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. 1996 Dec;119(8):1619–1627. doi: 10.1111/j.1476-5381.1996.tb16081.x

Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats.

S M Gardiner 1, P A Kemp 1, J E March 1, T Bennett 1
PMCID: PMC1915803  PMID: 8982510

Abstract

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS infusion caused additional hypotension and mesenteric vasodilatation, particularly. This effect was most marked in animals pretreated with losartan and SB 209670. 7. The results indicate that the initial (1-2 h) depressor and dilator effects of LPS infusion in conscious Long Evans rats are opposed by the actions of angiotensins II, rather than endothelin. However, between 2-8 h after the onset of LPS infusion the involvement of endothelin develops and that of angiotensin II fades. By 24 h after the start of infusion of LPS, the pressor and vasoconstrictor actions of endothelin wane, and a role of vasopressin is apparent. At no stage is there clear evidence for an involvement of bradykinin in the haemodynamic sequelae of endotoxaemia in this model.

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Selected References

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  1. Batin P., Gardiner S. M., Compton A. M., Bennett T. Differential regional haemodynamic effects of the non-peptide angiotensin II antagonist, DuP 753, in water-replete and water-deprived Brattleboro rats. Life Sci. 1991;48(8):733–739. doi: 10.1016/0024-3205(91)90087-r. [DOI] [PubMed] [Google Scholar]
  2. Bone R. C. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
  3. Campos M. M., Souza G. E., Calixto J. B. Upregulation of B1 receptor mediating des-Arg9-BK-induced rat paw oedema by systemic treatment with bacterial endotoxin. Br J Pharmacol. 1996 Mar;117(5):793–798. doi: 10.1111/j.1476-5381.1996.tb15262.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Douglas S. A., Edwards R. M., Elliott J. D., Ohlstein E. H. In vivo pharmacological characterization of the non-peptide endothelin receptor antagonist SB 209670. Br J Pharmacol. 1995 Jan;114(2):405–413. doi: 10.1111/j.1476-5381.1995.tb13241.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Douglas S. A., Gellai M., Ezekiel M., Feuerstein G. Z., Elliott J. D., Ohlstein E. H. Antihypertensive actions of the novel nonpeptide endothelin receptor antagonist SB 209670. Hypertension. 1995 Apr;25(4 Pt 2):818–822. doi: 10.1161/01.hyp.25.4.818. [DOI] [PubMed] [Google Scholar]
  6. Fasciolo J. C., Vargas L., Lama M. C., Nolly H. Bradykinin-induced vasoconstriction of rat mesenteric arteries precontracted with noradrenaline. Br J Pharmacol. 1990 Oct;101(2):344–348. doi: 10.1111/j.1476-5381.1990.tb12712.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gardiner S. M., Bennett T., Compton A. M. Regional haemodynamic effects of neuropeptide Y, vasopressin and angiotensin II in conscious, unrestrained, Long Evans and Brattleboro rats. J Auton Nerv Syst. 1988 Sep;24(1-2):15–27. doi: 10.1016/0165-1838(88)90131-2. [DOI] [PubMed] [Google Scholar]
  8. Gardiner S. M., Bennett T. Involvement of nitric oxide in the regional haemodynamic effects of perindoprilat and captopril in hypovolaemic Brattleboro rats. Br J Pharmacol. 1992 Dec;107(4):1181–1191. doi: 10.1111/j.1476-5381.1992.tb13426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gardiner S. M., Compton A. M., Bennett T. Regional hemodynamic changes following hypovolemia in conscious rats. Am J Physiol. 1989 May;256(5 Pt 2):R1076–R1083. doi: 10.1152/ajpregu.1989.256.5.R1076. [DOI] [PubMed] [Google Scholar]
