Cardiovascular responses evoked by carbachol microinjection into the posterior hypothalamus involves ganglionic nicotinic and muscarinic mechanisms

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Peptide YY administration into the posterior hypothalamic nucleus of the rat evokes cardiovascular changes by non-adrenergic, non-cholinergic mechanisms

1 Microinjection of peptide YY (PYY) (0.23-2.3 nmol) into the posterior hypothalamic nucleus (PHN) of conscious rats evokes a dose-dependent pressor response and a bradycardia. 2 The increase in mean arterial pressure evoked by 2.3 nmol of PYY was not blocked by intravenous pretreatment with: (i) the nicotinic ganglionic receptor antagonist pentolinium (PENT, 10 mg kg(-1)) alone, or in combination with the muscarinic receptor antagonist methylatropine (MeATR, 1 mg kg(-1)); (ii) the alpha(1)-adrenoceptor antagonist prazosin (PRAZ, 0.2 mg kg(-1)); (iii) the V(1)-vasopressin receptor antagonist [d(CH(2))(5)Tyr(Me)]AVP (AVPX, 20 microg kg(-1)); (iv) the combination of AVPX, PENT and MeATR; (v) the combination of PRAZ, AVPX, PENT, MeATR, and the alpha(2)-adrenoceptor antagonist yohimbine (0.3 mg kg(-1)); or (vi) the angiotensin II type 1 receptor antagonist ZD 7155 (1 mg kg(-1)). 3 Adrenal demedullation inhibited the PYY-evoked responses of drug-naive rats, and rats pretreated with the combination of PENT, MeATR and AVPX. 4 Transection of the splanchnic nerve innervating the adrenal medullae attenuated the bradycardia, as did ZD 7155, but not the PYY-evoked pressor response. 5 Systemic pretreatment of rats with the neuropeptide Y(1) receptor antagonist BIBP 3226 (1 mg kg(-1)) blocked the PYY-evoked cardiovascular changes, but not those evoked by microinjection of carbachol (5.5 nmol) into the PHN. 6 These results suggest that the cardiovascular changes evoked from the PHN by PYY requires the presence of the adrenal medullae, which are stimulated by: (i) a hormone to release an NPY-like substance that evokes the pressor response, and (ii) the splanchnic nerve to evoke the release of a substance that results in the bradycardia.     

The release of atrial natriuretic factor induced by central carbachol injection may be mediated by muscarinic M1 receptors.

We investigated the effect of selective muscarinic antagonists on atrial natriuretic factor (ANF) release induced by intracerebroventricular (i.c.v) injection of carbachol in the rat. The muscarinic antagonists were given by i.c.v. injection 1 min before carbachol, 1 micrograms/rat. 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), a rather selective M1 and M3 receptor antagonist, was the most potent inhibitor of carbachol-induced ANF release, its ID50 being 0.18 nmol/rat. Pirenzepine, a selective M1 antagonist, also potently inhibited the effect of carbachol, its ID50 being 2.74 nmol/rat. The M3-selective antagonist, p-fluoro-hexahydro-sila-diphenidol, was much weaker than pirenzepine, with an ID50 of 57.52 nmol/rat. The selective M2 receptor antagonist, methoctramine, on the other hand, was a very weak inhibitor of carbachol-induced ANF release. The rank order of potency as well as the - log ID50 of the antagonists tested were consistent with their pA2 values for muscarinic M1 receptors, suggesting that this receptor subtype may mediate the central effect of cholinergic mechanisms in the control of ANF release.     

Natriuresis, kaliuresis and antidiuresis induced by central carbachol injection are mediated by muscarinic M1 receptors

The present study investigated the effect of selective muscarinic antagonists on natriuresis, kaliuresis and antidiuresis induced by intracerebroventricular (i.c.v.) injection of carbachol in the rat. The muscarinic antagonists were given by i.c.v. injection 1 min before carbachol (1 microgram/rat). 4-Diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a rather selective M1 and M3 receptor antagonist, was the most potent inhibitor of carbachol-induced natriuresis, kaliuresis and antidiuresis, its ID50 being respectively 0.12, 0.04 and 0.56 nmol/rat. Pirenzepine, a selective M1 antagonist, potently inhibited the above mentioned carbachol effects, its ID50 being 1.85, 3.25 and 1.49 nmol/rat, respectively. On the other hand, the M2-selective antagonist methoctramine and the M3-selective antagonist p-fluoro-hexahydro-sila-difenidol were very weak inhibitors. Methoctramine at doses up to 60 nmol/rat produced non statistically significant inhibition of carbachol-induced natriuresis, kaliuresis and antidiuresis. Para-fluoro-hexahydro-sila-diphenidol showed an ID50 of 64.4 nmol/rat on carbachol-induced natriuresis, while at the maximum dose employed, 100 nmol/rat, the inhibition of carbachol-induced kaliuresis and antidiuresis was lower than 50%. The rank order of potency of the antagonists tested proved to be related to their pA2 values for muscarinic M1 receptors, suggesting that this receptor subtype mediates the central effects of cholinergic mechanisms on water and electrolyte excretion.     

