Assessment of the Effects of L- and N-Type Ca2+ Channel Blocking Drugs Using Canine Blood-Perfused Papillary Muscle Preparations

Abstract

It is important to accurately and conveniently assess the effects of L- and N-type Ca(2+) channel blocking drugs, which are commonly used for treatment of hypertension, but no method is available to simultaneously assess the effects of them in the same preparation. We have therefore designed an ex vivo method to measure the changes in contractile response of anterior papillary muscle of right ventricle and myocardial interstitial norepinephrine (NE) level using canine blood-perfused papillary muscle preparations. Papillary muscle-developed tension (PMDT) induced by an electronic stimulator was measured with force transducer. Myocardial interstitial NE effluent was collected by microdialysis fiber, which was implanted at the base of the papillary muscle, and measured with high performance liquid chromatography. Cilnidipine, a typical L- and N-type Ca(2+) channel blocker, was used to prove the efficiency of this method. First, to assess the effects of drugs on L-type Ca(2+) channel, the changes in basal PMDT were measured. Cilnidipine and nicardipine, a selective L-type Ca(2+) channel blocker, but not omega-conotoxin GVIA (omega-CTX), a selective N-type Ca(2+) channel blocking peptide, decreased basal PMDT dose-dependently. Second, to assess the effects of drugs on N-type Ca(2+) channel, the changes in PMDT and myocardial interstitial NE level by intracardiac sympathetic ganglion stimulation were measured. Cilnidipine and omega-CTX, but not nicardipine, dose-dependently reduced sympathomimetic increases in PMDT and myocardial interstitial NE level. These results indicate that our method is efficient to assess the effects of various L- and N-type Ca(2+) channel blocking drugs in the same papillary muscle preparation.