The mode of action of 4-aminopyridine on the chronotropic and inotropic responses in the isolated, blood-perfused dog heart

Abstract

The effects of 4-aminopyridine (4-AP, 0.3 to 300 μg) on atrial rate muscle contractile force were investigated in the isolated, blood-perfused dog atrial preparation. Low doses (less than 30 μg) of 4-AP injected into the sinus node artery caused a dose-dependent positive inotropic response and a negligible positive chronotropic response. A higher dose (300 μg) of 4-AP induced a transient positive chronotropic response followed by a negative response and positive and negative inotropic responses. The negative cardiac responses to 4-AP were completely inhibited by an adequate dose of atropine and were potentiated by physostigmine. TTX or C 6 suppressed partly, but significantly the negative responses induced by 4-AP. On the other hand, the negative responses to electrical stimulation (ES) were inhibited by atropine, C 6 and TTX and those to ACh were blocked by atropine but not by C 6 or TTX. The positive responses to 4-AP were not affected by propranolol but were potentiatedby atropine. The positive inotropic response to 4-AP was significantly suppressed by a calcium channel blocker, ditiazem. From these results, it is concluded that the cardiac responses to 4-AP are composed of direct positive responses and negative responses which are related to activation of parasympathetic ganglionic neurotransmission.