Suppressing Hypertension Preserves Renal Autoregulatory Behavior and Purinoceptor Response in Deoxycorticosterone Acetate‐salt (DOCA‐salt) Treated Rats
Authors: Guan Zhengrong , Cha Haword , Van Beusecum Justin P , Cook Anthony K , Inscho Edward W 
Published: November 2023

Inflammation contributes to renal microvascular autoregulatory impairment associated with hypertension. We have shown that anti‐inflammatory treatment with pentosan polysulfate prevents impairment of renal autoregulation in mineralocorticoid‐induced DOCA‐salt hypertensive rats despite persistent hypertension. Whether the autoregulatory impairment arises from elevated arterial pressure or directly from mineralocorticoid treatment is unclear. We hypothesize that suppression of hypertension with hydralazine, hydrochlorothiazide and reserpine (TTx) treatment protects renal autoregulatory function in DOCA‐salt rats. DOCA‐salt treatment was induced by subcutaneous implantation of DOCA pellets in uninephrectomized rats (UNx) simultaneously receiving TTx, 1% NaCl and 0.2% KCl in the drinking water for three weeks. Renal autoregulatory function was assessed in vitro using the blood‐perfused juxtamedullary nephron preparation on treatment day 21. Systolic blood pressure (tail‐cuff) and 24‐hour urine (metabolic cages) was monitored weekly. Over the 21 days of treatment, DOCA‐salt rats developed hypertension (183±6 mmHg, n=12) that was suppressed with TTx (DOCA‐salt+TTx) with systolic blood pressure averaging 126±3 and 111±4 mmHg on day 0 and day 21, respectively (n=8, P<0.05 vs. DOCA‐salt). DOCA‐salt+TTx rats (n=7) displayed normal autoregulation. Arteriolar diameter (14.0±1.0μm) decreased in a stepwise manner to 75±3% of the control diameter, as perfusion pressure was increased from 65 to 170 mmHg (P<0.05), resembling the pressure‐diameter profile in control UNx rats (69±2%, P>0.05 vs. DOCA‐salt+TTx) whereas DOCA‐salt hypertensive rats measured only 92±4% of control at 170 mmHg (P<0.05). Renal autoregulatory responses are linked to P2X1 receptor activation. Accordingly, arteriolar reactivity to the endogenous autoregulatory mediator ATP and P2X1 receptor agonist, β,γ‐methylene ATP (10−8‐10−4 mol/L) were assessed in separate groups. TTx treatment prevented the blunted constriction to ATP in DOCA‐salt rats. The maximal vasoconstriction was 74±4% of control at 10−4 mol/L similar to that in UNx (77±4%, P>0.05) but markedly different from DOCA‐salt hypertensive rats (95±4%, P<0.05). Similarly, TTx treatment significantly improved the arteriolar vasoconstriction to β,γ‐methylene ATP in DOCA‐salt rats. β,γ‐methylene ATP‐mediated vasoconstriction in DOCA‐salt+TTx was similar to the response in UNx rats from 10−8 to 10−5 mol/L though somewhat blunted at 10−4 mol/L (81±2% vs. 71±2%, P<0.05). In contrast, DOCA‐salt+TTx rats showed a significantly greater vasoconstriction to β,γ‐methylene ATP than DOCA‐salt hypertensive rats (91±2%, P<0.05). Protein and MCP‐1 excretion remained unchanged in DOCA‐salt+TTx (n=7) compared to UNx rats. These results support our hypothesis that suppression of hypertension with TTx confers significant renal protection against the decline of renal autoregulation and this is associated with improved reactivity to P2X1 receptor stimulation and reduction of renal inflammation.

Support or Funding Information

A post‐doctoral fellowship (0825465E) from the Greater Southeast Affiliate and a National Scientist Development Grant of the American Heart Association (10SDG3770010) for ZG, and grants from NIH (DK044628, HL074167, HL098135 and HL095499) for EWI.