A mechanism for the effects of caffeine on Ca2+ release during diastole and systole in isolated rat ventricular myocytes.
1. The fluorescent indicator Indo-1 was used to measure both [Ca2+]i and [caffeine]i in single ventricular myocytes. 2. Caffeine (at concentrations of 1 mM or above) produced a transient increase of resting [Ca2+]i attributed to the release of Ca2+ ions from the sarcoplasmic reticulum (SR). Simultaneous measurement of [caffeine]i showed that the Ca2+ release only began when [caffeine]i had risen to about 1 mM. Subsequently the rate of release was a steep function of [caffeine]i. It is suggested that this results from a positive feedback as the Ca2+ released activates further release. 3. If external Ca2+ was removed the release of Ca2+ produced by caffeine was delayed such that [caffeine]i rose to a greater concentration before release was initiated. This suggests that an increase of [Ca2+]i increases the efficacy of caffeine to release Ca2+ ions from the SR. 4. Lower concentrations of caffeine (50-500 microM) had no effect on diastolic [Ca2+]i. In contrast they increased systolic [Ca2+]i and contraction. This increase was most obvious if the systolic contraction had previously been decreased either by reducing [Ca2+]o from 1 to 0.25 mM or (in voltage-clamped cells) by decreasing the magnitude of the depolarizing pulse. 5. If the exposure to caffeine was prolonged, this increase of systolic [Ca2+]i and contraction was completely transient. On removal of caffeine, systolic [Ca2+]i and contraction decreased to below control before recovering. 6. During these transient changes of systolic [Ca2+]i and contraction there was no change of the sarcolemmal Ca2+ current. 7. It is suggested that the increase of systolic [Ca2+]i is due to caffeine increasing the fraction of the SR Ca2+ content released during the twitch. 8. The above results concerning both diastolic and systolic [Ca2+]i can be explained by a model in which caffeine increases the affinity with which Ca2+ ions activate Ca2(+)-induced Ca2+ release. At high enough [caffeine], the threshold [Ca2+]i for regenerative Ca2(+)-induced Ca2+ release will be reduced to below the resting [Ca2+]i thus producing a diastolic increase of [Ca2+]i. At lower [caffeine] the threshold is higher than resting [Ca2+]i and caffeine only serves to enhance the release produced during systole.
O'Neill
S C
SC
Department of Physiology, University College London.
Eisner
D A
DA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003971:Diastole; D005456:Fluorescent Dyes; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D013599:Systole; D013997:Time Factors
D005456:Fluorescent Dyes; D007211:Indoles; D002110:Caffeine; C048960:indo-1; D002118:Calcium