[Role of the kinin system in the pathogenesis of human burn disease. 1. State of the kinin system at various stages of burn disease].
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Role of kinins in the pathophysiology of myocardial ischemia. In vitro and in vivo studies.
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 post-ischemic 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-induced 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 PGI2 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 ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting 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.
Angiotensin-Converting Enzyme Inhibitors↗
Different B1 kinin receptor expression and pharmacology in endothelial cells of different origins and species.
In bovine aortic endothelial cells (BAECs), we previously demonstrated B1 and B2 kinin receptor-mediated increases in intracellular guanosine-3',5'-cyclic monophosphate (cGMP). In this study, the B2 kinin receptor agonist bradykinin increased cGMP in rat microvascular coronary endothelial cells (RMCECs) and human umbilical vein endothelial cells (HUVECs), which could be prevented with the specific B2 kinin receptor antagonist icatibant but not with the B1 kinin receptor antagonist des-Arg9-[Leu8]bradykinin or with the nonpeptide kinin receptor antagonist WIN 64338. B2 kinin receptor mRNA could be detected in all three cell types using reverse transcription-polymerase chain reaction and subsequent Southern blotting. The B1 kinin receptor agonist des-Arg9-bradykinin increased cGMP in RMCECs but not in HUVECs. The response in RMCECs could be prevented by des-Arg9-[Leu8]bradykinin as well as by WIN 64338 but not by icatibant. In BAECs, the B1 kinin receptor-mediated cGMP synthesis could be prevented by icatibant and desensitized by preincubation with des-Arg9-bradykinin as well as bradykinin. We detected B1 kinin receptor mRNA in RMCECs and HUVECs but not in BAECs. In HUVECs, the detection of B1 kinin receptor mRNA is in contradiction to the cGMP measurements. In BAECs, the atypical B1 kinin receptor pharmacology, the heterologous desensitization of the receptor and the failure to detect B1 kinin receptor mRNA cannot be explained by a typical B1 kinin receptor subtype. Thus, B2 kinin receptors with similar pharmacology are constitutively expressed in each of the three endothelial cell types. However, the endothelial cell types are heterogeneous in the expression of typical B1 kinin receptors and the pharmacology of the B1 kinin receptor-mediated responses.
Animals↗
Angiotensin-converting enzyme inhibitors and the kallikrein-kinin system.
The role of plasma kinin in the hypotensive mechanism of angiotensin-converting enzyme (ACE) inhibitors in essential hypertensive patients and in a dog myocardiac ischemic model is discussed. Both an increase in plasma kinin and a decrease in plasma angiotensin II might contribute to the hypotensive effects of ACE inhibitors in a normal-renin group. In a low-renin group, the hypotensive mechanism of this drug may be mainly the increase in plasma kinin levels. The augmentation of urine volume and urinary sodium excretion may also be related to the hypotensive effects of ACE inhibitors, and this mechanism might be explained by the renal blood flow increase and augmented activity in the renal kallikrein-kinin system. In a dog myocardial ischemia model, when an apparent myocardial ischemia occurred in the constricted group, plasma kinin levels in coronary sinus blood increased significantly. Following infusion of kinin into the left main coronary artery, 0.1 ng/kg/min of kinin for 5 min did not cause any change in plasma kinin levels in the artery or coronary sinus. A dose of 10 ng/kg/min of kinin for 5 min produced a significant elevation in plasma kinin in the coronary sinus from 12.8 to 142 pg/ml without any change in plasma kinin in the artery. However, such a level of kinin had no significant effect on coronary circulation, myocardial metabolism, or ECG ST segment in either group. Thus, the role of increased kinin in this dog model still remains unclear. Further studies including the administration of ACE inhibitors or bradykinin antagonist will be necessary to reach conclusions about the role of kinin in the heart.
Angiotensin-Converting Enzyme Inhibitors↗
Characterization of receptor-mediated actions of T-kinin.
