Impaired nitric oxide- and prostaglandin-mediated responses to flow in resistance arteries of hypertensive rats

In human and experimental hypertension, flow (shear stress)-induced dilation in large arteries is attenuated and resistant to nitric oxide blockade. We tested the hypothesis that a defect in nitric oxide-and/or prostaglandin-dependent flow-induced dilation might occur in mesenteric resistance arteries from spontaneously hypertensive rats (SHR). We measured resistance mesenteric artery diameter in situ by intravital microscopy and simultaneously measured mesenteric arterial pressure in a collateral artery. The flow-diameter-pressure relationship was established in normotensive Wistar-Kyoto rats (WKY) and in SHR under control conditions and after endothelium removal, inhibition of nitric oxide synthesis with N-omega-nitro-L-arginine methyl ester (10 mu mol/L), or inhibition of prostaglandin synthesis with indomethacin (10 mu mol/L). Production of prostaglandins was determined in the perfusate. Endothelium removal decreased artery diameter by 14+/-1.6% in WKY and 5+/-0.5% (P<.01 versus WKY) in SHR at a how rate of 400 mu L/min. In WKY, N-omega-nitro-L-arginine methyl ester and indomethacin decreased resistance artery diameter by 12+/-3% (P<.001) and 5+/-2% (P<.01), respectively, at a flow rate of 400 mu L/min; neither substance had any significant effect in SHR. In both strains, flow induced the production of 6-keto-prostaglandin F-1 alpha, the metabolite of prostacyclin; prostaglandin F-2 alpha; and thromboxane B-2, the stable metabolite of thromboxane A(2). Production of 6-keto-prostaglandin F-1 alpha and prostaglandin F-2 alpha was significantly lower in SHR than WKY, and TxB(2) production was significantly higher in SHR than WKY. The present findings suggest that in SHR mesenteric resistance arteries, dilation in response to increases in flow was resistant to nitric oxide and prostaglandin synthesis blockade. A modification of the ratio of vasodilator to vasoconstrictor prostaglandins might be at least partly responsible for the decreased dilator response to flow in SHR.