  10. Gardiner S. M., Kemp P. A., March J. E., Bennett T. Cardiac and regional haemodynamics, inducible nitric oxide synthase (NOS) activity, and the effects of NOS inhibitors in conscious, endotoxaemic rats. Br J Pharmacol. 1995 Oct;116(3):2005–2016. doi: 10.1111/j.1476-5381.1995.tb16405.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gardiner S. M., Kemp P. A., March J. E., Bennett T. Effects of dexamethasone and SB 209670 on the regional haemodynamic responses to lipopolysaccharide in conscious rats. Br J Pharmacol. 1996 May;118(1):141–149. doi: 10.1111/j.1476-5381.1996.tb15377.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gardiner S. M., Kemp P. A., March J. E., Bennett T. Enhancement of the hypotensive and vasodilator effects of endotoxaemia in conscious rats by the endothelin antagonist, SB 209670. Br J Pharmacol. 1995 Sep;116(2):1718–1719. doi: 10.1111/j.1476-5381.1995.tb16652.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gardiner S. M., Kemp P. A., March J. E., Bennett T. Influence of aminoguanidine and the endothelin antagonist, SB 209670, on the regional haemodynamic effects of endotoxaemia in conscious rats. Br J Pharmacol. 1996 Aug;118(7):1822–1828. doi: 10.1111/j.1476-5381.1996.tb15609.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gardiner S. M., March J. E., Kemp P. A., Mullins J. J., Bennett T. Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen-2)27), hypertensive rats. Br J Pharmacol. 1995 Oct;116(4):2237–2244. doi: 10.1111/j.1476-5381.1995.tb15059.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Guc M. O., Furman B. L., Parratt J. R. Endotoxin-induced impairment of vasopressor and vasodepressor responses in the pithed rat. Br J Pharmacol. 1990 Dec;101(4):913–919. doi: 10.1111/j.1476-5381.1990.tb14180.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hauser G. J., Dayao E. K., Zukowska-Grojec Z. Effect of neuropeptide Y on endotoxin-induced suppression of the response to various agonists in conscious rats. Life Sci. 1995;57(3):235–244. doi: 10.1016/0024-3205(95)00266-9. [DOI] [PubMed] [Google Scholar]
  17. Kasting N. W., Mazurek M. F., Martin J. B. Endotoxin increases vasopressin release independently of known physiological stimuli. Am J Physiol. 1985 Apr;248(4 Pt 1):E420–E424. doi: 10.1152/ajpendo.1985.248.4.E420. [DOI] [PubMed] [Google Scholar]
  18. Katori M., Majima M., Odoi-Adome R., Sunahara N., Uchida Y. Evidence for the involvement of a plasma kallikrein-kinin system in the immediate hypotension produced by endotoxin in anaesthetized rats. Br J Pharmacol. 1989 Dec;98(4):1383–1391. doi: 10.1111/j.1476-5381.1989.tb12688.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Linz W., Wiemer G., Gohlke P., Unger T., Schölkens B. A. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995 Mar;47(1):25–49. [PubMed] [Google Scholar]
  20. Mombouli J. V., Vanhoutte P. M. Kinins and endothelial control of vascular smooth muscle. Annu Rev Pharmacol Toxicol. 1995;35:679–705. doi: 10.1146/annurev.pa.35.040195.003335. [DOI] [PubMed] [Google Scholar]
  21. Momose N., Fukuo K., Morimoto S., Ogihara T. Captopril inhibits endothelin-1 secretion from endothelial cells through bradykinin. Hypertension. 1993 Jun;21(6 Pt 2):921–924. doi: 10.1161/01.hyp.21.6.921. [DOI] [PubMed] [Google Scholar]