T-Kinin (Ile-Ser-bradykinin) is unique to the rat. This study characterizes the receptors involved in T-kinin activity on both the intact isolated rat uterus and membrane receptor preparations of the rat uterus. The results show that T-kinin acts through kinin B2 receptors in the rat uterus as demonstrated by B2 receptor-antagonist inhibition. While the potency of T-kinin on rat uterus contraction was similar to that of bradykinin, binding studies showed that the affinity of T-kinin to the receptor was 10-fold lower than that of bradykinin. On the other hand, the D isomer of T-kinin, D-Ile-Ser-bradykinin, had an affinity for the receptor greater than that of T-kinin and was more potent in causing contraction. Comparing this finding with our previously published report that D-Ile-Ser-bradykinin is not active on the kinin receptor for vascular permeability indicates that the kinin receptors in the rat uterus are not the same as those previously reported in the smooth muscle of the vasculature, i.e. there exists subclasses of kinin B2 receptors. The data from binding studies on a variety of T-kinin analogues show that the substitution of hydroxyproline (Hyp) for Pro5, together with the D-configuration at Ile1 and/or Ser2 may be useful for the development of selective T-kinin antagonists. Studies involving pretreatment of the tissue with indomethacin demonstrated that prostaglandin release was more of a component of T-kinin's activity on the rat uterus than that of bradykinin.
Amino Acid Sequence↗
Kinin-related effects of angiotensin-converting enzyme inhibition.
Angiotensin-I-converting enzyme (ACE) converts angiotensin-I to angiotensin-II and splits bradykinin into inactive fragments. Inhibition of that enzyme attenuates kinin degradation and potentiates the action of kinins in many pharmacological investigations. Kinins are very potent vasodilating peptides which reduce blood pressure by lowering peripheral vascular resistance. Under experimental conditions in vitro kinins mediated a lot of metabolic and hemodynamic effects of the ACE inhibitors. However, it is still not known whether kinins also play a major role in the blood pressure-lowering effect of ACE inhibitors in vivo. New and highly specific assays are available to determine kinins in blood. But after ACE inhibition no homogeneous changes in circulating kinins are observed by reviewing recently published studies and even inhibition of kallikrein-kinin systems by either antibradykinin-antiserum or aprotinin does not clarify the role of kinins in the hemodynamic responses to ACE inhibition. The newly available bradykinin receptor antagonists inhibit in vitro and in vivo the effect of exogenous bradykinin. They were metabolized like kinins and in higher doses can develop kinin-like activities. After intravenous injection the bradykinin-receptor antagonists induce in vivo an increase in systemic blood pressure and thereby can reduce the blood pressure-lowering effect of ACE inhibitors markedly. However, it is unclear to date whether the bradykinin receptor antagonists developed their blood pressure-enhancing effect only by blocking the kinin-induced vasodilation or by some other stimulating effects on the vasopressor hormones. As long as the mechanisms of the hemodynamic action of the bradykinin antagonists are uncertain, no unequivocal interpretation of the results is possible and the role of kinins in the action of ACE inhibitors in vivo remains still uncertain.
Angiotensin-Converting Enzyme Inhibitors↗
Kinins, receptors, antagonists.