Effects of microinjected carbachol on the antinociceptive response to noxious heat stimuli

Injecting muscarinic receptor agonists into a specific area of the brainstem produces an antinociceptive response. The present study investigates whether direct injections of the cholinergic agonist, carbachol, into the rat nucleus reticularis gigantocellularis (NRGC)/nucleus reticularis gigantocellularis alpha (NRGCalpha) of the rostral ventrolateral medulla evokes antinociception, and then examines the interference action of cholinergic antagonists in rats. Microinjections of carbachol (0.75, 1.5, 3 micro g/site) prolonged hot plate (HP) and tail flick (TF) responses to noxious heat stimuli in a dose-dependent manner. The level of carbachol-induced antinociception during the HP and TF tests reached a maximum at 5-15 min after carbachol administration in all groups. Thereafter, the peak level progressively decreased and reached the baseline by the end of the experiment. Antinociception induced by carbachol at 3 micro g/site was attenuated by the prior administration of the muscarinic receptor antagonist, atropine (200, 500 ng/site). On the other hand, the nicotinic autonomic ganglion blocker, mecamylamine (1, 3 micro g/site), did not affect subsequent carbachol-induced antinociception. These results suggest that the antinociceptive effects induced by a microinjection of carbachol depend on muscarinic, but not nicotinic, mechanisms within the rat NRGC/NRGCalpha.     

Selective antagonists provide evidence that M1 muscarinic receptors may mediate carbachol-induced drinking in the rat

The present study served to investigate the ability of seven selective muscarinic antagonists to inhibit carbachol-induced drinking in the rat. The muscarinic antagonists were given by intracerebroventricular (i.c.v.) injection 1 min before the i.c.v. injection of carbachol (1 microgram/rat). The M2 antagonist, methoctramine, was inactive up to 80.3 nmol/rat. The M3 antagonist, p-fluoro-hexahydro-sila-difenidol, elicited a modest (42%) but statistically significant inhibition of drinking only at 80 nmol/rat. On the other hand, the selective M1 antagonists, (R)-trihexphenidyl, o-methoxy-sila-hexocyclium and pirenzepine, produced a marked and dose-dependent inhibition of carbachol-induced drinking, their ID50 values being 0.51, 7.36 and 9.31 nmol/rat. Also the M1/M3 antagonists, 4-diphenylacetoxy-N-methylpiperidine methiodide and hexahydro-sila-difenidol, were potent inhibitors of carbachol-induced drinking, their ID50 values (0.28 and 11.09 nmol/rat) being related to their pA2 values for M1 receptors in rabbit vas deferens. These data suggest that carbachol-induced drinking may be mediated by activation of muscarinic M1 receptors.     

Intradermal cholinergic agonists induce itch-associated response via M3 muscarinic acetylcholine receptors in mice

In the present study, we examined whether cholinergic agonists would elicit an itch-associated response in mice. When mice were given an intradermal injection of carbachol (1-10 nmol) or bethanechol (0.3-100 nmol) into the rostral back, they showed the dose-dependent increase of scratching. Nicotine (1-10 nmol) showed no effect. Pretreatment with naloxone, but not with terfenadine, significantly suppressed the carbachol-induced scratching. When intradermally co-injected with carbachol, atropine and 4-DAMP but neither methoctramine nor pancuronium significantly inhibited the carbachol-induced scratching. Muscarinic agonists are suggested to produce itch through activation of M3 muscarinic receptors in the skin.     

