Diltiazem Potentiates Angiotensin II-Mediated Renal Prostacyclin Synthesis

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Abstract
Summary: Diltiazem (DIL), a calcium antagonist, has variable effects on renal hemodynamics, and has been considered to act independently of renal prostaglandins (PGs). Angiotensin II (All) constricts renal vasculature but also increases renal vasodilator PG synthesis. We examined interactions between All and DIL on [14C]p-aminohippurate ([14C]PAH) clearance, mean arterial pressure (MAP), and urine 6-ketoprostaglandin F1α excretion (U6k) in groups of seven to nine conscious Sprague-Dawley rats. We calculated the renal vascular resistance (RVR) as the ratio of MAP/[14C]PAH clearance. AH infusion (10 ng/kg/min i.v.) increased the RVR by 50–80% for at least 120 min. DIL (1 mg/kg plus 2 μg/kg/min) reversed this vasoconstriction but adding in-domethacin to DIL prevented the reversal. DIL alone did not change the RVR at 30–60 min after starting an infusion but increased it by 22% at 90–120 min. Adding All to the DIL infusion actually decreased the RVR and this decrease was abolished by indomethacin. DIL alone had no effect on U6k while All increased it slightly (1.36 ± 0.12 to 1.86 ± 0.22 ng/30 min, n = 6, p < 0.05), and adding DIL to All increased it further (3.19 ng/30 min, n = 6, p < 0.05). We conclude that DIL enhances All-induced renal prostacyclin synthesis and that this is functionally relevant. This mechanism may explain the reported variability of the renal hemodynamic effects of DIL. Furthermore, DIL-enhanced renal vasodilator PG synthesis may help protect the kidney during vasoconstrictor stress.

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