title: Effects of heparin on the vasodilator action of protamine in the rabbit mesenteric artery.
abstract: 1. The effects of protamine on the rabbit isolated small mesenteric artery were investigated both in the presence and in the absence of heparin, by the isometric tension-recording method. 2. The dissociation constant for the binding of heparin to protamine has never been previously reported, so in order to minimize the effects of protamine, known to have a vasodilator action, and to examine only the effects of a heparin-protamine complex, the experiments with heparin were performed in the presence of high concentrations of heparin (21-700 u ml-1), concentrations at which heparin itself does not affect the vascular tone. 3. Protamine (15-500 micrograms ml-1), in the absence of heparin, was found to inhibit (P < 0.05) noradrenaline (1 microM)-induced contractions both in endothelium-intact and in endothelium-denuded tissues. 4. Such vasodilator action of protamine in either endothelium-intact or -denuded tissues continued, even in the presence of excess heparin at a heparin/protamine (H/P) ratio of 1.4 u micrograms -1, but was almost completely blocked in the presence of a much greater excess of heparin (H/P ratio > or = 4.7 u micrograms -1): heparin was present both before and during the application of protamine. 5. The vasodilator action of protamine in the absence of heparin was prolonged both in the endothelium-intact and -denuded tissues after protamine had been washed out from the bath with Krebs solution. Although this washing out with a Krebs solution containing excess heparin (4.7 u ml-1) readily reversed such prolonged vasodilator action of protamine both in the endothelium-denuded strips and in the endothelium-intact strips which had been pretreated with inhibitors of the endothelium-derived relaxing factor (EDRF) pathway, it did not affect the prolonged vasodilator action of protamine in the endothelium-intact strips which received no pharmacological intervention.6. These results suggest that: (1) only protamine, not a heparin-protamine complex, exerts vasodilator action in vitro; (2) the vasodilator action of protamine presumably has an EDRF-mediated component;and (3) protamine probably exerts its direct vasodilator action without entering the smooth muscle cell.
authors.affiliation: Department of Anaesthesiology and Critical Care Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Akata
authors.forename: K
authors.initials: K
authors.lastname: Kodama
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006493:Heparin / Q000494:pharmacology*; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D019335:Nitroarginine; D009638:Norepinephrine / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011479:Protamines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D011479:Protamines; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D006493:Heparin; D001120:Arginine; D011188:Potassium; D009638:Norepinephrine