Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative.
The cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride), a novel water-soluble forskolin derivative, were investigated in dogs. Intravenous (i.v.) injections of NKH477 (1-30 micrograms/kg) caused dose-related increases in left ventricular dP/dtmax (LVdP/dtmax), coronary and femoral artery blood flow (CBF, FBF), heart rate (HR), and myocardial oxygen consumption (MVO2) and a dose-related decrease in blood pressure (BP) in anesthetized dogs. The regression analysis between CBF and MVO2 showed that NKH477 did not influence substantially the balance of oxygen supply and demand. Infusions of NKH477 (0.15-0.6 microgram/kg/min i.v.) also increased LVdP/dtmax, cardiac output (CO), and HR and decreased BP, pulmonary arterial diastolic pressure, and total peripheral resistance (TPR) in a dose-dependent manner. In contrast to forskolin, NKH477 administered intraduodenally (0.05-0.2 mg/kg) and orally (0.15 and 0.3 mg/kg) clearly exhibited cardiovascular actions, as it did in i.v. administration, indicating that NKH477 is orally active. No arrhythmias were induced by NKH477 in any study. NKH477, like forskolin, showed adenylate cyclase stimulant activity in guinea pig ventricular membrane but did not inhibit Na+, K(+)-ATPase or phosphodiesterase (PDE) activity. Thus, NKH477 can be characterized as a potent, orally active, water-soluble forskolin derivative, which suggests that NKH477 is a useful inodilator for treatment of heart failure, especially in the severe stage with beta-adrenoceptor downregulation.
Hosono
M
M
Research Laboratories, Pharmaceuticals Group, Tokyo, Japan.
Takahira
T
T
Fujita
A
A
Fujihara
R
R
Ishizuka
O
O
Tatee
T
T
Nakamura
K
K
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D005576:Colforsin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012044:Regression Analysis; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D002316:Cardiotonic Agents; D005576:Colforsin; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; D000254:Sodium-Potassium-Exchanging ATPase