title: High affinity regulation of cardiac Cl- and Ca2+ conductances by (13R)-spiroforskolin.
abstract: The effects of a new forskolin derivative, (13R)-spiroforskolin, on the ventricular cAMP-activated chloride current (I(Cl(cAMP))) and the atrial L-type calcium current (I(Ca,L)) were measured by means of whole-cell recording from isolated guinea-pig cardiac myocytes at 30 degrees C and 20-22 degrees C, respectively. In contrast to forskolin, the derivative contains a tetrahydrofuran rather than a tetrahydropyran moiety. (13R)-spiroforskolin activated I(Cl(CAMP)) in 58% of the ventricular myocytes studied. The concentration required for the half maximal effect (EC50 value) amounted to 9.6x10(-11) M and was lower than the EC50 value for forskolin (2.4x10(-8) M). (13R)-spiroforskolin evoked a smaller maximal I(Cl(cAMP)) amplitude than forskolin. The rundown of the (13R)-spiroforskolin-activated I(Cl(cAMP)) was faster than that of the forskolin-induced current. Neither forskolin nor (13R)-spiroforskolin in maximally effective concentrations increased I(Cl(cAMP)) in cells containing high concentrations of cAMP. Furthermore, as an activator of atrial I(Ca,L) (13R)-spiroforskolin displayed a smaller activation and a lower EC50 value (5.8x10(-10) M) than forskolin (EC50 value: 3.7x10(-7) M). The effect of (13R)-spiroforskolin was observed in only 30% of the atrial cells studied. None of the drugs exerted a stimulatory effect in atrial cells containing a high [cAMP]. The washout of the drug effect was significantly faster in (13R)-spiroforskolin- than in forskolin-treated atrial myocytes. We conclude that (13R)-spiroforskolin as a forskolin derivative displays unique characteristics. It is a more potent but less efficacious activator of cardiac ionic conductances than the parent compound. The results suggest that (13R)-spiroforskolin, like forskolin, most probably exerts its effects via stimulation of the adenylyl cyclase.
authors.affiliation: Arbeitsgruppe Muskelphysiologie, Ruhr-Universität, Bochum, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Traebert
authors.forename: I
authors.initials: I
authors.lastname: Trebess
authors.forename: S
authors.initials: S
authors.lastname: Erlenkamp
authors.forename: J
authors.initials: J
authors.lastname: Hüser
authors.forename: J
authors.initials: J
authors.lastname: Kockskämper
authors.forename: H G
authors.initials: HG
authors.lastname: Glitsch
authors.forename: C
authors.initials: C
authors.lastname: Hartung
authors.forename: P
authors.initials: P
authors.lastname: Welzel
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016275:Atrial Function; D015220:Calcium Channels / Q000187:drug effects*; D018118:Chloride Channels / Q000187:drug effects*; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D018408:Patch-Clamp Techniques; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology; D013141:Spiro Compounds / Q000494:pharmacology*; D013997:Time Factors; D016276:Ventricular Function
chemical_list: D015220:Calcium Channels; D018118:Chloride Channels; D013141:Spiro Compounds; C116892:spiroforskolin; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP