Ovokinin, a peptide recently isolated from an enzymatic digest of ovalbumin, has been shown to mediate vasorelaxation of the canine mesenteric artery through bradykinin B1 receptors. Bradykinin can mediate both vasorelaxation and vasocontraction depending upon the tissue or species investigated. The aim of this study was to characterize ovokinin further by determining whether the effects of this peptide, like bradykinin, vary when using different species and tissue preparations as well as different contracting agents. Isolated aortic rings from guinea pigs, normotensive rats, and spontaneously hypertensive rats were exposed to phenylephrine, prostaglandin F2a, potassium chloride, or bradykinin. Bradykinin contracted guinea pig and spontaneously hypertensive rat aortas, however, it had no effect on normotensive rat aortas. In this study, ovokinin did not exhibit activity in any of the preparations except in guinea pigs, where it potentiated the contraction elicited by bradykinin only. This potentiation was blocked when rings were pretreated with captopril, a kininase II inhibitor. Ovokinin may also exhibit slight vasorelaxing activity in spontaneously hypertensive rat aortas precontracted with prostaglandin F2a. These findings suggest that, like bradykinin, the effects of ovokinin are species- and tissue-dependent. The action of ovokinin on the guinea pig aorta may involve kininase II, which is partly responsible for the degradation of bradykinin and other kinins. / Master of Science

Diss. (sammanfattning) Umeå : Univ., 2006. / Härtill 4 uppsatser.

Through the actions of bradykinin (BK) and angiotensin II (ANG II), the kallikrein-kinin and renin-angiotensin systems, respectively, regulate cardiovascular mechanisms in both mammals and fish. The myotropic and cardiovascular actions of homologous BK from the little skate, Leucoraja erinacea, were examined in the little skate. Administration of skate BK in vivo produced a biphasic increase in blood pressure and constricted the 1st branchial, mesenteric and celiac arteries in vitro. Co-administration of skate BK with several pharmacological agents suggest multiple pathways are involved in mediating the myoactivity of the BK in the little skate. The myotropic effects of ANG peptides were also assessed in the little skate and addition of homologous ANG II to pre-constricted vessels in vitro demonstrated a dose-dependent vasodilation. Morover, addition of skate BK in a heterologous bioassay produced a dose-dependent vasodilator effect in the aorta of the mouse suggesting conservation of this ancient peptide-receptor complex in mammals.

Through the actions of bradykinin (BK) and angiotensin II (ANG II), the kallikrein-kinin and renin-angiotensin systems, respectively, regulate cardiovascular mechanisms in both mammals and fish. The myotropic and cardiovascular actions of homologous BK from the little skate, Leucoraja erinacea, were examined in the little skate. Administration of skate BK in vivo produced a biphasic increase in blood pressure and constricted the 1st branchial, mesenteric and celiac arteries in vitro. Co-administration of skate BK with several pharmacological agents suggest multiple pathways are involved in mediating the myoactivity of the BK in the little skate. The myotropic effects of ANG peptides were also assessed in the little skate and addition of homologous ANG II to pre-constricted vessels in vitro demonstrated a dose-dependent vasodilation. Morover, addition of skate BK in a heterologous bioassay produced a dose-dependent vasodilator effect in the aorta of the mouse suggesting conservation of this ancient peptide-receptor complex in mammals.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1964. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 119-126).

