Vascular effects of 15-F2t-isoprostane in spontaneously hypertensive rats.
F2-isoprostanes are a family of compounds derived from arachidonic acid by free radical-catalyzed peroxidation. Among F2-isoprostanes, 15-F2t-IsoP is a vasoconstrictor in animal and human vascular beds. Several recent studies found increased 15-F2t-IsoP levels in animal models of hypertension. However, no data is available on the vascular effect of 15-F2t-IsoP in such models. The contractile responses of 15-F2t-IsoP (10(-9) to 3 x 10(-5) mol/L) were tested on rat thoracic aortic rings in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. The contraction induced by 15-F2t-IsoP was not significantly different in aortic rings from WKY rats and SHR (Emax 139% +/- 5% vs. 134% +/- 6%, respectively) and was mediated through thromboxane A2-prostaglandin H2 receptor activation as shown by the rightward shift of the concentration-contraction curves in presence of GR 32191, a specific thromboxane A2-prostaglandin H2 receptor antagonist. Endothelial denudation increased the maximal contraction compared to intact rings induced by 15-F2t-IsoP in both WKY rats (170% +/- 20% vs. 139% +/- 5%, p < 0.05) and SHR (194% +/- 11% vs. 134% +/- 6%, p < 0.01), whereas pretreatment with Nomega-nitro-L-arginine (10(-4) mol/L) or with indomethacin (10(-5) mol/L) increased the maximal contraction to 15-F2t-IsoP in WKY rats but not in SHR. SHRs treated with an angiotensin-converting enzyme inhibitor, enalapril, for four weeks showed decreased maximal contraction to 15-F2t-IsoP in vessels with and without endothelium compared with untreated SHR. In conclusion, 15-F2t-IsoP-induced vasoconstriction is similar in SHR compared with WKY rats. Endothelium modulates 15-F2t-IsoP contraction in both strains. However, whereas this effect is mediated through nitric oxide- and cyclooxygenase-dependent pathways in WKY rats, other mediators are implicated in SHR.
Marlière
Stéphanie
S
Laboratoire de Pharmacologie, Faculté de Médecine, La Tronche, France.
Cracowski
Jean-Luc
JL
Hakim
Ahmed
A
Stanke-Labesque
Françoise
F
Hoffmann
Pascale
P
Bessard
Germain
G
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D004656:Enalapril; D015237:Dinoprost