Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon

Abstract

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI. DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular beta-adrenoceptors) and clonidine (acting on neuronal alpha 2-adrenoceptors) and super-sensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional Differences in Calcium Sensitivity in the Guinea-pig Intestine

“…Opiate antagonism with naloxone did not affect it. These results suggested that a neuronal factor involving cholinergic transmission but not the opiate receptor might be partly related to the regulation of basal tone, because both tetrodotoxin and clonidine, but not naloxone, were reported to inhibit resting endogenous acetylcholine overflow in the guinea-pig colon (Marino et al 1994). These antagonists and agonists had no effects on the basal tone of the duodenum, jejunum, ileum and rectum (data not shown).…”

Activation of α‐ and β‐adrenoceptors by sympathetic nerve stimulation in the large intestine of the rat

“…This potentiation suggests that SNS‐evoked responses were caused by the activation of junctional receptors. Other studies have also used this line of reasoning to identify innervated receptors (Marino, Marcoli, de Ponti, Cosentino, Lecchini & Frigo, 1994).…”

Muscarinic modulation of endogenous noradrenaline release from adrenergic terminals in the guinea‐pig colon

“…In addition, an exogenously applied muscarinic agonist such as oxotremorine can aect NA release by activating inhibitory muscarinic receptors on adrenergic terminals. It has been shown that endogenous NA tonically inhibits acetylcholine release from enteric neurones (Marcoli et al, 1985;Marino et al, 1994). Facilitation of NA release by endogenous acetylcholine could thus represent an additional feedback mechanism for the modulation of neurotransmitter release from enteric cholinergic neurones.…”

“…In the rat stomach and jejunum, EP 3 prostanoid receptors (Racke et al, 1995) and interleukin-1 receptors (Hurst & Collins, 1993), respectively, have been reported. In the guinea-pig colon, we have recently provided evidence in favour of an a 2 -adrenoceptor-mediated feedback autoinhibition (Marino et al, 1994) as well as of the functional relevance of m and k opioid receptors (Marino et al, 1993;Cosentino et al, 1995a) and of glutamatergic receptors of the N-methyl-D-aspartate subtype (Cosentino et al, 1995b) in the modulation of NA release.…”

“…To the best of our knowledge, no data are available on the possible role of muscarinic receptors aecting NA release in the colon. Since at this level, sympathetic adrenergic ®bres tonically modulate transmitter release from enteric cholinergic neurones (Marcoli et al, 1985;Marino et al, 1994), modulation of NA release by muscarinic receptors could provide the functional basis for a cross-communication between sympathoadrenergic and cholinergic pathways at this level, similar to those operating in other tissues endowed with both sympathetic and parasympathetic innervation (Muscholl, 1980;Manabe et al, 1991).…”