Cysteinyl leukotrienes mediate enhanced vasoconstriction to angiotensin II but not endothelin-1 in SHR.
We assessed whether cysteinyl leukotrienes mediate the vasoconstrictor responses to angiotensin II and endothelin-1 in the mesenteric vascular bed of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) perfused ex vivo at a constant flow rate of 5 ml/min with Krebs buffer. Maximal perfusion pressure response (E(max)) but not EC(50) values to angiotensin II (P < 0.001) and endothelin-1 (P < 0.01) were significantly higher in the SHR, whereas the responses to potassium chloride remained unchanged. Inclusion of the selective 5-lipoxygenase inhibitor AA-861 or the cysteinyl leukotriene receptor antagonist MK-571 significantly reduced the vasoconstrictor responses to angiotensin II but not to endothelin-1 and potassium chloride. The reduction in E(max) to angiotensin II was more pronounced in SHR (P < 0.001) than in WKY (P < 0.05) rats. Cysteinyl leukotrienes LTC(4)-, LTD(4)-, and LTE(4) (1 microM)-evoked vasoconstrictor responses were significantly higher in SHR (P < 0.05), whereas LTB(4) failed to evoke any response in either strain. These data suggest that 5-lipoxygenase metabolites, particularly cysteinyl leukotrienes, contribute to the exaggerated vasoconstrictor responses to angiotensin II but not to endothelin-1.
Shastri
S
S
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education & Research, SAS Nagar, 160 062, India.
McNeill
J R
JR
Wilson
T W
TW
Poduri
R
R
Kaul
C
C
Gopalakrishnan
V
V
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D011921:Rats, Inbred WKY; D013152:Splanchnic Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*
D016227:Benzoquinones; D019332:Endothelin-1; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011804:Quinolines; D000804:Angiotensin II; C059141:verlukast; D011189:Potassium Chloride; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone