Relaxant effects of forskolin on guinea pig tracheal smooth muscle

Abstract

We investigated the relaxant effects of forskolin, a diterpene derivative isolated from the roots of Coleus forskohlii, on guinea pig airway smooth muscle by measuring the isometric tension of tracheal smooth muscle in vitro and transcutaneous Po2 during the histamine inhalation test (HIT) in vivo. Forskolin (10(-9)-10(-5) M) caused dose-dependent relaxant effects on resting tone and on leukotriene C4 (10(-7) M)-, leukotriene D4 (10(-7) M)-, and carbachol (3 X 10(-6) M)-induced contraction of tracheal smooth muscle. Moreover, with propranolol pretreatment the relaxant effect of forskolin on tracheal smooth muscle did not change, whereas with the same pretreatment the relaxant effect of isoproterenol diminished. Forskolin (10(-8)-10(-6) M) raised tissue cyclic AMP levels dose-dependently in tracheal smooth muscle (6.7-359.9 pmol/mg protein). Forskolin (1 mg/kg) administered subcutaneously raised the respiratory threshold of (RT-histamine in the HIT. The determination of the RT-histamine by measuring tcPo2 was possible without anesthesia. These results suggest that forskolin relaxes airway smooth muscle in guinea pigs in vitro and in vivo by raising tissue cyclic AMP levels and that its actions are independent of beta-adrenoceptors.

Relaxant effects of NKH477, a new water‐soluble forskolin derivative, on guinea‐pig tracheal smooth muscle: the role of Ca2+‐activated K+ channels

“…These findings suggest that NKH477 may have a potent bronchorelaxant action at doses showing positive inotropic and vasodilating effects. It was found by previous investigators that the EC 50 of forskolin in relaxing the guinea‐pig tracheal smooth muscle precontracted by cholinoceptor agonists or leukotrienes was in the range 94–740 n m (Tsukawaki et al , 1987; Hiramatsu et al , 1994). The bronchodilating potency of NKH477 may, therefore, be higher than that of forskolin.…”

“…Bronchorelaxation in response to β‐adrenoceptor stimulation is mediated, at least in part, by an increase of the intracellular concentration of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) (Torphy & Hall, 1994). This may suggest a potential benefit of drugs, which stimulate adenylate cyclase directly like forskolin (Seamon & Daly, 1981; Muller & Baer, 1983), as an alternative method for the treatment of bronchial asthma (Tsukawaki et al , 1987), because their effects may not be restricted by downregulation or desensitization of β‐adrenoceptors (Kume & Takagi, 1997). The poor water solubility and the low oral activity of forskolin has limited its clinical usage both as an i.v.…”

Structure-activity relationship in N3-alkyl-xanthine derivatives.

“…The test was performed using an organ bath method as previously reported (12). We also estimated the effect of each compound on c-AMP phosphodiesterase (PDE) in homogenates prepared from isolated guinea pig tracheal smooth muscle.…”

MaxiK Channel Mediates .BETA.2-Adrenoceptor-activated Relaxation to Isoprenaline through cAMP-dependent and -independent Mechanisms in Guinea-pig Tracheal Smooth Muscle.

“…The basis for this deeply engrained cAMP dogma is that isoprenaline and β2-adrenoceptor agonists elevates cAMP content through activating adenylyl cyclase that is coupled to a heterotrimeric guanine nucleotide-binding protein, Gs (Nakagawa et al, 1986;Jones et al, 1990;Ellis et al, 1995;McGrogan et al, 1995;Hoiting et al, 1996). Furthermore, the capability of airway smooth muscle to relax in response to adenylyl cyclase activators (Tsukawaki et al, 1987;Jones et al, 1990;Devillier et al, 2001), phosphodiesterase inhibitors (Tsukawaki et al, 1987;Jones et al, 1990;Devillier et al, 2001) and membranepermeable cyclic AMP analogues (Watanabe et al, 1976;Jones et al, 1990) also supports the primary role for cAMP in β2-adrenoceptor-activated airway smooth muscle relaxation. cAMP is considered to catalyze the activation of protein kinase A (PKA), which in turn phosphorylates key regulatory proteins associated with the control of airway smooth muscle tone (Johnson, 1998).…”