Characterization of muscarinic receptors mediating vasodilation in rat perfused kidney.
The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10(-7) M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasodilation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester approximately (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol approximately hexahydro-sila-difenidol > pirenzepine approximately p-fluoro-hexahydro-sila-difenidol approximately himbacine approximately AF-DX 384 approximately AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M1 and M2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M3 receptors.
Eltze
M
M
Department of Pharmacology, Byk Gulden Pharmaceuticals, Konstanz, Germany.
Ullrich
B
B
Mutschler
E
E
Moser
U
U
Bungardt
E
E
Friebe
T
T
Gubitz
C
C
Tacke
R
R
Lambrecht
G
G
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists; D009130:Muscle, Smooth / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D010277:Parasympathomimetics / Q000378:metabolism / Q000494:pharmacology*; D010477:Perfusion; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology*; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D018727:Muscarinic Antagonists; D010276:Parasympatholytics; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic