Presynaptic muscarinic receptors inhibiting endogenous noradrenaline release in the portal vein of the freely moving rat

Abstract

1 In the portal vein of the freely moving unanaesthetized rat, the existence of presynaptically located inhibitory muscarinic receptors was investigated by use of the muscarinic agonist methacholine (MCh) 2 Infusion of MCh (0.3pgmin-1) did not significantly inhibit the endogenous noradrenaline (NA) overflow in portal plasma. However, after inducing high intra-synaptic concentrations of NA by blocking the presynaptic a2-adrenoceptors with yohimbine (lmgkg-1), MCh (0.3jpgmin-1) was able to reduce the yohimbine-induced enhanced NA overflow by 38%. 3 The MCh-induced inhibition was almost completely abolished after blockade of the presynaptic muscarinic receptors with atropine (0.6 mg kg~-). 4 During electrical stimulation of the portal vein nervous plexus the evoked NA overflow was strongly inhibited (95%) during MCh-infusion (0.3jugmin'). Again atropine (0.6 mgkg 1) was able to reverse this inhibition. 5 These results show the existence of presynaptic muscarinic receptors inhibiting endogenous NA overflow from the portal vein nervous plexus under conditions of enhanced sympathetic activity in the freely moving rat.

Characterization of presynaptic vascular muscarinic receptors inhibiting endogenous noradrenaline overflow in the portal vein of the freely moving rat

“…Recently we showed, with freely moving, unanaesthetized, permanently cannulated rats (Remie & Zaagsma, 1986;Remie et al, 1988), a MCh-induced inhibition of NA overflow during electrical stimulation of the portal vein nervous plexus. This inhibition could be reversed to control values by using the non-selective muscarinic antagonist atropine, indicating the muscarinic nature of these inhibitory presynaptic receptors (Remie et al, 1989).…”

“…The pIC50 values of the antagonists for muscarinic receptors in the portal vein were calculated as the -log of the portal vein concentration (molar) of the antagonist causing 50% inhibition of the MCh-induced decrease of electricallyevoked NA overflow. Atropine (0.6mgkg-1), administered 15min before stimulation, was used in separate experiments to determine the maximal amount of electrically-evoked NA overflow in the presence of an antagonist; this was 122 + 8% of the control stimulation value which indicates a minor inhibition of NA overflow by endogeneous acetylcholine, released during co-stimulation of cholinergic neurones (Remie et al, 1989). To allow calculation of the pIC50 values this maximal effect was used for all the selective antagonists and the least square regression line analysis was used to determine the concentration needed to obtain 61% (pIC50) of the maximal effect.…”

“…Recently, we showed the existence of presynaptic muscarinic receptors that inhibited NA release from the nervous plexus of the portal vein in freely moving, unanaesthetized rats, with methacholine (MCh) as an agonist and atropine as a muscarinic antagonist (Remie et al, 1989).…”

Influence of the baroreceptor reflex on the modulation of noradrenaline overflow through prejunctional receptors in the portal vein of freely moving rats

“…Using this model, prejunctional receptor-induced changes in evoked endogenous noradrenaline overflow in the portal vein of freely moving rats can be studied. Several prejunctional receptor systems have now been investigated with this model and shown to have pronounced capacities to modulate vascular noradrenaline overflow in vivo (Remie et ai., 1988;Remie, Coppes & Zaagsma, 1989;Remie, Coppes, Meurs, Roffel & Zaagsma, 1990a;Coppes, Smit, Nashid Khali, Brouwer & Zaagsma, 1993). Problems, however, may arise when the drugs used possess not only a presynaptic activity.…”

Influence of nebivolol on the cardiovascular hemodynamics during postural changes and isometric exercise

“…There is little information available about the pharmacodynamic profiles of this drug in volunteers and hypertensive patients. In animal experiments it has been demonstrated that nebivolol has a presynaptic effect on the release of noradrenaline in the conscious rat [2] and induces a reduction of total peripheral vascular resistance (TPVR) in anesthetised dogs, even in low doses [3].…”