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Francois Alhencgelas - One of the best experts on this subject based on the ideXlab platform.
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kallikrein k1 Kinins and ace kininase ii in homeostasis and in disease insight from human and experimental genetic studies therapeutic implication
Frontiers in Medicine, 2019Co-Authors: Francois Alhencgelas, Nadine Bouby, Jean-pierre GirolamiAbstract:: Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and Kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and Kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of Kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.
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Kinins as therapeutic agents in cardiovascular and renal diseases
Current Pharmaceutical Design, 2011Co-Authors: Francois Alhencgelas, Nadine Bouby, Christine Richer, Louis Potier, Ronan Roussel, Michel MarreAbstract:A fair amount of data indicates that bradykinin and lysyl-bradykinin exert arterial, cardiac and renal effects which afford protection against organ damage in diseases, especially in the settings of ischemia or diabetes. The concept of Kinins acting as therapeutic agents is supported by the wide use of angiotensin I-converting enzyme (ACE) inhibitors. These inhibitors indeed potentiate kinin action by inhibiting kinin degradation. Experimental evidence strongly suggests that the cardiac and renal effects of ACE inhibitors are due, at least in part, to Kinins. Angiotensin AT1 receptor antagonists act also partly through Kinins. This paper reviews available evidence supporting a role for Kinins in the therapeutic effect of current drugs. It then discusses the opportunity to develop new drugs based on kinin action. Direct activation of the kinin B2 receptor by pharmacological agonists might provide higher therapeutic benefit than existing kinin- potentiating drugs. Possible occurrence of side effects is however a concern.
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prologue Kinins and related systems new life for old discoveries
American Journal of Physiology-heart and Circulatory Physiology, 2003Co-Authors: Randal A Skidgel, Francois Alhencgelas, William B CampbellAbstract:The current Special Topic section of the AJP: Heart and Circulatory Physiology presents papers on the theme: “Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems.” The topic is broad because of the diverse nature of research on the kallikrein-kinin
Nadine Bouby - One of the best experts on this subject based on the ideXlab platform.
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Kallikrein/K1, Kinins, and ACE/Kininase II in Homeostasis and in Disease Insight From Human and Experimental Genetic Studies, Therapeutic Implication
Frontiers in Medicine, 2019Co-Authors: François Alhenc-gelas, Nadine Bouby, Jean-pierre GirolamiAbstract:Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and Kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and Kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of Kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.
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kallikrein k1 Kinins and ace kininase ii in homeostasis and in disease insight from human and experimental genetic studies therapeutic implication
Frontiers in Medicine, 2019Co-Authors: Francois Alhencgelas, Nadine Bouby, Jean-pierre GirolamiAbstract:: Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and Kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and Kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of Kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.
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Kinins as therapeutic agents in cardiovascular and renal diseases
Current Pharmaceutical Design, 2011Co-Authors: Francois Alhencgelas, Nadine Bouby, Christine Richer, Louis Potier, Ronan Roussel, Michel MarreAbstract:A fair amount of data indicates that bradykinin and lysyl-bradykinin exert arterial, cardiac and renal effects which afford protection against organ damage in diseases, especially in the settings of ischemia or diabetes. The concept of Kinins acting as therapeutic agents is supported by the wide use of angiotensin I-converting enzyme (ACE) inhibitors. These inhibitors indeed potentiate kinin action by inhibiting kinin degradation. Experimental evidence strongly suggests that the cardiac and renal effects of ACE inhibitors are due, at least in part, to Kinins. Angiotensin AT1 receptor antagonists act also partly through Kinins. This paper reviews available evidence supporting a role for Kinins in the therapeutic effect of current drugs. It then discusses the opportunity to develop new drugs based on kinin action. Direct activation of the kinin B2 receptor by pharmacological agonists might provide higher therapeutic benefit than existing kinin- potentiating drugs. Possible occurrence of side effects is however a concern.
Jean-pierre Girolami - One of the best experts on this subject based on the ideXlab platform.
