Negative inotropic effects of the new class I antiarrhythmic agents berlafenone and alprafenone on electrically stimulated isolated cardiomyocytes.
Isolated cardiac myocytes from adult rats were used in a stimulation chamber to investigate the negative inotropic effects of propafenone and the new compounds berlafenone (1-2'-biphenyloxy)-3-tert-butylamino-propanol-2-hydrochloride, GK 23 G; CAS 18965-97-4) and alprafenone (1-(4-methylphenyl)-3-[3'-(2-hydroxy-3-tert-pentylaminopropoxy)-4'- methoxyphenyl]-1-propanonhydrochloride, AH 141; CAS 124316-02-5). This chamber is part of a new device that allows the simultaneous evaluation of mechanics and of the energetics of electrically induced contractions of the myocytes. 1. The contractile behaviour of attaches myocytes was analysed by an image processing system using digitized frames of a CCD camera. 2. The metabolic demand for excitation-contraction coupling was calculated from the drop in oxygen tension (registered by a Clark electrode) caused by suspended myocytes when stimulated in the presence of the contraction inhibiting agent 2,3-butanedione monoxime in the stimulation chamber. 3. The apparent refractory period was evaluated by pacing the myocytes with increasing stimulation rates and determining the frequency at which failure of single contractions occurred. All 3 agents produced a reduction in contraction amplitude of the electrically stimulated myocytes with a similar dose-response relationship (IC50 approx. 10 mumol/l). 4 mumol/l berlafenone reduced the contraction amplitude to 62% of control. Under these conditions the energy expenditure of the contracting cells for excitation and excitation-contraction coupling (ion-cycling) was also reduced (77 +/- 17% of control). Since most of this energy is used for Ca2+ (greater than 80%) it may be concluded that a reduced Ca2+ release causes the negative inotropic action of berlafenone.(ABSTRACT TRUNCATED AT 250 WORDS)
Rose
H
H
Institute of Physiology, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen, Fed. Rep. of Germany.
Ionescu
I
I
Pöpping
S
S
Fischer
Y
Y
Kammermeier
H
H
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D003864:Depression, Chemical; D004558:Electric Stimulation; D005260:Female; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D011427:Propiophenones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; D011427:Propiophenones; C061808:bipranol; C076009:alprafenone