Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87-7692 in the anesthetized dog.
Forskolin and milrinone both increase cyclic AMP concentrations to enhance cardiac contractility and cause vascular dilation in vitro and in vivo. However, forskolin acts via direct stimulation of adenylate cyclase while milrinone inhibits phosphodiesterase (PDE-III) activity. The forskolin analog, 7-desacetyl-7-(O-propionyl)-hydroxyl-aminocarbonyl-forskolin (P87-7692) has also been shown to directly stimulate adenylate cylase and increase cyclic AMP production in isolated cardiac tissue; however, the in vivo activity of this compound has not been described. Thus, the purpose of this study was to compare the cardiovascular effects of equivalent doses of these compounds and to further characterize the cardiotonic activity of P87-7692 in the anesthetized dog. It was found that both i.v. (3-30 micrograms/kg) and intracoronary (0.1-30 micrograms) administration of milrinone, forskolin, and P87-7692 caused dose-related positive inotropic, coronary, and peripheral vasodilator effects in anesthetized dogs; however, P87-7692 produced significantly greater and more sustained cardiotonic activity following a single 30-micrograms/kg, i.v., bolus injection when compared to the same dose of milrinone and forskolin. Analysis of the dose-response relationship between the changes in contractile force and heart rate for these compounds revealed that a 50% augmentation in contractile force was associated with increases in heart rate of 2.1% for milrinone, 6.4% for P87-7692, and 13.7% for forskolin. These data indicate an improved separation between the chronotropic and inotropic effects for P87-7692 as compared to forskolin. All three compounds also produced coronary vasodilation in vivo and in vitro; however, P87-7692 consistently showed greater activity relative to the same doses of milrinone and forskolin. Moreover, P87-7692 was significantly (p less than 0.05) more potent at relaxing KC1-precontracted canine coronary rings, with an EC50 of 2.1 x 10(-7) M as compared to 1.1 x 10(-6) M for forskolin and 3.2 x 10(-6) M for milrinone. The results of these studies indicate that structural modification of the forskolin molecule can increase the separation between positive inotropic and chronotropic effects, improve the overall hemodynamic profile, and prolong the duration of cardiotonic activity for this class of compounds.
Lebedinsky
Y
Y
Department of Biological Research, Hoechst-Roussel Pharmaceuticals Inc., Sommerville, New Jersey 08876-1258.
Nordstrom
S T
ST
Aschoff
S E
SE
Kapples
J F
JF
O'Malley
G J
GJ
Kosley
R W
RW
Fielding
S
S
Hubbard
J W
JW
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D005576:Colforsin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D002316:Cardiotonic Agents; D011728:Pyridones; D014665:Vasodilator Agents; C076520:7-desacetyl-7-(O-propionyl)hydroxyaminocarbonylforskolin; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D020105:Milrinone