GR32191, a highly potent and specific thromboxane A2 receptor blocking drug on platelets and vascular and airways smooth muscle in vitro

Br J Pharmacol. 1989 Jul;97(3):783-94. doi: 10.1111/j.1476-5381.1989.tb12017.x.

Abstract

1. The thromboxane A2 (TP)-receptor blocking activity and specificity of action of GR32191 ([1R-[1 alpha(Z),2 beta,3 beta,5 alpha]]-(+)-7-[5-([1,1'-biphenyl] -4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptoni c acid has been evaluated in human platelets and various smooth muscle preparations, both vascular and non-vascular, from a range of species including man. 2. Utilising a platelet counting method to assess aggregation the drug was found to antagonise, in a surmountable manner, human platelet aggregation produced by the TP-receptor agonists, U-46619, EP171 and SQ26655, in whole blood and physiological buffer, with pA2 values of approximately 8.3 and 8.7 in the two media respectively. In the presence of GR32191 the rate of aggregation induced by U-46619 was slowed. 3. The effect of GR32191 upon U-46619-induced platelet shape change and aggregation in platelet-rich plasma was evaluated utilising a turbidometric technique. Both shape change and aggregation were antagonised by GR32191. At relatively high concentrations of the drug a slowing of aggregation and shape change to U-44619 was seen and an unsurmountable antagonism became apparent. 4. The action of GR32191 upon human platelets was specific with platelet aggregation induced by adenosine 5'-diphosphate, platelet activating factor, vasopressin and adrenaline and the inhibitory effects of prostacylin (PGI2), prostaglandin D2 (PGD2) and N-ethylcarboxamide-adenosine (NECA) being unaffected by concentrations of the drug as high as 10 microM. Furthermore, at concentrations of up to 100 microM, the drug itself produced no shape change or aggregation, of human platelets. 5. GR32191 also specifically and potently antagonised in a competitive, surmountable manner the contractile actions of U-46619 upon human vascular smooth muscle and antagonised U-46619-induced contractions of vascular and airways smooth muscle preparations from rat, dog, guinea-pig and rabbit with varying potency. This is discussed in terms of possible heterogeneity of TP-receptors. 6. GR32191 therefore represents a highly potent and specific TP-receptor blocking drug. This profile of action, coupled to its long duration of effect in man described elsewhere, make it an ideal drug tool for elucidating the physiological and pathophysiological role of thromboxane A2.

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Animals
  • Aorta, Thoracic / drug effects
  • Biphenyl Compounds / pharmacology*
  • Blood Platelets / drug effects*
  • Dogs
  • Guinea Pigs
  • Heptanoic Acids / pharmacology*
  • Humans
  • In Vitro Techniques
  • Male
  • Muscle, Smooth / drug effects*
  • Muscle, Smooth, Vascular / drug effects*
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors
  • Prostaglandin Endoperoxides, Synthetic / pharmacology
  • Pulmonary Artery / drug effects
  • Rabbits
  • Rats
  • Receptors, Prostaglandin / drug effects*
  • Receptors, Prostaglandin / metabolism
  • Receptors, Thromboxane

Substances

  • Biphenyl Compounds
  • Heptanoic Acids
  • Platelet Aggregation Inhibitors
  • Prostaglandin Endoperoxides, Synthetic
  • Receptors, Prostaglandin
  • Receptors, Thromboxane
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • vapiprost