Distinct mixtures of muscarinic receptor subtypes mediate inhibition of noradrenaline release in different mouse peripheral tissues, as studied with receptor knockout mice.
The muscarinic heteroreceptors modulating noradrenaline release in atria, urinary bladder and vas deferens were previously studied in mice in which the M(2) or the M(4) muscarinic receptor genes had been disrupted. These experiments showed that these tissues possessed both M(2) and non-M(2) heteroreceptors. The analysis was now extended to mice in which either the M(3), both the M(2) and the M(3), or both the M(2) and the M(4) genes had been disrupted (M(3)-knockout, M(2/3)-knockout and M(2/4)-knockout). Tissues were preincubated with (3)H-noradrenaline and then stimulated electrically (20 pulses per 50 Hz). In wild-type atria, carbachol (0.01-100 microM) decreased the electrically evoked tritium overflow by maximally 60-78%. The maximum inhibition of carbachol was reduced to 57% in M(3)-knockout and to 23% in M(2/4)-knockout atria. Strikingly, the effect of carbachol was abolished in M(2/3)-knockout atria. In wild-type bladder, carbachol (0.01-100 microM) reduced the evoked tritium overflow by maximally 57-71%. This effect remained unchanged in the M(3)-knockout, but was abolished in the M(2/4)-knockout bladder. In wild-type vas deferens, carbachol (0.01-100 microM) reduced the evoked tritium overflow by maximally 34-48%. The maximum inhibition of carbachol was reduced to 40% in the M(3)-knockout and to 18% in the M(2/4)-knockout vas deferens. We conclude that the postganglionic sympathetic axons of mouse atria possess M(2) and M(3), those of the urinary bladder M(2) and M(4), and those of the vas deferens M(2), M(3) and M(4) release-inhibiting muscarinic receptors.
Trendelenburg
Anne-Ulrike
AU
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albertstrasse 25, D-79104 Freiburg i. Br., Germany. anne-ulrike.trendelenburg@pharma.novartis.com
Meyer
Angelika
A
Wess
Jürgen
J
Starke
Klaus
K
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism*; D009928:Organ Specificity; D043585:Receptor, Muscarinic M2 / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000235:genetics / Q000378:metabolism*; D001743:Urinary Bladder / Q000378:metabolism*; D014649:Vas Deferens / Q000378:metabolism*
D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D017661:Receptors, Presynaptic; D002217:Carbachol; D009638:Norepinephrine