During exercise muscle mechanoreflex mediated sympathoexcitation evokes renal vasoconstriction. Animal studies suggest that prostaglandins generated within the contracting muscle sensitize muscle mechanoreflexes. Thus, we hypothesized that local prostaglandin blockade would attenuate renal vasoconstriction during ischemic muscle stretch. Eleven healthy subjects performed static handgrip before and after local prostaglandin blockade (6 mg ketorolac tromethamine infused into the exercising forearm) via Bier block. Renal blood flow velocity (RBV; Duplex Ultrasound), mean arterial pressure (MAP; Finapres) and heart rate (HR; ECG) were obtained during handgrip, post-handgrip muscle ischemia (PHGMI) followed by PHGMI with passive forearm muscle stretch (PHGMI+stretch). Renal vascular resistance (RVR, calculated as MAP/RBV) was increased from baseline during all paradigms except during PHGMI+stretch after the ketorolac Bier block trial where RVR did not change from baseline. Before Bier block, RVR rose more during PHGMI+stretch than during PHGMI alone (P < .01). Similar results were found after a saline Bier block trial (53 ± 13% vs. 35 ± 10%; P < .01). However, after ketorolac Bier block, RVR was not greater during PHGMI+stretch than during PHGMI alone (39 ± 8% vs. 40 ± 12%; P = NS). HR and MAP responses were similar during PHGMI and PHGMI+stretch (P = NS). Passive muscle stretch during ischemia augments renal vasoconstriction suggesting that ischemia sensitizes mechanically sensitive afferents. Inhibition of prostaglandin synthesis eliminates this mechanoreceptor sensitization mediated constrictor responses. Thus, mechanoreceptor sensitization in humans is linked to the production of prostaglandins.