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Kallikrein/K1, Kinins, and ACE/Kininase II in Homeostasis and in Disease Insight From Human and Experimental Genetic Studies, Therapeutic Implication
Frontiers in Medicine, 2019Co-Authors: François Alhenc-gelas, Nadine Bouby, Jean-pierre GirolamiAbstract:Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and Kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and Kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of Kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.
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kallikrein k1 Kinins and ace kininase ii in homeostasis and in disease insight from human and experimental genetic studies therapeutic implication
Frontiers in Medicine, 2019Co-Authors: Francois Alhencgelas, Nadine Bouby, Jean-pierre GirolamiAbstract:: Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and Kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and Kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of Kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.
Bernward Scholkens - One of the best experts on this subject based on the ideXlab platform.
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antihypertensive and cardioprotective effects after angiotensin converting enzyme inhibition role of Kinins
Journal of Cardiac Failure, 1997Co-Authors: Carsten Tschope, Bernward Scholkens, W. Linz, Peter Gohlke, Thomas UngerAbstract:Abstract Kinins are potent bioactive peptides formed by the enzymatic action of kallikrein on kininogens. The discovery that angiotensin-converting enzyme, which generates angiotensin II, is also a major degrading enzyme of Kinins, gave rise to the hypothesis that kinin potentiation, in addition to angiotensin II reduction, may be involved in the therapeutic actions of angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitors have become important drugs in the treatment of hypertension, congestive heart failure, postmyocardial infarction, and diabetic nephropathy. Although angiotensin II reduction appears to be the predominant mechanism of the antihypertensive effect of chronic angiotensin-converting enzyme inhibitor treatment, the role of Kinins in the antihypertensive effects of angiotensin-converting enzyme inhibitors seems to be renin dependent and cannot be generalized for all models of hypertension. On the other hand, at least under experimental conditions, various cardioprotective effects of angiotensin-converting enzyme inhibitors appear to be due to the potentiation of endogenous Kinins, including improved cardiac function, structural changes following myocardial ischemia, and induction of capillary growth in hypertension-induced left ventricular hypertrophy.
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Role of Kinins in myocardial ischemia.
EXS, 1996Co-Authors: W. Linz, Gabriele Wiemer, Klaus Wirth, Piero A. Martorana, Bernward ScholkensAbstract:Kinins are potent vasoactive and inflammatory peptides derived from plasma precursors under conditions of tissue injury and ischemia [1]. Their vasoactive effects are mainly mediated through the release of different autacoids, generated by the endothelium. Recent evidence has been accumulated that the endothelium itself can release Kinins [2]. Activation of G protein coupled endothelial B2 kinin receptors, leads (by stimulating phospholipases C and A2) to the formation of the potent vasodilators nitric oxide (NO) and prostacyclin (PGI2) [2]. In blood vessels kininase II or angiotensin converting enzyme (ACE) is located mainly at the luminal surface of the endothelial cell membrane and appears to be largely responsible for the local proteolytic breakdown of vascular Kinins [3]. Thus under physiological conditions the effect of vascular generated and released Kinins is limited by the activities of endothelial ACE and enzymes in deeper layers of the vascular wall [4]. However, if the breakdown of Kinins is limited during ACE inhibition or the synthesis and/or release of Kinins is activated under ischemic conditions an enhanced production of both autacoids has been observed. NO and PGI2 released from myocardial endothelial cells can diffuse to the underlying smooth muscle cells, exerting vasodilatory, antiischemic, antiproliferative and antiatherosclerotic effects (Fig. 1).
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Kinins in the cardiovascular system.