CARDIOVASCULAR RESPONSES ELICITED BY MICROINJECTION OF CHOLINERGIC AGENTS INTO NUCLEUS DORSALIS RAPHE IN CATS

The effect of cholinomimetics and cholinoceptor blocking agents microinjected into nucleus dorsalis raphe (NDR) has been studied on heart rate and blood pressure to identify the nature and role of these cholinoceptors in cardiovascular regulation. Microinjection of the cholinoceptor agonists, pilocarpine and carbachol into NDR elicited bradycardia and hypotension accompanied by salivation which could be blocked by local pretreatment with ethybenztropine (a muscarinic receptor blocker), but not by chlorisondamine (a nicotinic receptor blocker). Pretreatment with atropine methylnitrate (i.v.), which blocks only peripheral muscarinic receptors, did not prevent these cardiovascular responses evoked by carbachol microinjection. These cholinergic receptors seem to be localized in NDR since, microinjection of carbachol into neural structures adjoining NDR, failed to induce any cardiovascular responses. Muscarinic cholinoceptors are present in NDR which modulate cardiovascular activity by influencing sympathetic preganglionic neurons in the intermediolateral columns of the spinal cord.     

Studies on the mechanism of wet dog shakes produced by carbachol in rats

In an attempt to elucidate the mechanism of wet dog shakes (WDS) produced by carbachol administered into the rat lateral brain ventricle, the effects of blockade of muscarinic and nicotinic receptors on shaking response and the effects of carbachol on central catecholaminergic, serotonergic (5-HT) and GABAergic functions were studied in rats. The muscarinic receptor antagonists, atropine and scopolamine attenuated WDS produced by carbachol, whilst a peripherally active muscarinic receptor antagonist, scopolamine methyl nitrate, failed to influence WDS. The nicotine antagonist, mecamylamine, did not affect WDS caused by carbachol either. Carbachol dose dependently decreased brain concentration of noradrenaline (NA) but failed to affect the concentration of dopamine (DA). While the brain concentration of 5-HT was unchanged, the concentration of 5-hydroxyindoleacetic acid (5-HIAA) was increased in a dose-related manner. The catecholamine turnover times were unaffected whereas 5-HT turnover time was significantly prolonged. Atropine, but not mecamylamine, prevented the decrease in brain NA induced by carbachol. Consequently, the carbachol-induced enhancement in the level of 5-HIAA was completely blocked by atropine and only slightly influenced by mecamylamine. Neither brain GABA concentration nor glutamic acid decarboxylase activity were affected by carbachol. Behavioral and biochemical data suggest that WDS produced by carbachol may be mediated through the stimulation of central muscarinic receptors. The anatomical localization and exact mechanism of carbachol-induced WDS remain to be elucidated.     

Carbachol activates a novel sodium current in isolated guinea pig ventricular myocytes via M2 muscarinic receptors.

Carbachol induces a novel tetrodotoxin-resistant Na+ current in guinea pig ventricular myocytes bathed in Tyrode's solution with 20 mM Cs+. This action of carbachol, which initiates a series of reactions that culminates in a catecholamine-independent positive inotropic effect, occurs through muscarinic rather than nicotinic cholinoceptive sites. The concentrations of muscarinic antagonists required to suppress the carbachol-induced current by 50% were 2.1 nM, 270 nM, and 1700 nM for atropine, AF-DX 116, and pirenzepine, respectively. These results indicate that an M2-selective antagonist, AF-DX 116, is more potent than an M1-selective antagonist, pirenzepine, as an inhibitor. The M1-selective agonist McN-A-343 did not induce an inward current and blocked that caused by carbachol, in a rapid and reversible manner. This finding is also consistent with the conclusion that the muscarinic receptor involved in the regulation of myocardial Na+ channels by carbachol cannot be distinguished from the M2 subtype of such receptors. Treatment with pertussis toxin did not affect the ability of carbachol to induce an inward current in ventricular myocytes and reversed the current activated by carbachol in atrial cells from outward to inward. The electrophysiological and pharmacological nature of the carbachol-induced current in ventricular myocytes is very similar to that of the acetylcholine-induced current in Xenopus oocytes transfected with porcine M2, but not M1, muscarinic receptors. In both preparations, Na+ is the dominant charge carrier, intracellular Ca2+ is not involved in opening the Na+ channel, and an M2 receptor is involved.     

