Vasodepressor activity of pharmaceutical formulations of heparin.

Thirty-four batches of heparin formulations were tested for vasodepressor activity in the anaesthetized cat in accordance with pharmacopoeial requirements. Batches containing chlorobutanol as preservative exerted hypotensive effects, similar to that of 0.1 microgram of histamine/kg, but the average heparin formulation without preservative also caused significant lowering of blood pressure. This effect was reduced by a histamine-H1-receptor antagonist. Heparin formulations, like histamine, caused contraction of the isolated guinea pig ileum which may indicate contamination with up to about 0.1 microgram histamine per 5000 IU of heparin. Using radioligand assays for substance P (SP) and vasoactive intestinal polypeptide (VIP), formulations of heparins of porcine intestinal origin were found not to inhibit 125I-BH-SP binding but some batches moderately reduced binding of 125I-VIP consistent with a maximal contamination with 50-100 ng of VIP per 5,000 IU. The results may have clinical implications for high-dose heparin therapy in connection with thoracic surgery. The results may also provide an argument for retaining the vasodepressor test in pharmacopoeial monographs for heparins.