Effects of a selective bradykinin B1 receptor antagonist on increased plasma extravasation in streptozotocin-induced diabetic rats: distinct vasculopathic profile of major key organs

Eur J Pharmacol. 2005 May 2;514(1):69-78. doi: 10.1016/j.ejphar.2005.03.023. Epub 2005 Apr 21.

Abstract

Diffuse vasculopathy is a common feature of the morbidity and increased mortality associated with insulino-dependent type 1 diabetes. Increased vascular permeability leading to plasma extravasation occurs in surrounding tissues following endothelial dysfunction. Such micro- and macro-vascular complications develop over time and lead to oedema, hypertension, cardiomyopathy, renal failure (nephropathy) and other complications (neuropathy, retinopathy). In the present investigation, we studied the effect of a selective bradykinin B(1) receptor antagonist, R-954, on the enhanced vascular permeability in streptozotocin (STZ)-induced diabetic Wistar rats compared with age-matched controls. Plasma extravasation was determined using Evans blue dye in selected target tissues (left and right heart atria, ventricles, lung, abdominal and thoracic aortas, liver, spleen, renal cortex and medulla), at 1 and 4 weeks following STZ administration. The vascular permeability was significantly increased in the aortas, cortex, medulla, and spleen in 1-week STZ rats and remained elevated at 4 weeks of diabetes. Both atria showed an increased vascular permeability only after 4-week STZ-administration. R-954 (2 mg/kg, bolus, s.c.), given 2 h prior to Evans blue dye, to 1- and 4-week diabetic rats significantly inhibited (by 48-100%) plasma leakage in most tested tissues affected by diabetes with no effect in healthy rats. These results showed that the inducible bradykinin B(1) receptor subtype participates in the modulation of the vascular permeability in diabetic rats and suggest that selective bradykinin B(1) receptor antagonism could have a beneficial role in reducing diabetic vascular complications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Bradykinin / analogs & derivatives
  • Bradykinin / pharmacology
  • Bradykinin B1 Receptor Antagonists*
  • Capillary Permeability / drug effects*
  • Cardiomyopathies / etiology
  • Cholesterol / blood
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Neuropathies / etiology
  • Diabetic Retinopathy / etiology
  • Evans Blue / pharmacokinetics
  • Extravasation of Diagnostic and Therapeutic Materials
  • Insulin / blood
  • Male
  • Rats
  • Rats, Wistar
  • Receptor, Bradykinin B1 / physiology
  • Renal Insufficiency / etiology
  • Time Factors
  • Tissue Distribution
  • Triglycerides / blood
  • Vascular Diseases / etiology

Substances

  • Ac-Orn-(Oic2, alpha-MePhe5, D-betaNal7, Ile8)desArg9-bradykinin
  • Blood Glucose
  • Bradykinin B1 Receptor Antagonists
  • Insulin
  • Receptor, Bradykinin B1
  • Triglycerides
  • Evans Blue
  • Cholesterol
  • Bradykinin