Kinins are potent myotropic agents acting on a variety of smooth muscle preparations: isolated arteries, veins, intestines, tracheae, urinary bladders, uteri, etc. In these tissues, kinins activate at least two different receptor types, B1 and B2. B1 and B2 receptors for kinins have been identified by measuring the order of potency of agonists and the affinities of specific and competitive antagonists. Results of pharmacological studies have been confirmed by several investigators using binding assays with labelled bradykinin (BK) or desArg9BK. Antagonists for kinins active on B1 and B2 receptors have been identified. Anti-B1 antagonists are specific, competitive and fairly potent: anti-B2 antagonists have been identified among compounds primarily developed as anti-tachykinins: these compounds are non-specific, non-competitive and rather weak. They however may provide interesting new pharmacological tools, active against both kinins and tachykinins, two groups of endogenous peptides involved in the inflammatory process. The type (direct, indirect) and the site (endothelial cell, smooth muscle fiber, autonomic nerve endings) of action of kinins in isolated vessels have been investigated. The results of various studies indicate that kinins do not act on the sympathetic nerve terminals of isolated organs in contrast with other peptides. Kinins do not promote the release of histamine or of 5-hydroxy-tryptamine from isolated arteries and veins. Kinins are equally active in the presence and absence of indomethacin (an inhibitor of cyclooxygenase) or of BW 755C (an inhibitor of lipoxygenase) in some organs, while the actions of kinins on other organs are reduced to a variable extent by these inhibitors. In general, B1 receptor systems do not depend on the activation of arachidonic acid, while B2 receptor systems do: activation of the arachidonic acid cascade may be a feature of B2 receptors. Stimulant effects of kinins on arterial or venous vessels are independent on the endothelium, while the relaxant effect on the dog carotid artery occurs only in vessels with intact endothelium. The mechanism of action of kinins and tachykinins appears to be different from that of acetylcholine, since the peptides effects are not influenced by BW 755C and ETYA, two inhibitors of lipooxygenase that reduce significantly the effect of acetylcholine.
Animals↗
Generation of kinins in synovial fluid from patients with arthropathy.
An enzyme-linked immunosorbent assay method is described for the measurement of kinin formation in synovial fluid from patients with rheumatoid and osteoarthritis (RA and OA). Basal kinin concentrations were less than 6 ng/ml in synovial fluid collected in the presence of inhibitors of kinin forming (kininogenase) and kinin metabolising (kininase) enzymes. During incubation of synovial fluid in the presence of kininase inhibitors alone, kinins were produced rapidly over the first 10 min, but production ceased completely within 30 min due to inhibition of the endogenous kininogenases; the rate of kinin generation during the early rapid phase correlated well with the plateau kinin concentration. Plateau kinin levels in synovial fluid from 15 patients with OA and RA ranged from 98 to 427 ng/ml, with a median value of 148 ng/ml. This study demonstrates clearly that synovial fluid from arthritis patients has the capacity to produce kinins. Although the number of patients was small, the amount of kinin generated in vitro varied over a wide range and a relationship between intra-articular kinin formation and clinical features may become apparent in a larger group of patients. The technique could also be used to investigate other biological systems in which a role has been proposed for kinins.
Arthritis, Rheumatoid↗
Kinins in relation to kallikrein activity, kininogen, electrolytes, aldosterone and catecholamines in urine from normal individuals.
The object of the present study was to test the hypothesis that urinary kinin excretion is an indicator of intrarenal kinin formation and to investigate urinary excretion of kinins in relation to natriuresis, kaliuresis, diuresis and urinary aldosterone and catecholamines in normal individuals on a free salt and water intake. In freshly voided urine collected from 24 normal individuals kinin concentration was directly related to kallikrein activity. Kininogen concentration was very low and neither related to kallikrein activity nor to kinin concentration. The excretion rates of kinins and kininogen were unrelated to the time interval between micturitions. In 24 hour urine collections from 50 normal individuals the excretion of kinins was positively correlated to natriuresis, kaliuresis and diuresis and also to dopamine but not to aldosterone, noradrenaline and adrenaline. Kinin excretion was inversely related to age and was lower in women than in men. On the basis of these results it is concluded that urinary kinin excretion reflects intrarenal kinin formation in normal ambulatory individuals and that urinary kinins are formed mainly in the interstitial and vascular space of the kidney. Furthermore, kinins and dopamine seem to play a physiological role in the renal handling of electrolytes and water.
Adult↗
Renal effects of Fab fragments of kinin antibodies on deoxycorticosterone acetate-salt-treated rats.
