piperidines and alinidine

The effect of alinidine, a bradycardic agent, on the vasodilator responses to acetylcholine was examined in isolated and perfused dog coronary arteries. Single injections of acetylcholine (10(-12)-10(-6) mol) and carbachol (10(-10)-10(-6) mol) produced dose-dependent vasodilations. The endothelial removal by a bolus injection of saponin (1 mg) inhibited those vasodilations. Alinidine (10(-6) M) shifted the dose-response curves of acetylcholine and carbachol to the right, but it did not affect those for isosorbide dinitrate, isoproterenol and adenosine. The rank order of potency of muscarinic antagonists for inhibiting the acetylcholine-induced vasodilation was 4-DAMP greater than or equal to atropine greater than AF-DX 116 greater than or equal to pirenzepine greater than alinidine. Alinidine was approximately 100 times less potent than atropine. Single injection of alinidine (10(-8)-10(-6) mol) dilated the dog coronary artery in a dose-related manner. The vasodilation was not affected by the pretreatment with phentolamine (10(-6) M), pindolol (10(-6) M), atropine (10(-6) M), chlorpheniramine (10(-6) M), cimetidine (10(-6) M) or methysergide (10(-6) M). These results suggest that alinidine has a weak anti-muscarinic effect on the endothelium-dependent vasodilation of the dog coronary artery.

Topics: Acetylcholine; Animals; Carbachol; Clonidine; Coronary Vessels; Dogs; Female; In Vitro Techniques; Male; Parasympatholytics; Piperidines; Pirenzepine; Vasodilation

Vascular smooth muscle differs from myocardial tissue in several critical ways: (1) calcium ion entry is achieved by at least two channels; (2) both alpha-1 and alpha-2 postjunctional receptors regulate vascular tone; (3) calmodulin increases the activity of the myosin light chain kinase; (4) cyclic AMP decreases rather than increases cytosolic calcium ion concentration; (5) angiotensin increases vascular tone without a positive inotropic effect by acting on angiotensin receptors which ultimately increase vascular cytosolic calcium. Each of these factors allows for a specific therapeutic approach to the problem of congestive heart failure by altering vascular tone. Alternatively, positively inotropic interventions aim to increase the cytosolic calcium ion concentration in the myocardium. Besides the conventional approach by digitalis glycosides, beta-agonists and amrinone are also thought to increase the myocardial cytosolic calcium ion concentration. Hence many of the therapeutic approaches to congestive heart failure aim to reduce vascular smooth muscle calcium or to increase myocardial muscle cell calcium.

Topics: Calcium; Calcium Channel Blockers; Calmodulin; Cardiotonic Agents; Clonidine; Cyclic AMP; Cytosol; Digitalis Glycosides; Diuretics; Heart Failure; Humans; Ketanserin; Models, Cardiovascular; Muscle, Smooth, Vascular; Myocardium; Myosins; Piperidines; Receptors, Adrenergic, alpha; Vasodilator Agents