Immunopharmacology, 1996Co-Authors: Bernward ScholkensAbstract:Abstract Growing evidence points to the existence of the components of the kallikrein-kinin-system (KKS) in cardiac and vascular tissue forming systemic and local KKS pathways involving different cell types like endothelial cells, cardiomyocytes and vascular smooth muscle cells. Kinins may contribute to the regulation of the cardiovascular system in health and disease and to the pharmacological effects of cardiovascular agents via autocrine-paracrine mechanisms. Based on observations from experimental models of hypertension, hypertrophy, ischemia, remodelling and preconditioning one can assume that modulation of local KKS pathways is instrumental for endogenous cardio- and vasculoprotective mechanisms. The role of Kinins as possible mediators of such protective mechanisms is not only based on the existence of their generating pathways and their release, but also on observations that Kinins, when given locally or being increased by inhibition of their breakdown, exert beneficial cardiovascular effects, whereas antagonism of their receptors worsens these effects. Indispensable pharmacological tools like ACE inhibitors and kinin receptor antagonists have helped to clarify these assumptions, which are now further elucidated by molecular biology and by clinical research. Especially the wealth of experimental and clinical findings with ACE inhibitors present a continuous challenge to investigate the role of Kinins in the cardiovascular system and to have a closer look at the interdependence of KKS and the Renin-Angiotensin-System (RAS). Within our decade one might not only reach a clearer molecular perception of Kinins in the cardiovascular system, and their role in human health and disease, but might also come to improved innovative treatment by modulation of the KKS pathways.
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role of Kinins in the pathophysiology of myocardial ischemia in vitro and in vivo studies
Diabetes, 1996Co-Authors: W. Linz, Gabriele Wiemer, Bernward ScholkensAbstract:In ischemia, the heart generates and releases Kinins as mediators that seem to have cardioprotective actions. Kinin-generating pathways are present in the heart. Kininogen, kininogenases, Kinins, and B2 kinin receptors can be measured in cardiac tissue. Kinins are released under conditions of ischemia. In anesthetized rats and dogs with coronary artery ligation and in human patients with myocardial infarction, kinin plasma levels are increased. In isolated rat hearts, the outflow of Kinins is enhanced during ischemia but markedly attenuated after deendothelialization, pointing to the coronary vascular endothelium as the main possible source. Kinins administered locally exert beneficial cardiac effects. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin (BK) reduces the duration and incidence of ventricular fibrillation, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energy-rich phosphates and glycogen stores. In anesthetized animals, intracoronary BK is followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of BK and related peptides induces beneficial cardiac effects. Treatment with ACE inhibitors such as ramipril increases cardiac kinin levels and reduces postischemic reperfusion injuries in isolated rat hearts and infarct size in anesthetized animals. The importance of an intact endothelium that continuously generates Kinins is supported by observations that basal and ramipril-in-duced release of Kinins and PGI2 is markedly reduced after deendothelialization of isolated hearts. Blockade of B2 kinin receptors increases ischemia-induced effects. Endothelial formation of NO and P6I2 by ACE inhibition is prevented by the specific B2 kinin receptor antagonist icatibant. In isolated hearts, ischemia-reperfusion injuries deteriorate with icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous BK. Infarct size reduction by ACE inhibitors and by BK in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemie preconditioning because preconditioning or BK-induced antiarrhythmic and infarct sizelimiting effects are attenuated by icatibant. In conclusion, Kinins may act as mediators of endogenous cardioprotective mechanisms. Kinins are generated and released during ischemia, with subsequent formation of PGI2 and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profile resembles that of ACE inhibitors.
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furosemide enhances the release of endothelial Kinins nitric oxide and prostacyclin
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Gabriele Wiemer, Bernward Scholkens, W. Linz, Edwin Fink, Max Hropot, Paulus WohlfartAbstract:Despite a wealth of data, the mechanism of the direct dilator effect of furosemide on the systemic arterial and venous systems is far from being satisfactorily understood. Therefore, we investigated whether furosemide is capable of stimulating the production of the endogenous vasodilators nitric oxide and prostacyclin in primary cultured bovine aortic endothelial cells by an enhanced synthesis and release of endothelium-derived Kinins. Nitric oxide production was assessed in terms of intracellular guanosine cyclic-39,59 monophosphate accumulation; kinin and prostacyclin release were determined by specific radioimmunoassays. Furosemide concentration- and time-dependently increased the formation of nitric oxide and prostacyclin. Maximal increases of both autacoids were already obtained after a 5-min incubation with 3 x 10(-7) to 10(-6) mol/l of furosemide. In the same concentration range, furosemide led to an enhanced release of Kinins into the supernatant of the cells. This observation was supported by the inhibitory effect of the specific B2 kinin receptor antagonist icatibant (Hoe 140) on the furosemide-induced increase of nitric oxide and prostacyclin. Thus the hemodynamic effects, and in particular the direct early dilator effect, of furosemide may be explained in part by an enhanced endothelial synthesis and release of bradykinin and related Kinins, which in turn stimulates endothelial autacoid formation via B2 kinin receptor activation.
