Differential effects of tert-butyl-benzohydroquinone, a putative SR Ca2+ pump inhibitor, on isometric relaxation during the staircase in the rabbit and rat ventricle.
1. The effects of 2,5 di-(tert-butyl)-1,4-benzohydroquinone (TBQ), a putative inhibitor of the sarcoplasmic reticulum Ca2+ pump, on mechanical relaxation and contraction-relaxation coupling have been studied at different frequencies (0.5-3 Hz) in isometrically contracting isolated right ventricular preparations of rabbit and rat at 37 degrees C. Two types of mechanical responses have been studied: the twitch tension and the force transient (rewarming spike, RSp) following a rapid cooling contracture (RCC, an index of sarcoplasmic reticulum Ca2+ content) on return to 37 degrees C. 2. The coupling between contraction and relaxation was assessed by two methods: (a) by evaluation of the variation of the slope relating the maximal rate of tension fall to twitch peak tension; (b) by modelling the twitch according to the following equation: TwT (t) = C x (t/A)B x exp(1-(t/AB) where TwT(t) is the time course of isometric tension, t is time, C and A are an inotropic and a chronotropic index respectively and B, a contraction-relaxation coupling index (Nwasokwa, 1993). 3. In the rabbit ventricle, 30 microM TBQ did not prevent the frequency-induced shortening of the twitch time to half-relaxation (t1/2) and of the time constant (tau) describing the final part of the RSp relaxation (tau decreased from 140 ms (0.5 Hz) to 133 ms (3 Hz) in control and from 253 ms (0.5 Hz) to 197 ms (3 Hz) after exposure to TBQ). By contrast, at a given frequency, the prolongation of relaxation induced by TBQ was proportional to its inotropic effect (unchanged slopes and B values) but TBQ did not prevent the acceleration of relaxation observed at high frequencies: B increased from 2.02 (0.5 Hz) to a peak value of 2.18 (1 Hz) in control and from 1.88 (0.5 Hz) to a maximum of 2.48 (2 Hz) after TBQ exposure. TBQ significantly attenuated the decay of RCCs elicited after increasingly longer periods of muscle quiescence as normally observed in control conditions. 4. In the rat ventricle, TBQ depressed relaxation more than expected on the basis of its negative inotropic effects (B decreased from 2.16 to 1.84 at 0.5 Hz and from 2.15 to 1.66 at 3 Hz). TBQ also slowed the rate of RSp relaxation (tau increased from 95 ms to 168 ms at 0.5 Hz, and from 109 ms to 149 ms at 3 Hz) and increased twitch t1/2. By contrast with the results obtained in the rabbit ventricle, B, tau and t1/2 were frequency-insensitive whether or not TBQ was present. 5. TBQ exerts negative inotropic effects consistent with inhibition of the SR Ca2+ pump. In the rabbit ventricle, the TBQ-induced potentiation of relaxation acceleration at high pacing frequencies suggests the involvement of counteracting Ca(2+)-mediated mechanisms probably via Ca(2+)-calmodulin-activated kinases. In the rat ventricle, TBQ did not have any differential effect on relaxation depending on the frequency, probably because the extent of the negative staircase was small in the present experimental conditions.
Baudet
S
S
Laboratoire de Physiologie et Pharmacologie Cellulaire et Moléculaire, Hôpital G. R. Laënnec, Nantes.
Khammari
A
A
Noireaud
J
J
Le Marec
H
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D006873:Hydroquinones / Q000494:pharmacology*; D066298:In Vitro Techniques; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010210:Papillary Muscles / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D013045:Species Specificity; D016276:Ventricular Function
D004791:Enzyme Inhibitors; D006873:Hydroquinones; C019359:2,5-di-tert-butylhydroquinone; D000252:Calcium-Transporting ATPases; D002118:Calcium