chronically implanted cannula. Tranylcypromine was given also by the intraperitoneal route.2. The hypothermic effect of the catecholamines and the hyperthermic effect of 5-HT previously demonstrated in anaesthetized dogs were obtained also in an unanaesthetized dog, but 5-HT was effective only in doses under 20 mug.3. Tranylcypromine (1 mg) injected into the third ventricle of dogs anaesthetized with pentobarbitone sodium produced shivering and a rise in temperature.4. Tranylcypromine (10 mg/kg) injected intraperitoneally caused a rise in temperature in the unanaesthetized dog. For a time shivering and panting, two effects which produce opposite change in temperature, were observed together. When injected shortly before an intraperitoneal injection of an anaesthetizing dose of pentobarbitone sodium, tranylcypromine not only prevented the fall in temperature which is normally produced by the anaesthetic but caused a greater and longer lasting rise than when given alone.5. The intraperitoneal injections of tranylcypromine produced profuse salivation, a peripheral effect which persisted after acute denervation and which was not abolished by atropine or tolazoline.6. In rhesus monkeys anaesthetized with intraperitoneal pentobarbitone sodium, noradrenaline, adrenaline, 5-HT and 5-hydroxytryptophan (5-HTP) were injected into the cannulated third ventricle. The catecholamines caused a fall in rectal temperature. No evidence was obtained that the fall resulted from a rise in hypothalamic temperature. The injections of 5-HT or of its precursor 5-HTP raised rectal temperature. Monkeys thus respond to the monoamines injected intraventricularly, in the same way as cats and dogs, and unlike rabbits, sheep, goats, oxen and rats.

Animals↗
PubMed1990

Modes of action of local hypothalamic and skin thermal stimulation on salivary secretion in rats.

1. In urethane or ketamine-anaesthetized rats, salivary secretion was observed when local brain sites or trunk skin were stimulated thermally or electrically. 2. Salivary secretion was facilitated by bilateral local brain warming. Sensitive sites were restricted to the preoptic area and anterior hypothalamus, but in a region distinct from a previously reported sensitive site for producing saliva-spreading behaviour. 3. Unilateral warming of the preoptic area produced greater salivary secretion from the ipsilateral submandibular/sublingual salivary glands than from the contralateral glands. Electrical stimulation of the same sites elicited salivation only from the ipsilateral glands. 4. Trunk skin, not including the scrotum, was unilaterally cooled when spontaneous salivary secretion was observed in a hot environment. Salivary secretion from both sides was equally suppressed in response to the unilateral skin cooling. 5. We conclude that efferent signals from the anterior part of the hypothalamus project dominantly to the ipsilateral salivary gland for thermally induced salivary secretion. Thermal signals from the skin of either side of the trunk, on the other hand, appear to be integrated and to affect salivary secretion bilaterally.

Animals↗
PubMed1993

Nitric oxide-related vasodilator responses to parasympathetic stimulation of the submandibular gland in the cat.

1. The extent to which parasympathetic vasodilator responses, in the submandibular gland of the cat, depend upon release of nitric oxide related (NO chi) or endothelium-derived relaxing factor (EDRF) within the gland has been investigated in anesthetized cats given N omega-nitro-L-arginine methyl ester (L-NAME) which specifically blocks the synthesis of EDRF from arginine. 2. Close intra-arterial infusions of L-NAME (> or = 100 mg kg-1) produced a steady and significant rise in mean aortic pressure together with a steady increase in basal submandibular vascular resistance over the next 20-30 min, which persisted thereafter. 3. In cats pretreated with propranolol, to block beta-adrenoceptor-mediated vasodilatation, salivation and vasodilatation in response to stimulation of the chorda-lingual nerve were reduced but not abolished by L-NAME (> or = 100 mg kg-1, I.A.). Subsequent administration of atropine (> or = 1 mg kg-1 I.V.) completely suppressed the secretory response and virtually eliminated the vascular response. 4. In cats pretreated with atropine (> or = 1.0 mg kg-1 I.V.) administration of L-NAME (> or = 100 mg kg-1 I.A.) effectively suppressed the vasodilator response to chorda-lingual stimulation at 2 Hz continuously, or at 20 Hz for 1 s at 10 s intervals. 5. Administration of L-NAME (> or = 100 mg kg-1 I.A.) effectively suppressed the submandibular vasodilator response to infusions of VIP (10 and 20 ng I.A.) and significantly reduced, but did not abolish that to acetylcholine (100 ng min-1 I.A.). 6. These results provide further support for the view that both acetylcholine and vasoactive intestinal polypeptide-like immunoreactivity (VIP) are released from the postganglionic parasympathetic nerve terminals and produce effects on the blood vessels in submandibular glands of the cat. They also provide evidence for a direct vascular action of acetylcholine, independent of NO chi, but VIP appears to act indirectly via NO chi formation.