Comparative in vivo uroselectivity profiles of anticholinergics, tested in a novel anesthetized rabbit model

The aim of this study was to describe a new experimental animal model for simultaneous measurement of carbachol-induced increase in intravesical pressure and salivary secretion in rabbits. Further, we also compared the in vivo potency and urinary bladder versus salivary gland selectivity profiles of Oxybutynin, Tolterodine, Solifenacin and Darifenacin. The intravesical pressure and salivary secretion were evoked by intra-arterial injection of carbachol (1.5 microg/kg). The carbachol-induced increase in intravesical pressure and salivation was simultaneously recorded before and after increasing doses of test drugs administered intravenously. The basal mean changes in intravesical pressure and salivation subsequent to carbachol administration were in the range of 6.7-7.5 mm Hg and 0.5-0.7 g respectively. Repeated administration of vehicle did not elicit any appreciable changes in intravesical pressure and salivary secretion to carbachol administration from the basal values till 3 h. All the test drugs exhibited a dose-dependent inhibition of carbachol-induced increase in intravesical pressure and salivary secretion. Darifenacin demonstrated a greater potency compared to other muscarinic receptor antagonists for inhibiting carbachol-induced increase in intravesical pressure. It also exhibited functional selectivity for the urinary bladder versus salivary gland. In contrast, Oxybutynin was functionally more selective in inhibiting carbachol-induced increase in salivary secretion. The observed urinary bladder versus salivary selectivity values were 0.6+/-0.2, 1.1+/-0.2, 1.7+/-0.5, and 2.3+/-0.5 for Oxybutynin, Tolterodine, Solifenacin and Darifenacin respectively. These results suggest that the functional selectivity of muscarinic receptor antagonists between urinary bladder and salivary glands can be readily detected in this model. Thus rabbits may represent a useful animal model for evaluating putative bladder selective muscarinic receptor antagonists for the treatment of overactive bladder.     

Muscarinic M4 receptor inhibition of dopamine D1-like receptor signalling in rat nucleus accumbens

Several studies have indicated the occurrence of an antagonistic interaction between muscarinic and dopamine D1-like receptors in the ventral striatum, but the subtype(s) of muscarinic receptor involved has not been characterized. We show that in membranes of rat nucleus accumbens, carbachol inhibited the stimulation of adenylyl cyclase activity by dopamine and the dopamine D1-like receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine without affecting the binding properties of dopamine to dopamine D1-like receptors. The carbachol inhibition was competitively counteracted by receptor antagonists with a rank order of potency typical of the involvement of the muscarinic M(4) receptor subtype. Moreover, muscarinic toxin 3, a selective muscarinic M(4) receptor antagonist, completely blocked the carbachol inhibition, whereas muscarinic toxin 7, a selective muscarinic M(1) receptor antagonist, had no effect. The muscarinic inhibition occurred to a similar extent in the core and shell regions. These data demonstrate that in nucleus accumbens, muscarinic M(4) receptors exert a direct inhibitory control on dopamine D1-like receptor signalling.     

Characterization of muscarinic receptors mediating contractions of circular and longitudinal muscle of human isolated colon.

1. The effects of seven muscarinic receptor antagonists were used to characterize the receptors which mediate carbachol-evoked contractions of intertaenial circular and taenial longitudinal muscle in human isolated colon. The effects of these antagonists were studied upon colon contractions induced by cumulatively added carbachol which had mean EC50 values of 11.7 +/- 2.3 microM (n = 8) and 12.6 +/- 2.3 microM (n = 8) respectively upon circular and longitudinal smooth muscle. 2. All antagonists displaced concentration-response curves to carbachol to the right in a parallel manner. The maximum concentration of each antagonist added (30 nM-10 microM) did not significantly suppress the maximum response. 3. In circular muscle, the M3 muscarinic receptor antagonists, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), hexahydrosiladiphenidol (HHSiD) and para-fluoro-hexahydrosiladiphenidol (p-F-HHSiD) inhibited responses with pA2 values of 9.41 +/- 0.23, 7.17 +/- 0.07, 6.94 +/- 0.18 respectively. The M2 muscarinic receptor antagonist, AF-DX 116, the M2/M4 muscarinic receptor antagonist, himbacine, and the M1 muscarinic receptor antagonist, pirenzepine, yielded pA2 values of 7.36 +/- 0.43, 7.47 +/- 0.14 and 7.23 +/- 0.48 respectively. The non-selective antagonist, atropine, had a pA2 of 8.72 +/- 0.28. 4. In longitudinal muscle 4-DAMP, HHSiD, p-F-HHSiD, AF-DX 116, himbacine and pirenzepine gave pA2 values of 9.09 +/- 0.16, 7.45 +/- 0.43, 7.44 +/- 0.21, 6.44 +/- 0.1, 7.54 +/- 0.40, 6.87 +/- 0.38 respectively. Atropine yielded a pA2 value of 8.60 +/- 0.08.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the central muscarinic cholinoceptors involved in the cholinergic pressor response in anesthetized dogs.

