Roles of K+ and Cl- channels in cAMP-induced pulmonary vasodilation

Exp Lung Res. Jan-Feb 1998;24(1):71-83. doi: 10.3109/01902149809046055.

Abstract

Increase in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) is a common pathway for many clinically used drugs to cause pulmonary artery (PA) relaxation. Activity of sarcolemmal K+ and Cl(-)-channels is an important determinant of membrane potential (Em), which, in turn, plays a critical role in regulating pulmonary vascular tone. Whether K+ and Cl- channels were involved in cAMP-induced PA relaxation was tested using isolated rat PA rings. Raising extracellular K+ concentration from 20 to 142.7 mM increased the K(+)-evoked contraction, but significantly decreased the relaxation induced by the adenylate cyclase activator, forskolin (FSK, 2.5 microM), suggesting that FSK-induced PA relaxation depended on transmembrane K+ gradient. Indeed, the FSK-induced relaxation was inhibited by 4-aminopyridine (4-AP, 10 mM), a voltage-gated K+ (Kv) channel blocker. Neither the Ca(2+)-activated K+ channel blocker, charybdotoxin, nor the ATP-sensitive K+ channel blocker, glibenclamide, had this effect. Furthermore, reducing extracellular Cl- concentration from 142.7 to 50 mM significantly decreased the FSK-induced relaxation in PA rings precontracted with 142.7 mM K+ (Ek approximately 0 mV), but negligibly affected the evoked contraction. This indicates that transmembrane Cl- gradient also regulates FSK-induced PA relaxation. Indeed, the Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 10 microM), significantly inhibited the FSK-induced relaxation in PA rings preconstricted by 142.7 mM K+. In summary, the data suggest that the cAMP-induced PA relaxation is attributable, at least partly, to both activation of the 4-AP-sensitive Kv channels and stimulation of the NPPB-sensitive Cl- channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Membrane / metabolism
  • Chloride Channels / physiology*
  • Colforsin / pharmacology
  • Cyclic AMP / physiology*
  • In Vitro Techniques
  • Male
  • Membrane Potentials / physiology
  • Muscle Relaxation / drug effects
  • Muscle Relaxation / physiology*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology*
  • Potassium Channel Blockers
  • Potassium Channels / physiology*
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Vasodilation / drug effects
  • Vasodilation / physiology*

Substances

  • Chloride Channels
  • Potassium Channel Blockers
  • Potassium Channels
  • Colforsin
  • Cyclic AMP