Klin Monbl Augenheilkd 2001; 218(5): 338-340
DOI: 10.1055/s-2001-15894
EXPERIMENTELLE STUDIE

Georg Thieme Verlag Stuttgart · New York

Vasorelaxing effect of the potassium (K+)-channel opener pinacidil in isolated porcine ciliary arteries

Vasorelaxierende Eigenschaften von Pinacidil an isolierten Ziliararterien des SchweinesThomas Morf, Peili Zhu, Josef Flammer, Ivan  O. Haefliger
  • Laboratory of Ocular Pharmacology and Physiology, University Eye Clinic Basel, Mittlere Straße 91, PO Box, CH-4012 Basel
Further Information

Publication History

Publication Date:
31 December 2001 (online)

Hintergrund Die vorliegende pharmakologische Studie wurde durchgeführt, um die vasorelaxierende Wirkung von Pinacidil (ein Kalium-Kanal-Öffner) an isolierten Ziliararterien des Schweines zu evaluieren.

Material und Methoden An Ziliararterien wurde mittels eines Myographsystems die isometrische Kraft bei kumulativ zunehmenden Konzentrationen (1 nM - 100 μM) von Pinacidil gemessen. Die Experimente wurden an durch Thromboxane A2 Analogon U 46619 (0,1 μM) präkontrahierten Ziliararterien durchgeführt. Relaxationen wurden in Prozent einer durch U 46619 (0,1 μM) induzierten Kontraktion exprimiert.

Ergebnisse Pinacidil zeigte eine starke konzentrationsabhängige Abnahme der Kontraktionskraft in mit U 46619 präkontrahierten Ziliararterien (100 μM: 112 ± 2 %; n=7). Dieser Effekt war signifikant (p < 0,0001) verschieden von einer Kontrollgruppe (18 ± 6 %; n=6). Die Konzentration von Pinacidil, welche 50 % der maximalen Relaxation induzierte (pD50), betrug 5,3 ± 0,1 (- log M).

Schlussfolgerung Pinacidil zeigt an isolierten Ziliararterien des Schweines starke vasorelaxierende Eigenschaften.

Abstract

Purpose The aim of this study was to investigate the vasorelaxing properties of pinacidil (a potassium-channel-opener) in isolated porcine ciliary arteries.

Methods Isometric contractions of isolated porcine ciliary arteries were measured with a myograph system. The vessels were first precontracted with the thromboxane A2 analog U 46619 (0.1 μM), and then exposed, in a cumulative manner, to increasing concentrations of pinacidil (1 nM - 100 μM). Relaxations have been expressed in percent of the maximal contraction evoked by U 46619 (0.1 μM).

Results Pinacidil showed a pronounced concentration-dependent relaxing effect in isolated porcine ciliary arteries. The difference between pinacidil and time-control experiments was significant (100 μM: 112 ± 2 % vs. 18 ± 6 %, P < 0.0001). The half-maximal concentration (pD50) value was 5.3 ± 0.1 (- log M).

Conclusions The present study indicates that pinacidil has marked vasorelaxing properties in isolated porcine ciliary arteries.

References

  • 01 Lawson  K. Potassium channel activation: A potential therapeutic approach?.  Pharmacol Ther. 1996;  70 39-63
  • 02 Atwal  K S. Pharmacology and structure-activity relationships for KATP modulators: Tissue-selective KATP openers.  J Cardiovasc Pharmacol. 1994;  24 (Suppl) 12-17
  • 03 Bareggi  S R, Gambaro  V, Valenti  M, Benvenuti  C. Pharmacodynamics and Pharmacokinetics of Pinacidil in Normotensive Volunteers after Repeated Doses of a New Slow-release Tablet Formulation.  Arzneim.-Forsch./Drug Res. 1999;  49 21-25
  • 04 Ahnfelt-Ronne  I. Pinacidil. Preclinical investigations.  Drugs. 1988;  36 (Suppl 7) 4-9
  • 05 Iwamoto  T, Nishimura  N, Morita  T, Sukamoto  T. Differential vasorelaxant effects of K(+)-channel openers and Ca(2+)-channel blockers on canine isolated arteries.  J Pharm Pharmacol. 1993;  45 292-297
  • 06 O'Donnell  S R, Wanstall  J C, Kay  C S, Zeng  X P. Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF2 alpha or endothelin.  Br J Pharmacol. 1991;  102 311-316
  • 07 Nielsen-Kudsk  J E, Bang  L. Effects of pinacidil and other cyanoguanidine derivatives on guinea-pig isolated trachea, aorta and pulmonary artery.  Eur J Pharmacol. 1991;  201 97-102
  • 08 Masuzawa  K, Matsuda  T, Asano  M. Evidence that pinacidil may promote the opening of ATP-sensitive K+ channels yet inhibit the opening of Ca2(+)-activated K+ channels in K(+)-contracted canine mesenteric artery.  Br J Pharmacol. 1990;  100 143-149
  • 09 Nakajima  S, Kurokawa  K, Imamura  N, Ueda  M. A study on the hypotensive mechanism of pinacidil: relationship between its vasodilating effect and intracellular Ca2+ levels.  Jpn J Pharmacol. 1989;  49 205-213
  • 10 Haefliger  I O, Flammer  J, Lüscher  T F. Nitric oxide and endothelin-1 are important regulators of human ophthalmic artery.  Invest Ophthalmol Vis Sci. 1992;  33 2340-2343
  • 11 Haefliger  I O, Flammer  J, Lüscher  T F. Heterogeneity of endothelium-dependent regulation in ophthalmic and ciliary arteries.  Invest Ophthalmol Vis Sci. 1993;  34 1722-1730
  • 12 Dettmann  E S, Lüscher  T F, Flammer  J, Haefliger  I O. Modulation of endothelin-1-induced contractions by magnesium/calcium in porcine ciliary arteries.  Graefe's Arch Clin Exp Ophthalmol. 1998;  236 47-51
  • 13 Zhu  P, Beny  J L, Flammer  J, Lüscher  T F, Haefliger  I O. Relaxation by bradykinin in porcine ciliary artery. Role of nitric oxide and K+-channels.  Invest Ophthalmol Vis Sci. 1997;  38 1761-1767
  • 14 Zhu  P, Dettmann  E S, Resink  T J, Lüscher  T F, Flammer  J, Haefliger  I O. Effect of Ox-LDL on endothelium-dependent response in pig ciliary artery: prevention by an ET(A) antagonist.  Invest Ophthalmol Vis Sci. 1999;  40 1015-1020
  • 15 Starrett  J E, Dworetzky  S I, Gribkoff  V K. Modulators of large-conductance calcium-activated potassium channels as potential therapeutic targets.  Curr Pharm Design. 1996;  2 413-428
  • 16 Fletcher  A E, Battersby  C, Adnitt  P, Underwood  N, Jurgensen  H J, Bulpitt  C J. Quality of life on antihypertensive therapy: a double-blind trial comparing quality of life on pinacidil and nifedipine in combination with a thiazide diuretc. European Pinacidil Study Group.  J Cardiovasc Pharmacol. 1992;  20 108-114
  • 17 Corder  C N, Goldberg  M R, Alaupovic  P A, Price  M D, Furste  S S. Lipid and apolipoprotein leves during therapy with pinacidil combined with hydrochlorothiazide.  Eur J Clin Pharmacol. 1992;  42 65-70
  • 18 Stone  C K, Wellington  K L, Willick  A, Sullebarger  J T, Liang  C S. Acute hemodynamic effects of pinacidil patients with and without propranolol pretreatment.  J Clin Pharmacol. 1991;  31 333-341
  • 19 Goldberg  M R, Rockhold  F W, Offen  W W, Dornseif  B E. Dose-effect and concentration-effect relationships of pinacidil and hydrochlorothiazide in hypertension.  Clin Pharmacol Ther. 1989;  46 208-218
  • 20 Steensgaard-Hansen  F, Carlsen  J E. Effects of long term treatment with pinacidil and nifedipine on left ventricular anatomy and function in patients with mild to moderate systemic hypertension.  Drugs. 1988;  36 (Suppl 7) 70-76
  • 21 Sterndorff  B, Johansen  P. The antihypertensive effect of pinacidil versus prazosine in mild to moderate hypertensive patients seen in general practice.  Acta Med Scand. 1988;  224 329-336
  • 22 Callaghan  J T, Goldberg  M R, Brunelle  R. Double-blind comparator trials with pinacidil, a potassium channel opener.  Drugs. 1988;  36 (Suppl 7) 77-82
  • 23 Shields  M B. Textbook of Glaucoma, 4th edition. Williams & Wilkins, Baltimore, MA.; 1998: 1-588
  • 24 Flammer  J, Haefliger  I O, Orgül  S, Resink  T. Vascular dysregulation: a principal risk factor for glaucomatous damage?.  J Glaucoma. 1999;  8 212-219
  • 25 Haefliger  I O, Flammer  J. The logic of prevention of glaucomatous damage progression.  Curr Opin Ophthalmol. 1997;  8 64-67
  • 26 Godtfredsen  W O. New ophthalmic preparation for treating glaucoma. World patent application WO 89/10757 1989. 1989:
  • 27 Millar  C, Wilson  W S. Comparison of the effects of vasodilator drugs on intraocular pressure and vascular relaxation.  Br J Pharmacol. 1991;  104 (Abstract) 55P
  • 28 Edwards  G, Weston  A H. The pharmacology of ATP-sensitive potassium channels.  Annu Rev Pharmacol Toxicol. 1993;  33 597-637
  • 29 Brayden  J E, Nelson  M T. Regulation of arterial tone by activation of calcium-dependent potassium channels.  Science. 1992;  256 532-535
  • 30 McManus  O B. Calcium-activated potassium channels - regulation by calcium.  J Bioenerg Biomembr. 1991;  23 537-560
  • 31 Olesen  S P. Activators of large-conductance Ca2+-dependent K+-channels.  Exp Opin Invest Drugs. 1994;  3 1181-1188
  • 32 Hardy  P, Abran  D, Hou  X, Lahaie  I, Peri  K G, Asselin  P, Varma  D R, Chemtob  S. A major role for prostacyclin in nitric oxide-induced ocular vasorelaxation in the piglet.  Circ Res. 1998;  83 721-729
    >