Animals↗
PubMed2002

Pharmacological profile of (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301), an orally and centrally active neurokinin-1 receptor antagonist.

In comparison with a series of reference compounds, (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301) was characterized as a specific, orally, and centrally active neurokinin-1 (NK(1)) receptor antagonist with subnanomolar affinity for the human NK(1) receptor (K(i): 0.45 nM) and over 200-fold selectivity toward NK(2) and NK(3) receptors. R116301 inhibited substance P (SP)-induced peripheral effects (skin reactions and plasma extravasation in guinea pigs) and a central effect (thumping in gerbils) at low doses (0.08-0.16 mg/kg, s.c. or i.p.), reflecting its high potency as an NK(1) receptor antagonist and excellent brain disposition. Higher doses blocked various emetic stimuli in ferrets, cats, and dogs (ED(50) values: 3.2 mg/kg, s.c.; 0.72-2.5 mg/kg, p.o.). Even higher doses (11-25 mg/kg, s.c.) were required in mice (capsaicin-induced ear edema) and rats (SP-induced extravasation and salivation), consistent with lower affinity for the rodent NK(1) receptor and known species differences in NK(1) receptor interactions. R116301 inhibited the ocular discharge (0.034 mg/kg) but not the dyspnoea, lethality, or cough (>40 mg/kg, s.c.) induced by [betaALA(8)]-neurokinin A (NKA) (4-10) in guinea pigs, attesting to NK(1) over NK(2) selectivity. R116301 did not affect senktide-induced miosis (>5 mg/kg, s.c.) in rabbits, confirming the absence of an interaction with the NK(3) receptor. R116301 was inactive in guinea pigs against skin reactions induced by histamine, platelet-aggregating factor, bradykinin, or Ascaris allergens (>10 mg/kg, s.c.). In all species, R116301 showed excellent oral over parenteral activity (ratio, 0.22-2.7) and a relatively long duration (6.5-16 h, p.o.). The data attest to the specificity and sensitivity of the animal models and support a role of NK(1) receptors in various diseases.

Administration, Oral↗
PubMed2004

Cholinergic stimulation of salivary secretion studied with M1 and M3 muscarinic receptor single- and double-knockout mice.

Identification of the specific muscarinic acetylcholine receptor (mAChR) subtypes mediating stimulation of salivary secretion is of considerable clinical interest. Recent pharmacological and molecular genetic studies have yielded somewhat confusing and partially contradictory results regarding the involvement of individual mAChRs in this activity. In the present study, we re-examined the roles of M(1) and M(3) mAChRs in muscarinic agonist-mediated stimulation of salivary secretion by using M(1) and M(3) receptor single-knockout (KO) mice and newly generated M(1)/M(3) receptor double-KO mice. When applied at a low dose (1 mg/kg, s.c.), the muscarinic agonist pilocarpine showed significantly reduced secretory activity in both M(1) and M(3) receptor single-KO mice. However, when applied at higher doses, pilocarpine induced only modestly reduced (5 mg/kg, s.c.) or unchanged (15 mg/kg, s.c.) salivation responses, respectively, in M(1) and M(3) receptor single-KO mice, indicating that the presence of either M(1) or M(3) receptors is sufficient to mediate robust salivary output. Quantitative reverse transcriptase-polymerase chain reaction studies with salivary gland tissue showed that the inactivation of the M(1) or M(3) mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Strikingly, the sialagogue activity of pilocarpine was abolished in M(1)/M(3) receptor double-KO mice. However, salivary glands from M(1)/M(3) receptor double-KO mice remained responsive to stimulation by the beta-adrenergic receptor agonist, (S)-isoproterenol. Taken together these studies support the concept that a mixture of M(1) and M(3) receptors mediates cholinergic stimulation of salivary flow.

Animals↗