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.