[Studies on cardiac ingredients of plants (IV). Effect of reduced proscillaridins on guinea-pig hearts].
Five hydrogenated proscillaridins (bufa-4,20-dienolide (PH21), bufa-4,20 (22)-dienolide (PH22), 20R-bufa-4-enolide (PH4-R), 20S-bufa-4-enolide (PH4-S), chola-4-enoate (PH4-E) ) were prepared semi-synthetically, and their pharmacological effect was studied using guinea pigs. The positive inotropic effect (PIE) was examined in papillary muscles isolated from guinea-pig hearts. These compounds produced PIE, dose-dependently; the Dose-PIE curve was characterized by a faster PIE development than that by the parent compound proscillaridin (PS). The concentrations at which half maximum PIE just developed (pD2) were as follows: PS, 7.4; PH22, 6.2; PH21, 5.8; PH4-R, 5.3; PH4-E, 5.0; and PH4-S, 4.9. The time required to the half maximum effect (T50) at a given concentration of pD2 was measured in min: PS, 33; PH4-E, 22; PH22, 15; PH21, 7; PH4-S, 7; and PH4-R, 2. The speeds of inotropy of these compounds depended on the position of lactone ring reduction, though they have the same lipophilicity (Rm). Concentration-PIE curves of reduced PS-compounds were characterized by a decrease in potency and an increase in efficacy. PH21 and PH4-R produced PIE over wider range of concentrations than those of the other compounds. When PH21 at the dose of 11.9 mg/kg, an equivalent dose of 4.4 times the pD2 values, was administrated intravenously by bolus injection into guinea pigs, no arrhythmias were observed on the ECG.(ABSTRACT TRUNCATED AT 250 WORDS)
Sakakibara
J
J
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Mori
J
J
Nagai
S
S
Hotta
Y
Y
Takeya
K
K
D000818:Animals; D002018:Bufanolides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011442:Proscillaridin / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
D002018:Bufanolides; D011442:Proscillaridin