Stimulation of ganglionic muscarinic M1 receptors by a series of tertiary arecaidine and isoarecaidine esters in the pithed rat.
The cardiovascular effects of a series of tertiary esters of arecaidine (1-methyl-1,2,5,6-tetrahydro-3-carboxy-pyridine) and isoarecaidine (1-methyl-1,2,5,6-tetrahydro-4-carboxy-pyridine) were investigated in the pithed rat. For some esters (e.g. arecoline, arecaidine propargyl ester, isoarecoline) a prominent elevation in mean arterial pressure and heart rate was observed following an initial short-lasting and atropine-sensitive depressor response and bradycardia (dose range: 0.1-10 mumol/kg i.v.). The increase in blood pressure and heart rate was not affected by pretreatment with mecamylamine (0.5 and 5 mg/kg i.v.), but could be totally blocked by N-methylatropine (500 micrograms/kg i.v.). Furthermore, the M1 receptor antagonist pirenzepine (300 micrograms/kg i.v.) selectively antagonized these stimulatory cardiovascular responses, indicating that these effects are due to an activation of muscarinic M1 receptors in sympathetic ganglia. As tertiary arecaidine and isoarecaidine esters easily penetrate the blood-brain barrier, they might also stimulate central M1 receptors and thus become lead compounds in the search for an effective drug treatment of Alzheimer's disease.
D000818:Animals; D001115:Arecoline / Q000031:analogs & derivatives* / Q000494:pharmacology; D003655:Decerebrate State; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects*
D011976:Receptors, Muscarinic; C015000:arecaidine esters; D010862:Pilocarpine; D001115:Arecoline