Journal of the Korea Academia-Industrial cooperation Society (한국산학기술학회논문지)

The Korea Academia-Industrial cooperation Society (한국산학기술학회)
권호 표지
DOI QR코드

DOI QR Code

Antihypertensive activity of KR-31081, an orally active nonpeptide AT1 receptor antagonist

안지오텐신 수용체 리간드 KR-31081의 생체 내 활성에 관한 연구

  • Lee, Sung-Hou (Department of Biomedical Technology, Sangmyung University)
  • 이승호 (상명대학교 공과대학 의생명공학과)
  • Published : 2009.11.30
Download PDF
⟨ Previous Next ⟩

Abstract

The pharmacological profile of KR-31081, a newly synthesized AT1 receptor antagonist, was evaluated in pithed rats, conscious renal hypertensive rats (RHRs) and conscious furosemide-treated beagle dogs. In pithed rats, KR-31081 (i.v.) induced a non-parallel right shift in the dose-pressor response curve to angiotensin II (ID50: 0.05 mg/kg) with a dose-dependent reduction in the maximum responses; this antagonistic effect was about 40 times more potent than losartan (ID50: 1.74 mg/kg) which showed competitive antagonism. KR-31081 did not alter the responses induced by other agonists such as norepinephrine and vasopressin. In RHRs, orally given KR-31081 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a higher potency to losartan (ED20: 0.30 and 3.36 mg/kg, respectively). In furosemide-treated dogs, orally given KR-31081 produced a dose-dependent and long-lasting (>8h) antihypertensive effect with a rapid onset of action (time to Emax: 1-1.5 h) and 20-fold greater potency than losartan (ED20: 0.41 and 8.13 mg/kg, respectively). These results suggest that KR-31081 is a potent, orally active AT1 receptor antagonist useful for the research and diagnostic tools as an added exploratory potential.

비펩타이드성 안지오텐신 수용체 길항제로 새롭게 개발된 KR-31081에 대한 생체 내 활성을 세가지 동물모델에서 검증하였다. 척수장애 동물모델에서 KR-31081은 로사탄보다 40배 이상의 경쟁적인 혈압강하 효과를 나타내었으며, 신성고혈압쥐 모델에서 KR-31081은 로사탄보다 10배 가량의 지속형 효과를 나타내었다. 또한 개실험에서 구강 투여한 KR-31081은 로사탄보다 20배 이상의 지속적인 혈압강하 효과를 나타내었다. 실험에 사용된 동물 모델 시스템에서 다른 혈관조절물질들과 상호작용을 하지 않는 것으로 나타난 KR-31081은 향후 고혈압 및 혈관질환에 대한 연구 및 진단에 활용될 수 있을 것이라고 판단된다.

