PACAP induces bradycardia in guinea-pig heart by stimulation of atrial cholinergic neurones.
Based on previous studies which indicated that pituitary adenylate cyclase activating peptide (PACAP) acts as a positive inotropic and chronotropic substance in different species via the cAMP signal transduction pathway, the objective of the present work was to investigate cAMP-regulated myocardial key proteins in response to PACAP in isolated ventricular cells of the guinea pig. Surprisingly, the two molecular forms of PACAP, PACAP(1-27) and PACAP(1-38), showed no effect on intracellular cAMP-levels, L-type Ca2+ channel current or phosphorylation of troponin inhibitor (TnI) and phospholamban (PLB). Additionally, inotropy of isolated guinea-pig ventricular strips was not affected by the neuropeptide. However, in isolated spontaneously beating guinea-pig atria, PACAP(1-27) and PACAP(1-38), but not VIP induced severe bradycardia in a dose-dependent manner. This effect could be prevented by preincubation with the PACAP receptor antagonist PACAP(6-38), by atropine and by omega-conotoxin, a blocker of neuronal N-type Ca2+ channels. PACAP stimulates release of [3H]-labelled acetylcholine. Only preparations showing an increase in [3H]acetylcholine release developed bradycardia, indicating a causal relationship between both phenomena. It was concluded that PACAP exerts no influence on guinea-pig ventricular tissue, but induces negative chronotropic effects in isolated guinea-pig atria by stimulation of acetylcholine release from parasympathetic neurons via PACAP type 1 receptors.
Department of Internal Medicine, University of Kiel, Germany.
J
J
Seebeck
W E
WE
Schmidt
H
H
Kilbinger
J
J
Neumann
N
N
Zimmermann
S
S
Herzig
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001919:Bradycardia / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051381:Rats; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000378:metabolism; D015398:Signal Transduction; D000099211:Phospholamban
D000109:Acetylcholine; D001285:Atropine; D002135:Calcium-Binding Proteins; D000242:Cyclic AMP; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D000099211:Phospholamban; C495403:Adcyap1 protein, rat