Increased levels of prostaglandin-like material in the canine blood during arterial hypotension produced by hydralazine, dihydralazine and minoxidil.

Abstract

1. Indomethacin completely reversed within 15 min the hypotension produced by hydralazine or dihydralazine in anaesthetized dogs. Acetylsalicylic acid, diclofenac sodium and flufenamic acid inhibitors of prostaglandin synthesis structurally dissimilar to indomethacin — had the same effect. Pretreatment of anaesthetized dogs with indomethacin prevented in part the hypotension in response to a subsequent injection of hydralazine. 2. The development of hypotension in response to hydralazine or dihydralazine was paralleled by an increase in the concentration of prostaglandin-like (PG-like) material in the renal venous blood as determined with the blood bathed organ technique. PG-like material increased to a lesser extent, also in the femoral venous and in the aortic blood. Subsequent injection of indomethacin reduced PG-like material in the blood to levels no longer detectable by bioassay and reversed the hypotension produced by either of the two vaso-active antihypertensives. 3. Hydralazine and dihydralazine raised also the blood levels of angiotensin II. While there was no decrease in the elevated concentrations of PG-like material at 3 h after the injection of hydralazine, angiotensin II levels started to fall after 1 h and at 2 h an increase was no longer detected. 4. Pretreatment of the dogs with the betaadrenoceptor blocking agent propranolol had no major influence on the hydralazine-induced hypotension and on the induced appearance of PG-like material in the renal venous blood. 5. Although hydralazine raised the levels of PG-like material in the renal venous blood more than in femoral venous or aortic blood, exclusion of both kidneys from the circulation did not modify the hypotensive effect of the drug. 6. While the infusion of neither PGE2 nor PGI2 into the aorta was able to mimic the actions of hydralazine and dihydralazine on both blood pressure and the responses of the blood bathed assay organs, a combined infusion of PGE2 and PGI2 at a ratio of 4:1 was able to do so. 7. The hypotension in response to minoxidil —another vasoactive antihypertensive — was also accompagnied by the appearance of PG-like material in the renal venous blood. The increase in PG-like material was, however, smaller than that after hydralazine and dihydralazine in spite of a similar fall in blood pressure, and the hypotensive effect of minoxidil was only partially antagonized by indomethacin. The hypotension in response to the alpha-adrenoceptor blocking drug prazosin, to the adrenergic neurone blocking drug guanethidine, and to the centrally acting clonidine were neither accompagnied by the appearance of PG-like material in the renal venous blood nor influenced by indomethacin. 8. In the conscious dog and in the anaesthetized guinea pig indomethacin antagonized the hypotensive action of dihydralazine only partially and in other species such as the rat, the rabbit and the cat — all studied under anaesthesia — failed to affect the drug-induced hypotension. 9. The present results suggest that in the anaesthetized dog the hypotensive effects of hydralazine and dihydralazine — and in part of minoxidil — are mediated through vasodilator prostaglandins.