Previous reports have shown that an intracisternal (i.c.) injection of acetylcholine in the dog increases both arterial blood pressure and plasma levels of noradrenaline and vasopressin via central muscarinic receptors. The aim of the present study was to characterize the central muscarinic cholinoceptor subtypes involved in such central cholinergic responses in anesthetized male Beagle-Harrier dogs (n = 12). For this purpose, we studied the relative potency of various muscarinic receptor antagonists to block the acetylcholine-induced pressor responses (30 microg kg(-1) i.c.). The acetylcholine-induced pressor response was inhibited in a dose-dependent manner by the i.c. administration of the non-selective muscarinic receptor antagonist atropine (ID50 = 0.5 microg kg(-1)), the muscarinic M receptor antagonist pirenzepine (ID50 = 0.45 microg kg(-1)), the muscarinic M2 receptor antagonist methoctramine (ID50 = 8.5 microg kg(-1)) and the muscarinic M3 receptor antagonist para-fluoro-hexahydro-sila-difenidol (ID50) = 43.7 microg kg(-1)). The order of potency of these four muscarinic receptor antagonists was: atropine = pirenzepine > methoctramine > para-fluoro-hexahydro-sila-difenidol. In order to confirm the selectivity for muscarinic M1 receptors of this dose of pirenzepine, we checked that 40- to 50-fold higher concentrations were necessary to block a typical muscarinic M2 receptor response (bradycardia) and a typical muscarinic M3 receptor response (endothelial vasodilation) compared with methoctramine and para-fluoro-hexahydro-sila-difenidol, respectively. These results suggest that the pressor response elicited by intracisternal injection of acetylcholine in anesthetized Beagle-Harrier dogs is mediated through the activation of the muscarinic M1 cholinoceptor subtype.     

Opposing influences on behavior mediated by muscarinic and nicotinic receptors in the rat posterior hypothalamic nucleus

Microinjection of carbachol into the posterior hypothalamic nucleus (PHN) of freely moving rats evoked marked behavioral changes characterized by an escape reaction. This response was quantitated by measuring locomotor activity. In contrast, cholinergic stimulation of the PHN with neostigmine produced sedation and inactivity. Local pretreatment with the nicotinic receptor blocking agent mecamylamine blocked the excitatory effects of carbochol while the muscarinic antagonist atropine abolished the inhibitory effect of neostigmine on motor activity. It is concluded that behavioral changes evoked through cholinergic stimulation of the PHN may be mediated by a muscarinic system which controls sedation and a nicotinic pathway which mediates arousal.     

Antidiuretic effects of alpha- and beta-adrenoceptor agonists microinjected into the hypothalamic paraventricular nucleus in a water-loaded and ethanol-anesthetized rat

Effects of catecholamines microinjected into the paraventricular nucleus in the hypothalamus on urine outflow in a rat which was loaded with water and anesthetized with ethanol were studied. L-Norepinephrine, L-epinephrine and L-isoproterenol induced potent antidiuresis with similar time courses to each other. The ED50 values for L-norepinephrine, L-epinephrine and L-isoproterenol were approximately 5, 10 and 5 nmol, respectively. The D-isomer of isoproterenol demonstrated no significant antidiuretic activity. The effect of L-norepinephrine was inhibited strongly by premicroinjection of alpha- and beta-adrenoceptor antagonists. The effect of DL-isoproterenol was inhibited strongly by beta-adrenoceptor antagonists, but not affected by alpha-adrenoceptor antagonist. Premicroinjection of a muscarinic antagonist, atropine, partially inhibited anti-diuretic effects induced by L-norepinephrine and DL-isoproterenol. Visceral functions other than urine outflow such as mean blood pressure, respiration rate, heart rate and rectal temperature were not significantly altered when the urine outflow decreased down to 20-30% of the control by microinjection of L-norepinephrine and DL-isoproterenol. The results demonstrated that stimulation of alpha- and beta-adrenoceptor in the paraventricular nucleus induced potent antidiuretic effects, partial inhibition of which by atropine suggested a possible presynaptic facilitation of the release of ACh by the stimulation of the adrenoceptors.     