J.u.l.i. Chao - One of the best experts on this subject based on the ideXlab platform.
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Expression and Cellular Localization of the Kallikrein–Kinin System in Human Ocular Tissues
Experimental Eye Research, 1996Co-Authors: J.x. Ma, Q.i.n.g. Song, H C Hatcher, L E E Chao, R K Crouch, J.u.l.i. ChaoAbstract:Tissue kallikrein is a serine proteinase which processes kininogens to release bioactive Kinins. Kinins mediate a variety of biological processes through the interaction with kinin receptors. Kinins are involved in the regulation of blood pressure and local blood flow, vasodilation, smooth muscle contraction and relaxation, production of pain and inflammation, and stimulation of cell proliferation. The tissue kallikrein–kinin system has been implicated in a number of pathophysiological processes such as hypertension, allergy and diabetes mellitus. In the present study, we have identified the expression and localization of components of the kallikrein–kinin system in the human eye by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analyses, and in situ hybridization histochemistry. RT-PCR and Southern blot analyses have detected mRNAs of the key components of the system including tissue kallikrein, low molecular weight kininogen, and bradykinin B1and B2receptors at high levels in human retina, choroid and ciliary body, and relatively low levels in the optic nerve. In situ hybridization has identified cellular localization of these four mRNAs in ocular tissues. They are expressed in retinal neuronal cells including the outer nuclear layer, inner nuclear layer and ganglion cell layer. These mRNAs were also identified in endothelial cells of ocular blood vessels, ciliary muscle and lens epithelial cells. The sense riboprobes showed negative staining, which indicates the specificity of the antisense riboprobes. These results suggest that the tissue kallikrein–kinin system is produced endogenously in human ocular tissues. Similar expression patterns of kallikrein, kininogen and kinin receptors indicate that the kallikrein–kinin system may function in an autocrine or paracrine fashion in the eye.
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Expression and cellular localization of the kallikrein-kinin system in human ocular tissues
Exp.Eye Res., 1996Co-Authors: J.x. Ma, Q.i.n.g. Song, H C Hatcher, L E E Chao, R K Crouch, J.u.l.i. ChaoAbstract:Tissue kallikrein is a serine proteinase which processes kininogens to release bioactive Kinins. Kinins mediate a variety of biological processes through the interaction with kinin receptors. Kinins are involved in the regulation of blood pressure and local blood flow, vasodilation, smooth muscle contraction and relaxation, production of pain and inflammation, and stimulation of cell proliferation. The tissue kallikrein- kinin system has been implicated in a number of pathophysiological processes such as hypertension, allergy and diabetes mellitus. In the present study, we have identified the expression and localization of components of the kallikrein-kinin system in the human eye by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analyses, and in situ hybridization histochemistry. RT-PCR and Southern blot analyses have detected mRNAs of the key components of the system including tissue kallikrein, low molecular weight kininogen, and bradykinin B1 and B2 receptors at high levels in human retina, choroid and ciliary body, and relatively low levels in the optic nerve. In situ hybridization has identified cellular localization of these four mRNAs in ocular tissues. They are expressed in retinal neuronal cells including the outer nuclear layer, inner nuclear layer and ganglion cell layer. These mRNAs were also identified in endothelial cells of ocular blood vessels, ciliary muscle and lens epithelial cells. The sense riboprobes showed negative staining, which indicates the specificity of the antisense riboprobes. These results suggest that the tissue kallikrein- kinin system is produced endogenously in human ocular tissues. Similar expression patterns of kallikrein, kininogen and kinin receptors indicate that the kallikrein-kinin system may function in an autocrine or paracrine fashion in the eye
