Bronchodilator and Cardiovascular Effects of NKH477, a Novel Water-Soluble Forskolin Derivative, in Guinea Pigs

Abstract

ABSTRACT-The bronchodilator and cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride) were evaluated. In anesthetized guinea pigs, i.v. bolus injections of NKH477 (1-100 pg/kg) inhibited the bronchoconstriction induced by inhaled leukotriene D4, increased the heart rate (HR) and decreased the diastolic arterial blood pressure (DBP) in a dose-dependent manner. The bronchodilator effect of NKH477 was 1500 times more potent than that of aminophylline and 17 times less potent than that of isoproterenol. The selectivity of NKH477 for bronchodilation vs an increase in HR was 15 times higher than that of isoproterenol and similar to that of aminophylline; and vs a decrease in DBP, the selectivity was 4 times higher than that of aminophylline and similar to that of isoproterenol. I.v. infusion of NKH477 (0.1-3 fig/kg/min) for 2 hr dose-dependently inhibited the bronchoconstriction induced by i.v. histamine. Isoproterenol (0.1 1,,g/kg/min, i.v.) enhanced the bronchoconstriction after termination of the infusion, whereas NKH477 did not. In conscious guinea pigs, inhalation of NKH477 (0.1-5 mg/ml) concentrationdependently inhibited the bronchoconstriction induced by inhaled histamine, and a high concentration of NKH477 (35.4 mg/ml) increased the HR. The bronchodilator effect of inhaled NKH477 was 15 times less potent than that of isoproterenol. The selectivity of inhaled NKH477 was similar to that of isoproterenol. These results indicate that NKH477 may be useful as a bronchodilator.

Three-Dimensional In Vitro Reaggregates of Embryonic Cardiomyocytes: A Potential Model System for Monitoring Effects of Bioactive Agents

“…As a therapeutic, ISO causes bronchodilation in the bronchial walls and was therefore used to prevent bronchoconstriction due to allergic reactions as well as to treat asthma, bronchitis, and emphysema. [24][25][26] However, several side effects of the β-agonist ISO were reported, including increased heart rate, arrhythmia, and ventricular fibrillation. [27][28][29][30] It was also described in former scientific reports that ISO influences the beating behavior of the heart muscle system of mammals and humans.…”