endothelin-1 and ifetroban

We tested the hypothesis that cyclooxygenase (COX), thromboxane A2 synthase (TxA2-S), thromboxane prostanoid receptors (TP-Rs), or superoxide anion (O2-) mediates enhanced contractions of renal afferent arterioles (Aff) of angiotensin II (Ang II)-infused rabbits. Rabbits were infused with vehicle (sham), Ang II 60 ng x kg(-1) x min(-1) (Ang II 60) or 200 ng x kg(-1) x min(-1) (Ang II 200). There was a selective enhanced vasoconstriction of Affs from Ang II 60 rabbits to Ang II (Deltadiameter-78+/-8% versus -43+/-9%; P<0.01) that was normalized by a TP-R antagonist but not by a superoxide dismutase (SOD) mimetic. Affs from Ang II 200 rabbits had increased (P<0.01) mRNA for COX-2 and enhanced vasoconstriction to Ang II, U-46 619 (TP-R mimetic), and endothelin-1 that was normalized by ifetroban plus tempol together. Endothelium removal enhanced Ang II responses of Affs from sham rabbits but blunted responses from Ang II 200 rabbits and abolished responses to ifetroban. Affs from Ang II 200 rabbits had an endothelium-dependent contraction factor (EDCF) response to that was blunted (P<0.001) by a SOD mimetic or antagonists of COX-1 or TxA2-S but normalized by antagonists of COX-2 or TP-R. Thus, enhanced Ang II responses in Affs from rabbits infused with slow pressor Ang II are mediated independently by O2- in the vascular smooth muscle cells and by an EDCF that is principally a vasoconstrictor prostaglandin generated by COX-2 >-1 activating TP-Rs, whereas enhanced responses in rabbits infused with a lower Ang II dose are dependent on TP-R but not O2-.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 8,11,14-Eicosatrienoic Acid; Angiotensin II; Animals; Arterioles; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Cyclooxygenase 2; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Endothelium, Vascular; Isoenzymes; Kidney; Male; Nitroarginine; Norepinephrine; Oxazoles; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rabbits; Receptors, Thromboxane; RNA, Messenger; Spin Labels; Superoxides; Vascular Resistance; Vasoconstriction

Interactions among angiotensin II (Ang II), endothelin-1 (ET-1) and thromboxane A2 (TXA2) may play an important role in the regulation of renal function. The present study investigated the participation of TXA2 and ET-1 in the increase in renal vascular resistances (RVR) induced by Ang II, as well as the consequences of diabetes, hypertension, and the combination of both on this response.. Isolated kidneys from male normoglycemic or streptozotocin-induced diabetic Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were used. The increase in perfusion pressure (PP) produced by Ang II was studied in the absence or presence of the TXA2 receptor antagonist, ifetroban, or the ETA/ETB receptor antagonist, PD145065.. Systolic arterial pressure (SAP) was higher in SHR than in WKY, but diabetic rats (D) from each strain showed lower SAP values than their respective non-diabetic rats. Basal renal PP was higher in WKY and SHR than in WKY-D and SHR-D. Increases in renal PP produced by Ang II were comparable in the kidneys from all groups. Either ifetroban or PD145065 reduced the maximal Ang II response in all animals. The maximal inhibitory effect of ifetroban was higher (P<0.05) in WKY than in the other groups. However, the maximal inhibitory effect of PD145065 was lower in SHR than in the other groups.. This study supports a role for ET-1 and TXA2 as mediators of the increase in renal vascular resistance produced by Ang II. These results indicate that the participation of ET-1 in the renal vasoconstriction produced by Ang II was reduced under hypertensive conditions, and that of TXA2 was reduced by both diabetes and hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Kidney; Male; Oligopeptides; Oxazoles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Endothelin; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Thromboxane A2; Vascular Resistance; Vasoconstriction