The role of the renal kallikrein-kinin system in the regulation of renal function is not completely understood. Intrarenal kinins can influence renal function by acting as paracrine hormones at basolateral, luminal, or both sites in the distal nephron. To examine the role of intrarenal kinins in deoxycorticosterone acetate-salt-treated rats, which have high renal kallikrein, Fab fragments of antibradykinin antibody or DArg[Hyp3Thi5,8DPhe7]bradykinin, a kinin antagonist, were used to block kinins. At the dose used, the antibody (25 mg) and kinin antagonist (10 micrograms/min/rat) inhibited the hypotensive effect of intra-arterially injected bradykinin (100 ng) by 70% and 52%, respectively. The antibody appeared in the urine within 30 minutes after administration. Urinary volume was lowered from 9.4 +/- 0.2 to 6.7 +/- 0.4 microliters/min/g kidney wt (p less than 0.001, paired t test) by the antibody and from 8.5 +/- 0.3 to 6.8 +/- 0.4 microliters/min/g kidney wt (p less than 0.004, paired t test) by the kinin antagonist. The antibody lowered urine sodium excretion from 1.11 +/- 0.04 to 0.88 +/- 0.06 mueq/min/g kidney wt (p less than 0.001, paired t test), whereas the kinin antagonist had no significant effect. Neither altered blood pressure, renal blood flow, or glomerular filtration rate. These data suggest that in deoxycorticosterone acetate-salt-treated rats, excretion of water and sodium is regulated in part by kinins. The antidiuretic effect of the antibody and kinin antagonist might be due to blockade of kinins in the vascular-interstitial space of the kidney, since the kinin antagonist is likely hydrolyzed in the proximal tubule and does not reach the lumen of the distal nephron.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Kinin receptors of the central nervous system of spontaneously hypertensive rats related to the pressor response to bradykinin.
1. Kinin analogues bradykinin (BK), T-kinin, Met-Lys-BK, Lys-Lys-BK, Des-Arg9-BK with agonist activity and D-Arg0-Hyp3-Thi5,8-D-Phe7-BK (DAHTDBK) and Arg9-Leu8-BK with antagonist activity were injected into the posterior portion of the fourth cerebral ventricle of unanaesthetized rats implanted with permanent cannulae and arterial pressure was measured directly from the abdominal aorta. 2. The spontaneously hypertensive rats (SHR) were more sensitive than normotensive Wistar rats (NWR) to the pressor effect of BK and other kinin analogues. The SHR did not differ in sensitivity of the pressor response to centrally administered angiotensin II or endothelin-1. 3. Experiments with selective kinin agonists and antagonists revealed that in the SHR, as in the NWR, the receptors which mediated the central pressor response are of the BK2 subtype. 4. Measurements of the pressor activity of kinins with different degrees of susceptibility to degradation, as well as experiments with kininase inhibitors, enalaprilat and CPP-Ala-Ala-Phe-pAB, suggest that the kininase activity in the central nervous system of SHR is reduced in comparison to that of NWR. 5. The SHR also showed increased sensitivity to BK and Lys-Lys-BK, compared with the NWR, when the kinins were injected following the administration of a mixture of the kininase inhibitors, suggesting that mechanisms other than kininase activity may play a role in the increased sensitivity of the SHR to the central pressor action of kinins. 6. An in vivo characterization of the kinin receptors which mediate the central pressor response showed that the interaction with DAHTDBK was reversible and of competitive nature. The pA2 in vivo estimated for the kinin receptors of the SHR was 0.7 logarithm units larger than that obtained in the NWR. 7. The kinin receptors which mediate the central BK pressor effect in the SHR are of the BK2 subtype and are similar to receptors in the NWR. The increased sensitivity to kinins in the SHR may be explained, at least in part, by their decreased kininase activity. At present it is impossible to conclude whether the difference observed in the pA2 represents an increased affinity of the kinin receptors or can be attributed to differences amongst strains in the enzymatic degradation of the antagonist.
Angiotensin II↗
Kinin-B1 receptors in ischaemia-induced pancreatitis: functional importance and cellular localisation.
