Thromboxane A(2) contributes to the enhanced tubuloglomerular feedback activity in young SHR

We performed micropuncture studies to determine the role of thromboxane A(2 ) in the exaggerated tubuloglomerular feedback (TGF) activity in young spon taneously hypertensive rats (SHR). Glomerular function was assessed by chan ges in proximal tubular stop-flow pressure (SFP) produced by different rate s of orthograde perfusion through Henle's loop. Seven-week-old SHR exhibite d an exaggerated TGF activity compared with Wistar-Kyoto rats (WKY) during euvolemia, confirming earlier studies. During control periods, the feedback -induced maximal SFP response (Delta SFP) was greater in SHR (18-19 vs. 12- 13 mmHg in WKY), whereas basal SFP and proximal tubular free-flow pressure were similar in both strains. In one series, the thromboxane A(2) agonist U -46619 was added to the tubular perfusate for a final concentration of 10(- 6) M. In WKY, Delta SFP was increased by 100% to 26 mmHg. In contrast, Delt a SFP in young SHR was unaffected by the thromboxane A(2) agonist. In other animals, the thromboxane synthase inhibitor pirmagrel (50 mg/kg) was injec ted intravenously to inhibit thromboxane production. In SHR, pirmagrel decr eased Delta SFP by 8.5 mmHg and reduced reactivity. Less attenuation was ob served in WKY; Delta SFP was reduced by 3 mmHg, whereas reactivity was unch anged. In other studies, tubular perfusion with the thromboxane receptor in hibitor SQ-29548 (10-6 M) reduced Delta SFP more in SHR (7 vs. 3 mmHg in WK Y) and also decreased reactivity more in SHR (2.3 vs. 0.5 mmHg.nl(-1.) min( -1)). Coperfusion of SQ-29548 and U-46619 resulted in an 85% block of the e ffect of U-46619 on Delta SFP. Tubular perfusion with the agonist U-46619 d uring thromboxane synthase inhibition markedly enhanced Delta SFP in both s trains, with a greater effect in WKY. These results suggest that elevated l evels of thromboxane A(2) in young SHR contribute to the exaggerated TGF co ntrol of glomerular function in SHR during the developmental phase of hyper tension.