Keywords

References

  1. P. B. Timmermans, P. C. Wong, A. T. Chiu, W. F. Herblin, P. Benfield, D. J. Carini, R. J. Lee, R. R. Wexler, J. A. Saye, and R. D. Smith, "Angiotensin II receptors and angiotensin II receptor antagonists", Pharmacol Rev, 45, pp. 205-51, 1993.
  2. K. K. Griendling, B. Lassegue, T. J. Murphy, and R. W. Alexander, "Angiotensin II receptor pharmacology", Adv Pharmacol, 28, pp. 269-306, 1994. https://doi.org/10.1016/S1054-3589(08)60498-6
  3. A. T. Chiu, D. E. McCall, W. A. Price, P. C. Wong, D. J. Carini, J. V. Duncia, R. R. Wexler, S. E. Yoo, A. L. Johnson, and P. B. Timmermans, "Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 753, an orally active antihypertensive agent", J Pharmacol Exp Ther, 252, pp. 711-8, 1990.
  4. P. C. Wong, W. A. Price, A. T. Chiu, J. V. Duncia, D. J. Carini, R. R. Wexler, A. L. Johnson, and P. B. Timmermans, "Nonpeptide angiotensin II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent", J Pharmacol Exp Ther, 252, pp. 719-25, 1990.
  5. P. C. Wong, S. D. Hart, J. V. Duncia, and P. B. Timmermans, "Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs", Eur J Pharmacol, 202, pp. 323-30, 1991. https://doi.org/10.1016/0014-2999(91)90274-T
  6. P. C. Wong, W. A. Price, Jr., A. T. Chiu, J. V. Duncia, D. J. Carini, R. R. Wexler, A. L. Johnson, and P. B. Timmermans, "In vivo pharmacology of DuP 753", Am J Hypertens, 4, pp. 288S-298S, 1991. https://doi.org/10.1093/ajh/4.3.288
  7. B. Dahlof, S. E. Keller, L. Makris, A. I. Goldberg, C. S. Sweet, and N. Y. Lim, "Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension", Am J Hypertens, 8, pp. 578-83, 1995. https://doi.org/10.1016/0895-7061(95)00081-Y
  8. J. M. Mallion, and A. I. Goldberg, "Global efficacy and tolerability of losartan, an angiotensin II subtype 1-receptor antagonist, in the treatment of hypertension", Blood Press Suppl, 2, pp. 82-6, 1996.
  9. P. C. Wong, W. A. Price, Jr., A. T. Chiu, J. V. Duncia, D. J. Carini, R. R. Wexler, A. L. Johnson, and P. B. Timmermans, "Nonpeptide angiotensin II receptor antagonists. XI. Pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent", J Pharmacol Exp Ther, 255, pp. 211-7, 1990.
  10. W. B. Mathews, S. E. Yoo, S. H. Lee, U. Scheffel, P. A. Rauseo, T. G. Zober, G. Gocco, K. Sandberg, H. T. Ravert, R. F. Dannals, and Z. Szabo, "A novel radioligand for imaging the AT1 angiotensin receptor with PET", Nucl Med Biol, 31, pp. 571-4, 2004. https://doi.org/10.1016/j.nucmedbio.2003.10.014
  11. J. Xia, E. Seckin, Y. Xiang, M. Vranesic, W. B. Mathews, K. Hong, D. A. Bluemke, L. O. Lerman, and Z. Szabo, "Positron-emission tomography imaging of the angiotensin II subtype 1 receptor in swine renal artery stenosis", Hypertension, 51, pp. 466-73, 2008. https://doi.org/10.1161/HYPERTENSIONAHA.107.102715
  12. T. G. Zober, W. B. Mathews, E. Seckin, S. E. Yoo, J. Hilton, J. Xia, K. Sandberg, H. T. Ravert, R. F. Dannals, and Z. Szabo, "PET Imaging of the AT1 receptor with [11C]KR31173", Nucl Med Biol, 33, pp. 5-13, 2006. https://doi.org/10.1016/j.nucmedbio.2005.08.005
  13. J. S. Gillespie, and T. C. Muir, "A method of stimulating the complete sympathetic outflow from the spinal cord to blood vessels in the pithed rat", Br J Pharmacol Chemother, 30, pp. 78-87, 1967. https://doi.org/10.1111/j.1476-5381.1967.tb02114.x
  14. M. Cazes, D. Provost, A. Versigny, and A. Cloarec, "In vivo pharmacological characterization of UP 269-6, a novel nonpeptide angiotensin II receptor antagonist", Eur J Pharmacol, 284, pp. 157-70, 1995. https://doi.org/10.1016/0014-2999(95)00395-2
  15. R. Zacest, E. Gilmore, and J. Koch-Weser, "Treatment of essential hypertension with combined vasodilation and beta-adrenergic blockade", N Engl J Med, 286, pp. 617-22, 1972. https://doi.org/10.1056/NEJM197203232861201
  16. E. M. Sorkin, and S. P. Clissold, "Nicardipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders", Drugs, 33, pp. 296-345, 1987. https://doi.org/10.2165/00003495-198733040-00002
  17. S. D. Longman, J. C. Clapham, C. Wilson, and T. C. Hamilton, "Cromakalim, a potassium channel activator: a comparison of its cardiovascular haemodynamic profile and tissue specificity with those of pinacidil and nicorandil", J Cardiovasc Pharmacol, 12, pp. 535-42, 1988. https://doi.org/10.1097/00005344-198811000-00006
  18. R. J. Cody, "Haemodynamic responses to specific renin-angiotensin inhibitors in hypertension and congestive heart failure. A review", Drugs, 28, pp. 144-69, 1984. https://doi.org/10.2165/00003495-198428020-00004
  19. A. Hilditch, A. A. Hunt, A. Travers, J. Polley, G. M. Drew, D. Middlemiss, D. B. Judd, B. C. Ross, and M. J. Robertson, "Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist", J Pharmacol Exp Ther, 272, pp. 750-7, 1995.