Thromboxane A2 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 spontaneously hypertensive rats (SHR). Glomerular function was assessed by changes in proximal tubular stop-flow pressure (SFP) produced by different rates of orthograde perfusion through Henle's loop. Seven-week-old SHR exhibited 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, Delta SFP in young SHR was unaffected by the thromboxane A(2) agonist. In other animals, the thromboxane synthase inhibitor pirmagrel (50 mg/kg) was injected intravenously to inhibit thromboxane production. In SHR, pirmagrel decreased Delta SFP by 8.5 mmHg and reduced reactivity. Less attenuation was observed in WKY; Delta SFP was reduced by 3 mmHg, whereas reactivity was unchanged. In other studies, tubular perfusion with the thromboxane receptor inhibitor SQ-29548 (10-6 M) reduced Delta SFP more in SHR (7 vs. 3 mmHg in WKY) 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 effect of U-46619 on Delta SFP. Tubular perfusion with the agonist U-46619 during thromboxane synthase inhibition markedly enhanced Delta SFP in both strains, with a greater effect in WKY. These results suggest that elevated levels of thromboxane A(2) in young SHR contribute to the exaggerated TGF control of glomerular function in SHR during the developmental phase of hypertension.