In this study we compare the role of kinin-B1 and B2 receptors during ischaemia/reperfusion of rat pancreas. Our investigations were prompted by the observation that infusion of a kinin-B2 receptor antagonist produced significant improvement in acute experimental pancreatitis. In an acute model with two hours of ischaemia/two hours of reperfusion, application of the kinin-B1 receptor antagonist (CP-0298) alone, or in combination with kinin-B2 receptor antagonist (CP-0597), significantly reduced the number of adherent leukocytes in post-capillary venules. In a chronic model with five days of reperfusion, the continuous application of kinin-B1 receptor antagonist or a combination of kinin-B1 and B2 receptor antagonists markedly reduced the survival rate. In kinin-receptor binding studies kinin-B1 receptor showed a 22-fold increase in expression during the time of ischaemia/reperfusion. Carboxypeptidase M activity was up-regulated 10-fold following two hours of ischaemia and two hours of reperfusion, provided the appropriate specific ligand, des-Arg10-kallidin and/or des-Arg9-bradykinin, was used. The occurrence of kinin-B1 receptor binding sites on acinar cell membranes was demonstrated by micro-autoradiography. With a specific antibody, the localisation of kinin-B1 receptor protein was confirmed at the same sites. In conclusion, we have demonstrated the up-regulation of the pancreatic acinar cell kinin-B1 receptors during ischaemia/reperfusion. The novel functional finding was that antagonism of the kinin-B1 receptors decreased the survival rate in an experimental model of pancreatitis.
Animals↗
Development biology of the renal kallikrein-kinin system.
Kinins are endothelium-dependent vasodilators and natriuretic paracrine peptides that participate in the regulation of blood pressure, renal hemodynamics and sodium excretion. Several lines of evidence suggest an important role for intrarenal kinins and their receptors in kidney growth and development. (1) The developing rat kidney expresses all the components of the tissue kallikrein-kinin system: tissue kallikrein, low molecular weight (LMW) kininogen, kininase II and kinin receptors. Also, the developing liver expresses high molecular weight and LMW kininogens. Thus, a complete kinin-generating system exists in the developing kidney. (2) Gene transcription, mRNA and protein abundance, and enzymatic activity of renal kallikrein are all markedly up-regulated during postnatal kidney growth, and a positive correlation exists between renal kallikrein synthesis and the maturational rise in renal blood flow. (3) Rat glomerular mesangial cells in culture express the kinin receptors and proliferate in response to bradykinin, suggesting that endogenous kinins and their receptors modulate glomerular growth. (4) The newborn period is characterized by an activation of kinin receptor gene expression, and chronic pharmacological blockade of kinin receptors suppresses DNA synthesis in the developing but not adult kidney. Collectively, these data provide the basis for the hypothesis that endogenous kinins and the kinin receptors play an important role in the developmental biology of the metanephric kidney.
Animals↗
Role of endothelial kinins in control of coronary nitric oxide production.
The purpose of the present study was to determine whether interventions that promote kinin production or decrease kinin inactivation affect nitric oxide production in isolated canine coronary microvessels. Accordingly, bradykinin (10[-8] to 10[-5] mol/L), ramiprilat (10[-10] to 10[-8] mol/L), A23187 (10[-8] to 10[-6] mol/L), kallikrein (1 to 20 U/mL), and kininogen (0.5 to 10 microg/mL) were used to stimulate endothelium-dependent nitric oxide production. Receptor antagonists, serine protease inhibitors, and a kinin antibody were used to inactivate local kallikrein-kinin activity. Nitrite, the metabolite of nitric oxide in aqueous solution, was measured using the Griess reaction. All the agonists significantly increased nitrite release. For instance, the highest dose of bradykinin, ramiprilat, A23187, kallikrein, and kininogen markedly increased nitrite production, from 60+/-10 to 156+/-12, 153+/-11, 161+/-15, 176+/-15, and 168+/-16 pmol/mg (all P<.05), respectively. The increased nitrite production caused by these agents was not only blocked by N omega-nitro-L-arginine methyl ester (L-NAME) and HOE 140 (which blocks B2 kinin receptor) but by the kinin antibody also. For instance, nitrite production elicited by bradykinin, ramiprilat, A23187, and kininogen was reduced to 95+/-8, 87+/-8, 94+/-11, and 85+/-11 pmol/mg (all P<.05), respectively, by the kinin antibody. Carbachol-induced nitrite production (from 66+/-8 to 144+/-13) was blocked by L-NAME but not by HOE 140 or the kinin antibody. These results suggest that either increasing kininogen to promote endogenous kinin formation or inhibiting angiotensin-converting enzyme to decrease kinin breakdown, increases nitric oxide production in isolated coronary microvessels. These data indicate that a microvessel kallikrein-kinin system has an important role in the control of nitric oxide production in coronary microvessels.
