Potassium channel modulation: a new drug principle for regulation of smooth muscle contractility. Studies on isolated airways and arteries
- PMID: 8960816
Potassium channel modulation: a new drug principle for regulation of smooth muscle contractility. Studies on isolated airways and arteries
Abstract
K+ channels play a key role in regulation of membrane potential and cell excitability. Several different types of K+ channels have been identified and the presence, characteristics and functions of these channels vary among different tissues. The 3 most important K+ channels in smooth muscle are the KATP (activated by a fall in intracellular ATP and a rise in nucleotide diphosphates and blocked by glibenclamide), BKCa (activated by a rise in intracellular Ca2+) and Kv (activated by depolarization). Cromakalim, pinacidil and nicorandil are members of a rapidly increasing group of novel drugs which open K+ channels. Opening of such channels leads to K+ efflux, membrane hyperpolarization, reduced excitability and smooth muscle relaxation. The purpose of the studies included in this thesis was to investigate this novel drug principle of K+ channel modulation on smooth muscle contractility of isolated airways and arteries and on neuroeffector transmission in airways. Smooth muscle contractility was measured in airway and vascular ring preparations suspended in isometric myographs. Neurotransmitter release was elicited by transmural electrical field stimulation. The major findings were: 1) Membrane depolarization by high extracellular K+ concentrations induced contraction of airway smooth muscle that was easily relaxed by Ca2+ antagonists and abolished in a Ca2+ free medium indicating that K+ contraction is triggered by Ca2+ influx through voltage-operated Ca2+ channels. Indomethacin was required to obtain reproducible responses upon repeated exposure to K+ suggesting that endogenous prostaglandins are released by K+ and interferes with its contractile effect. K+ depolarization was shown to be a valuable pharmacological tool for detection of drugs acting by K+ channel opening. The prototype K+ channel opener cromakalim relaxed contractions induced by 20-30 mM K+ but had no effect against contraction induced by 124 mM K+. This was a unique profile of action not shared by other types of airway and vascular smooth muscle relaxants. As the extracellular K+ concentration is raised the outward directed electrochemical gradient for K+ is reduced and at high K+ concentrations the effect of K+ channel opening is negligible. Although the K+ channel opener pinacidil had a higher relaxant potency against contraction induced by 30 mM K+ than by 124 mM K+, it still relaxed the latter contraction indicating an additional K+ channel independent mechanism of action of the drug. When K+ depolarization is used as a pharmacological tool, it is essential to maintain osmolarity. Addition of KCI directly to the tissue bath solution, which previously was a commonly applied technique, produced confounding and unwanted effects due to hyperosmolarity per se. 2) Pinacidil and cromakalim relaxed guinea-pig trachea either tone was spontaneous or induced by a range of airway spasmogens (histamine, PGF2 alpha, LTC4/LTD4 or carbachol) of relevance as asthma mediators. The relaxant effectiveness of the drugs was reduced when tone was elicited by carbachol. The airway smooth muscle relaxation produced by pinacidil and cromakalim was selectively blocked by the antidiabetic sulfonylureas glibenclamide, glipizide and glibornuride and also by phentolamine. These drugs are blockers of KATP which therefore indicates that this channel is the target for cromakalim and pinacidil in airway smooth muscle. Additional to the antagonistic action against K+ channel openers the sulfonylurea KATP blockers and phentolamine at higher concentrations relaxed airway smooth muscle by yet unknown mechanisms that seemed unrelated to KATP. 3) Cromakalim and pinacidil inhibited nerve-mediated e-NANC contractile responses in guinea-pig bronchi. Such responses are due to release of SP and related tachykinins from sensory nerve endings. These neuropeptides cause bronchoconstriction and airway inflammation and may possibly play an important role in the pathophysiology of asthma.
Similar articles
-
Effects of antidiabetic sulphonylureas, cromakalim and their interaction in guinea-pig isolated tracheal smooth muscle.Pulm Pharmacol. 1993 Sep;6(3):185-92. doi: 10.1006/pulp.1993.1025. Pulm Pharmacol. 1993. PMID: 8219573
-
Pharmacology and structure-activity relationships for KATP modulators: tissue-selective KATP openers.J Cardiovasc Pharmacol. 1994;24 Suppl 4:S12-7. J Cardiovasc Pharmacol. 1994. PMID: 7898103 Review.
-
RP 49356 and cromakalim relax airway smooth muscle in vitro by opening a sulphonylurea-sensitive K+ channel: a comparison with nifedipine.J Pharmacol Exp Ther. 1991 Feb;256(2):480-5. J Pharmacol Exp Ther. 1991. PMID: 1899701
-
The inhibitory effects of cromakalim and its active enantiomer BRL 38227 against various agonists in guinea pig and human airways: comparison with pinacidil and verapamil.J Pharmacol Exp Ther. 1992 May;261(2):429-37. J Pharmacol Exp Ther. 1992. PMID: 1578358
-
Potassium channel opening drugs and the airways.Braz J Med Biol Res. 1992;25(10):983-98. Braz J Med Biol Res. 1992. PMID: 1342832 Review.
Cited by
-
Testosterone Enhances KV Currents and Airway Smooth Muscle Relaxation Induced by ATP and UTP through P2Y4 Receptors and Adenylyl Cyclase Pathway.Int J Mol Sci. 2024 Apr 24;25(9):4652. doi: 10.3390/ijms25094652. Int J Mol Sci. 2024. PMID: 38731872 Free PMC article.
-
Theophylline-Induced Relaxation Is Enhanced after Testosterone Treatment via Increased KV1.2 and KV1.5 Protein Expression in Guinea Pig Tracheal Smooth Muscle.Int J Mol Sci. 2023 Mar 20;24(6):5884. doi: 10.3390/ijms24065884. Int J Mol Sci. 2023. PMID: 36982957 Free PMC article.
-
Antispasmodic Effect of Asperidine B, a Pyrrolidine Derivative, through Inhibition of L-Type Ca2+ Channel in Rat Ileal Smooth Muscle.Molecules. 2021 Sep 9;26(18):5492. doi: 10.3390/molecules26185492. Molecules. 2021. PMID: 34576962 Free PMC article.
-
Choline Triggers Exacerbations of Chronic Obstructive Pulmonary Disease in Patients Infected with Pseudomonas aeruginosa.Curr Respir Med Rev. 2016;12(2):167-174. doi: 10.2174/1573398X12999160506104327. Curr Respir Med Rev. 2016. PMID: 29386986 Free PMC article.
-
Chloroform Extract of Artemisia annua L. Relaxes Mouse Airway Smooth Muscle.Evid Based Complement Alternat Med. 2017;2017:9870414. doi: 10.1155/2017/9870414. Epub 2017 Nov 12. Evid Based Complement Alternat Med. 2017. PMID: 29259649 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Research Materials
Miscellaneous