Ability of cyclohexenonic long-chain fatty alcohol to ameliorate diabetes-induced cystopathy in the rat

We investigated the pharmacological effects of N-hexacosanol on diabetic rat detrusor. Eight-week-old male Sprague-Dawley rats were randomly divided into 4 groups: diabetic rats induced by 50 mg/kg intraperitoneally of streptozotocin treated with N-hexacosanol (0, 2 or 8 mg/kg, subcutaneously every day) and control rats. Bladder function was estimated by functional studies using carbachol and KCl. Contractile response curves to increasing concentrations of carbachol were constructed in the absence and presence of various concentrations of subtype-selective muscarinic antagonists, that is, atropine, pirenzepine, methoctramine and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP). The participation levels of muscarinic M(2) and M(3) receptor mRNAs in detrusor were investigated by real-time polymerase chain reaction. Treatment with N-hexacosanol did not alter diabetic status of the rats, but significantly improved the diabetes-induced hypercontractility of the rat bladder. Estimations of the pA(2) values for atropine, pirenzepine, methoctramine and 4-DAMP indicate that the carbachol-induced contractile response is mediated through the M(3) receptor subtype in all groups. Furthermore, N-hexacosanol ameliorated the diabetes-induced upregulation of muscarinic M(2) receptor mRNAs in streptozotocin-diabetic rat detrusor. Our data indicate that N-hexacosanol has therapeutic effects on hypercontractility in the diabetic bladder by ameliorating overexpression of muscarinic M(2) and M(3) receptor mRNAs without significant alternations of pharmacological profiles.     

Muscarinic inhibition of excitatory neurotransmission in guinea-pig olfactory cortex slices: weak antagonism by M3-muscarinic receptor antagonists.

Dose-dependent depression of the electrically evoked surface-negative field potential (N-wave) produced by bath-superfusion of carbachol was measured in guinea-pig olfactory cortex slices maintained in vitro. The possible involvement of M3 (smooth muscle/glandular) type muscarinic receptors in partly mediating this response was investigated by testing the effectiveness of the muscarinic M3 receptor antagonists hexahydro-sila-difenidol (HHSiD) and p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD). Low doses of HHSiD (10-100 nM) or p-F-HHSiD (up to 1 microM), pre-applied for 30 min, produced no obvious antagonism of carbachol responses. However, a clear competitive-type inhibition of carbachol effects was observed in 250 nM-1 microM HHSiD or 10-50 microM p-F-HHSiD respectively. Schild plot analysis (regression slope constrained to unity) of pooled data yielded pA2 values of 6.6 for HHSiD (n = 6 slices) and 5.5 for p-F-HHSiD (n = 6 slices) respectively, suggesting a weak competitive antagonism by both compounds. In addition, combination experiments using either HHSiD or p-F-HHSiD with atropine, produced dose-ratio shifts close to those predicted for two antagonists competing for a common receptor site. By comparison, another suggested M3-receptor antagonist, 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (4-DAMP) was a potent competitive blocker of carbachol responses. Schild analysis for 4-DAMP versus carbachol gave a pA2 of 7.9 (n = 6 slices). It is concluded that the muscarinic receptors involved in the suppression of the olfactory cortical N-wave possess a low affinity for HHSiD and particularly for p-F-HHSiD, but not 4-DAMP.(ABSTRACT TRUNCATED AT 250 WORDS)     

A quantitative study of the effects of some muscarinic antagonists on the guinea-pig olfactory cortex slice.

1. Muscarinic depression of the electrically-evoked surface-negative field potential (N-wave) was measured in guinea-pig olfactory cortex slices maintained in vitro. 2. The effects of three muscarinic receptor antagonists, pirenzepine, atropine and gallamine on this muscarinic response were analysed in detail. 3. Pirenzepine was a potent competitive antagonist of carbachol (CCh)-evoked responses. Schild plot analysis yielded a pA2 value of 7.9 (Schild slope constrained to unity). A similar analysis for atropine versus CCh responses gave a pA2 of 8.9. 4. Combination experiments using pirenzepine and atropine produced dose-ratio shifts close to those expected for two antagonists competing for a similar receptor site. 5. Gallamine was only a weak antagonist of responses to CCh. 6. Oxotremorine behaved as a competitive antagonist at this muscarinic receptor (pA2 = 6.1). 7. It is concluded that the presynaptic muscarinic receptor mediating depression of the N-wave in the olfactory cortex slice is of the M1-subtype.