Diltiazem potentiates angiotensin II-mediated renal prostacyclin synthesis.
Diltiazem (DIL), a calcium antagonist, has variable effects on renal hemodynamics, and has been considered to act independently of renal prostaglandins (PGs). Angiotensin II (AII) constricts renal vasculature but also increases renal vasodilator PG synthesis. We examined interactions between AII and DIL on [14C]p-aminohippurate ([14C]PAH) clearance, mean arterial pressure (MAP), and urine 6-ketoprostaglandin F1 alpha 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. AII infusion (10 ng/kg/min i.v.) increased the RVR by 50-80% for at least 120 min. DIL (1 mg/kg plus 2 micrograms/kg/min) reversed this vasoconstriction but adding indomethacin 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 AII to the DIL infusion actually decreased the RVR and this decrease was abolished by indomethacin. DIL alone had no effect on U6k while AII increased it slightly (1.36 +/- 0.12 to 1.86 +/- 0.22 ng/30 min, n = 6, p less than 0.05), and adding DIL to AII increased it further (3.19 ng/30 min, n = 6, p less than 0.05). We conclude that DIL enhances AII-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.
D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014563:Urodynamics / Q000187:drug effects; D010130:p-Aminohippuric Acid / Q000378:metabolism
D000804:Angiotensin II; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D004110:Diltiazem; D010130:p-Aminohippuric Acid