Kallikrein rK10‐induced kinin‐independent, direct activation of NO‐formation and relaxation of rat isolated aortic rings

• Published in: British journal of pharmacology 1995-05, Vol.115 (2), p.356-360
• Main Authors: Wassdal, Irene, Hull, Robert, Gerskowitch, V. Paul, Berg, Torill
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacology; Analysis of Variance; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Aprotinin - pharmacology; Arginine - analogs & derivatives; Arginine - pharmacology; Biological and medical sciences; Blood vessels and receptors; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Dose-Response Relationship, Drug; Electrophysiology; Fundamental and applied biological sciences. Psychology; isolated aortic rings of rat; Kallikrein rK10; Kallikreins - metabolism; Kallikreins - pharmacology; kinin; Kinins - antagonists & inhibitors; Kinins - metabolism; Male; Muscle Contraction - drug effects; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; NG-Nitroarginine Methyl Ester; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - biosynthesis; Rats; Rats, Wistar; Vascular Resistance - drug effects; Vertebrates: cardiovascular system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb15885.x

1 rK10, a weak T‐kininogenase isolated from the rat submandibular gland, is a protein belonging to the rat kallikrein family. In the present work, we have studied the biological effects of rK10 with respect to its ability to alter vascular resistance, either directly like rK9, i.e., another kallikrein‐like protein, trypsin and thrombin, or through the release of kinins like tissue kallikrein (rK1). The direct effect was studied by its vasomotor activity on rat isolated aortic rings since this preparation was insensitive to the action of kinins. Its ability to induce altered vascular resistance through kinin‐generation was investigated by blood pressure studies in whole animals. The studies were performed in comparison to rK1. 2 Unlike rK1, which induces hypotension when administered intravenously to rats (ΔBP = − 56 ± 5 mmHg, 5 μg kg−1), rK10 did not have any: effect on systemic blood pressure (ΔBP= −3 ± 1, 5 μg kg−1, i.v.) 3 rK10 was without effect on uncontracted aortic rings, but showed a concentration‐dependent (10−8−10−6 m) relaxant effect on tissue precontracted with phenylephrine (10−6m). After removal of endothelial cells, no relaxation was observed. The relaxant response to rK10 was transient. rK1 (with and without endothelium), bradykinin and T‐kinin (with endothelium) had no effect on contracted or uncontracted aortic rings. 4 The relaxant effect of rK10 was dependent on its enzymatic activity since preincubation with aprotinin (1.02 mm) significantly reduced vasorelaxation from 74 ± 4% to 24 ±3%. 5 The relaxant effect was not inhibited by the kinin antagonist Hoe 140 (10−7 m; 34 ± 4% without, versus 30 ± 2% with Hoe 140), but was totally inhibited by the NO‐synthase inhibitor N.nitro‐L‐arginine methyl ester (l‐NAME) (2.5 × 10−4m; 27 ± 3% without and 2± 1% with l‐NAME). 6 These results show that rK10 has the ability to induce vascular relaxation by a specific, direct effect on endothelial cell NO‐synthesis, dependent on rK10 proteolytic activity, but independent of its ability to generate kinin. This effect, or its T‐kininogenase activity in blood, was not sufficient for rK10 to have an effect on peripheral vascular resistance since intravenous injections of rK10, unlike rK1, did not induce hypotension. Thus, rK10 does not seem to play a role in blood pressure homeostasis but may have a local effect on vascular resistance.