国立情報学研究所で電子化したコンテンツを使用している。

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Protamin antagonisiert die antikoagulierende Wirkung von Heparin. Nach intravenöser Protaminapplikation treten als häufige unerwünschte Wirkungen ein systemischer Blutdruckabfall, Herzfrequenzabfall sowie eine Erhöhung des pulmonalarteriellen Widerstandes auf. Die Protamin-assoziierten Nebenwirkungen sind zum Teil lebensbedrohlich. Der ihnen zugrunde liegende Mechanismus wurde in der vorliegenden Arbeit auf Zellkultur- und Gesamttierebene analysiert sowie mögliche Therapieoptionen aufgezeigt. Heparin-Protamin-Komplexe aktivieren auf Endothelzellen den Blutgerinnungsfaktor XII. Aktiver Faktor XII startet über sein Substrat Plasmakallikrein die Freisetzung des Peptidhormons Bradykinin aus hochmolekularem Kininogen. Funktions-inhibierende Antikörper oder pharmakologische Inhibitoren von Plasmakallikrein oder Faktor XII blockierten die Heparin-Protamin induzierte Bradykininbildung auf Zellen. Stickstoffmonoxid-spezifische Fluorophore zeigten, dass Bradykinin-Bindung an Kinin B2 Rezeptoren die endotheliale Stickstoffmonoxid-Synthase aktiviert. B2 Rezeptorantagonisten blockierten die Heparin-Protamin induzierte Stickstoff-monoxidbildung. Die intravenöse Infusion von Protamin in heparinisierte Wildtypmäuse senkte den systemischen Blutdruck und die Herzfrequenz. Im Gegensatz dazu waren Faktor XII und B2 Rezeptor Gen-defiziente Mäuse oder Tiere, die Faktor XII Inhibitoren oder B2 Rezeptorantagonisten infundiert bekamen, vor Heparin-Protamin-Effekten geschützt. Mit dieser Arbeit konnte gezeigt werden, dass Heparin-Protamin-Komplikationen durch eine Faktor XII-getriebene Bradykininbildung verursacht werden. Eine Blockade der Bradykininbildung oder -wirkung eröffnet eventuell eine Möglichkeit, die Heparin-Protamin-Nebenwirkungen auch beim Patienten zu therapieren. / Protamine is the antidot for anticoagulant effects of heparin. Intravenous application of protamine may cause systemic hypotension, heart rate decrease and increase in pulmonary pressure. Adverse effects associated with protamine are common and potentially life-threatening. This work characterizes the pathomechanism of heparin-protamine-effects in cell culture and in transgenic mice and suggests therapeutic options to block the adverse effects. Heparin-protamine-complexes activate blood coagulation factor XII on endothelial cells. Active factor XII initiates the generation of the vasoactive peptide hormone bradykinin from high molecular weight kininogen by plasmakallikrein action. Antibodies or low molecular weight inhibitors that interfere with factor XII or plasmakallikrein activity blocked heparin-protamine-induced bradykinin effects on cells. Nitric oxide-specific dyes revealed that bradykinin-binding to kinin B2 receptors activates the endothelial nitric oxide synthase. B2 receptor antagonists interfered with heparin/protamine-driven nitric oxide generation. Intravenous application of protamine into heparinized wildtype mice reduced systemic blood pressure and heart rate. Factor XII or B2 receptor deficient mice were protected from heparin-protamine-effects. Consistently, pharmacological targeting of B2 receptors or factor XII inhibited protamine associated cardiovascular effects in heparinized wildtype mice. Together, this work demonstrates that heparin-protamine-adverse effects are due to factor XII activation that culminates in the generation of bradykinin. Inhibition of bradykinin formation or signaling may offer novel strategies to block adverse heparin-protamin-effects in patients.

Chronic neuropathic pain is a disease that impacts the livelihood of millions of people in the United States with no effective pain treatments and limited information pertaining to the underlying mechanisms. Opioid therapy is considered the gold standard for pain therapeutics, but chronic use of these medications brings about serious side effects such as tolerance, addiction, and respiratory depression which limit their overall therapeutic potential. Herein, two approaches are discussed to circumvent these issues: i) a multifunctional approach using N-phenyl-N-piperidin-4-yl-propionamide (Ppp) coupled to various endogenous opioid ligand scaffolds, and ii) non-opioid dynorphin A (DYN A) ligands at the Bradykinin-2 receptor (B2R). The μ-opioid receptor (MOR) upon agonist stimulation provides analgesia and concomitant activation of the δ-opioid receptor (DOR) leads to an increased antinociceptive effect. Chronic activation of the MOR has been correlated with an upregulation of the κ-opioid receptor (KOR) and KOR associated side effects such as anxiety and depression. The discovery of a new class of opioid receptor (OR) ligands that have the biological profile of MOR/DOR agonists and KOR antagonists would be beneficial considering they would have an increased analgesic effect, leading to a lower dosage being administered and thus lower overall side effects, and block symptoms elicited from KOR stimulation. Discussed are various structure activity relationships (SARs) of numerous scaffolds that present novel biological profiles. Ultimately, we discovered a compound that, to our knowledge, is the 1st MOR/DOR agonist and KOR antagonist. DYN A is the endogenous ligand for the KOR and its [des-Tyr1]-DYN A fragment interacts with the B2R, but not the KOR, promoting hyperalgesia. Peptidomimetic non-opioid DYN A analogues were synthesized and evaluated at the B2R. A minimum pharmacophore was identified and antagonists with both improved biological stability and affinity were discovered.