title: Bradykinin-induced vasodilation of human forearm resistance vessels is primarily mediated by endothelium-dependent hyperpolarization.
abstract: Bradykinin (BK) stimulates endothelial cells to release a number of relaxing factors, such as NO, prostanoids (PGs), and an endothelium-derived hyperpolarizing factor (EDHF). However, the contributions of NO, PG, and EDHF in the vascular relaxation to BK vary with species and anatomic origin of blood vessels used. Therefore, the present study was designed to investigate the contributions of NO, PG, and EDHF in vasodilation caused by BK in human forearm resistance vessels. Forearm blood flow (FBF) was recorded with venous occlusion plethysmography in healthy nonsmoking subjects. At first, studies were performed to validate the NO clamp technique for its ability to inhibit endogenous NO generation. Brachial artery infusion of serotonin (0.6, 1.8, and 6 ng. 100 mL forearm volume [FAV](-1). min(-1)) caused significant forearm vasodilation (2.6 to 4.6 mL. 100 mL FAV(-1). min(-1)), which is known to be NO mediated. Indeed, during the NO clamp, cumulative doses of serotonin caused no vasodilation (2.4 to 2.6 mL. 100 mL FAV(-1). min(-1)), indicating that the generation of endogenous NO was completely blocked. Thereafter, the vasodilative actions of BK were investigated. Brachial artery infusion of BK (50, 100, and 200 ng. 100 mL FAV(-1). min(-1)) caused significant forearm vasodilation in all studies (from 3.1 to 20.4 mL. 100 mL FAV(-1). min(-1)). After the inhibition of cyclooxygenase and NO synthase activity through the use of aspirin and the NO-clamp technique, BK increased FBF in a similar manner (3.9 to 18.9 mL. 100 mL FAV(-1). min(-1)), indicating that the vasodilative actions of BK are independent of NO and PG generation. However, vasodilation caused by the 2 lower doses of BK were significantly attenuated after K(Ca) channel activity was blocked with tetraethylammonium chloride (0.1 mg. 100 mL FAV(-1). min(-1)), suggesting that in the lower dose range, BK mediates vasodilation through the opening of vascular potassium channels. In conclusion, BK is a potent vasodilator peptide in human forearm resistance vessels, causing vasodilation through hyperpolarization of the vascular wall independent of NO and PG production. In addition, the NO-clamp technique is a valid instrument to investigate the contribution of NO in the vasodilative response to different agents.
authors.affiliation: Department of Vascular Medicine and Diabetes, University Hospital Utrecht, Utrecht, The Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: Honing
authors.forename: P
authors.initials: P
authors.lastname: Smits
authors.forename: P J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: T J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000293:Adolescent; D000328:Adult; D001916:Brachial Artery / Q000187:drug effects* / Q000502:physiology; D001920:Bradykinin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D008875:Middle Aged; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D026902:Potassium Channel Blockers; D012701:Serotonin / Q000494:pharmacology; D019789:Tetraethylammonium / Q000494:pharmacology; D014655:Vascular Resistance; D014664:Vasodilation; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D012701:Serotonin; D019789:Tetraethylammonium; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D001920:Bradykinin