Interactions of DPI 201-106, a novel cardiotonic agent, with cardiac calcium channels.
The interaction of DPI 201-106, a novel cardiotonic agent, with the calcium entry blocker receptor complex was studied using porcine cardiac sarcolemmal membranes. DPI 201-106 and the chemically-related calcium antagonist, cinnarizine, produce concentration-dependent inhibition of nitrendipine, gallopamil and diltiazem binding to their respective sites in these vesicles. This effect of DPI 201-106 is not stereoselective since resolved stereoisomers of this compound display equal potency in inhibiting each of the binding reactions. Equilibrium ligand binding studies revealed that DPI 201-106 and cinnarizine cause mixed inhibitory patterns at the aralkylamine and benzothiazepine sites (i.e. both Kd and Bmax values were affected) while mainly increasing Kd at the dihydropyridine site. The kinetics of ligand dissociation from the three calcium entry blocker receptors, together with measurements of dihydropyridine association kinetics, further demonstrate that DPI 201-106 interacts at a unique site in the receptor complex and allosterically modulates binding of nitrendipine, gallopamil and diltiazem. The functional consequences of the above interactions with the calcium channel were studied in isolated cardiac preparations. In guinea-pig atria, DPI 201-106 increased force of contraction. This inotropic effect is seen only with the S(-) enantiomer and is unaltered by nitrendipine-, verapamil- or diltiazem-pretreatment, indicating DPI 201-106 does not act as a stimulant of this channel. Furthermore, DPI 201-106 did not alter the inotropic action of Bay K 8644, a calcium channel stimulant. Spontaneous rate of guinea-pig right atria is decreased by both DPI 201-106 and cinnarizine. In addition, potassium-induced contractures in cat papillary muscles are reduced by both agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Siegl
P K
PK
Cardiovascular Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486.
Garcia
M L
ML
King
V F
VF
Scott
A L
AL
Morgan
G
G
Kaczorowski
G J
GJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002936:Cinnarizine / Q000494:pharmacology; D004110:Diltiazem / Q000378:metabolism; D005711:Gallopamil / Q000378:metabolism; D066298:In Vitro Techniques; D008566:Membranes / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009568:Nitrendipine / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D013552:Swine
D015220:Calcium Channels; D002316:Cardiotonic Agents; D010879:Piperazines; D005711:Gallopamil; D002936:Cinnarizine; C046261:DPI 201-106; D009568:Nitrendipine; D004110:Diltiazem; D011188:Potassium; D002118:Calcium