  22. Muller A. F., Gardiner S. M., Compton A. M., Bennett T. Regional haemodynamic effects of captopril, enalaprilat and lisinopril in conscious water-replete and water-deprived Brattleboro rats. Clin Sci (Lond) 1990 Oct;79(4):393–401. doi: 10.1042/cs0790393. [DOI] [PubMed] [Google Scholar]
  23. Ohlstein E. H., Nambi P., Douglas S. A., Edwards R. M., Gellai M., Lago A., Leber J. D., Cousins R. D., Gao A., Frazee J. S. SB 209670, a rationally designed potent nonpeptide endothelin receptor antagonist. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8052–8056. doi: 10.1073/pnas.91.17.8052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Parratt J. R. Myocardial and circulatory effects of E. coli endotoxin; modification of responses to catecholamines. Br J Pharmacol. 1973 Jan;47(1):12–25. doi: 10.1111/j.1476-5381.1973.tb08154.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Paya D., Stoclet J. C. Involvement of bradykinin and nitric oxide in the early hemodynamic effects of lipopolysaccharide in rats. Shock. 1995 May;3(5):376–379. [PubMed] [Google Scholar]
  26. Regoli D., Barabé J. Pharmacology of bradykinin and related kinins. Pharmacol Rev. 1980 Mar;32(1):1–46. [PubMed] [Google Scholar]
  27. Ruetten H., Thiemermann C., Vane J. R. Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat. Br J Pharmacol. 1996 May;118(1):198–204. doi: 10.1111/j.1476-5381.1996.tb15386.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schaller M. D., Waeber B., Nussberger J., Brunner H. R. Angiotensin II, vasopressin, and sympathetic activity in conscious rats with endotoxemia. Am J Physiol. 1985 Dec;249(6 Pt 2):H1086–H1092. doi: 10.1152/ajpheart.1985.249.6.H1086. [DOI] [PubMed] [Google Scholar]
  29. Sugiura M., Inagami T., Kon V. Endotoxin stimulates endothelin-release in vivo and in vitro as determined by radioimmunoassay. Biochem Biophys Res Commun. 1989 Jun 30;161(3):1220–1227. doi: 10.1016/0006-291x(89)91372-7. [DOI] [PubMed] [Google Scholar]
  30. Szabó C., Mitchell J. A., Thiemermann C., Vane J. R. Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock. Br J Pharmacol. 1993 Mar;108(3):786–792. doi: 10.1111/j.1476-5381.1993.tb12879.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vemulapalli S., Chiu P. J., Rivelli M., Foster C. J., Sybertz E. J. Modulation of circulating endothelin levels in hypertension and endotoxemia in rats. J Cardiovasc Pharmacol. 1991 Dec;18(6):895–903. doi: 10.1097/00005344-199112000-00017. [DOI] [PubMed] [Google Scholar]
  32. Waller J., Gardiner S. M., Bennett T. Regional haemodynamic responses to acetylcholine, methoxamine, salbutamol and bradykinin during lipopolysaccharide infusion in conscious rats. Br J Pharmacol. 1994 Aug;112(4):1057–1064. doi: 10.1111/j.1476-5381.1994.tb13190.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wellings R. P., Corder R., Vane J. R. Lack of effect of ET antibody or SB 209670 on endotoxin-induced renal failure. J Cardiovasc Pharmacol. 1995;26 (Suppl 3):S476–S478. [PubMed] [Google Scholar]
  34. Yoshida K., Yasujima M., Kohzuki M., Kanazawa M., Yoshinaga K., Abe K. Endothelin-1 augments pressor response to angiotensin II infusion in rats. Hypertension. 1992 Sep;20(3):292–297. doi: 10.1161/01.hyp.20.3.292. [DOI] [PubMed] [Google Scholar]
  35. Yoshida K., Yasujima M., Kohzuki M., Tsunoda K., Kudo K., Kanazawa M., Yabe T., Abe K., Yoshinaga K. Chronic synergistic effect of endothelin-1 and angiotensin II on blood pressure in conscious rats. J Cardiovasc Pharmacol. 1991;17 (Suppl 7):S514–S516. doi: 10.1097/00005344-199100177-00147. [DOI] [PubMed] [Google Scholar]

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