Animals↗
Visualisation of tissue kallikrein, kininogen and kinin receptors in human skin following trauma and in dermal diseases.
During dermal injury and inflammation the serine proteases kallikreins cleave endogenous, multifunctional substrates (kininogens) to form bradykinin and kallidin. The actions of kinins are mediated by preferential binding to constitutively expressed kinin-B2 receptors or inducible kinin-B1 receptors. A feature of the kinin-B1 receptors is that they show low levels of expression, but are distinctly upregulated following tissue injury and inflammation. Because recent evidence suggested that kinin-B1 receptors may perform a protective role during inflammation, we investigated the specific occurrence of the kallikrein-kinin components in skin biopsies obtained from normal skin, patients undergoing surgery, basalioma, lichenificated atopic eczema, and psoriasis. The tissue was immunolabeled in order to determine the localisation of tissue pro-kallikrein, kallikrein, kininogen and kinin receptors. The kinin components were visualised in normal, diseased and traumatised skin, except that no labelling was observed for kininogen in normal skin. Of the five types of tissue examined, upregulation of kinin-B1 receptors was observed only in skin biopsies obtained following surgery. In essence, the expression of kinin-B1 receptors did not appear to be enhanced in the other biopsies. Within the multiple steps of the inflammatory cascade in wound healing, our results suggest an important regulatory role for kinin-B1 receptors during the first phase of inflammation following injury.
Aged↗
The synthesis and distribution of the kinin B1 and B2 receptors are modified in the hippocampus of rats submitted to pilocarpine model of epilepsy.
Kinins, a special class of polypeptides, are represented by bradykinin (BK), kallidin (Lys-BK), as well as their metabolites. The biological actions of these polypeptides binding on their receptors (B1 and B2) have been related to inflammation process, cytokines action, glutamate release and prostaglandins production. Usually, kinin B1 receptor is not expressed at a significant level under physiologic conditions in most tissues, but its expression is induced by injury, or upon exposure in vivo or in vitro to pro-inflammatory mediators. The kinin B2 receptor subtype is constitutively and widely expressed throughout the central and peripheral nervous system. These data raise the possibility for de novo expression of those receptors during the temporal lobe epilepsy (TLE), which has been related to cell death, gliosis and hippocampal reorganization. To correlate kinin system and TLE, adult male Wistar rats were submitted to pilocarpine model of epilepsy. The hippocampi were removed 6 h, 5 and 60 days after status epilepticus (SE) onset. The collected tissues were used to study the expression of kinin B1 and B2 mRNA receptors, using Real-Time PCR. Immunohistochemistry assay was also employed to visualize kinin B1 and B2 distribution in the hippocampus. The results show increased kinin B1 and B2 mRNA levels during acute, silent and chronic periods and changes in the kinin B1 and B2 receptors distribution. In addition, the immunoreactivity against kinin B1 receptor was increased mainly during the silent period, where neuron clusters of could be visualized. The kinin B2 receptor immunoreactivity also showed augmentation but mainly during the acute and silent periods. Our results suggest that kinin B1 and B2 receptors play an important role in the epileptic phenomena.
Animals↗
Physiological role of renal kallikrein-kinin system in human.
The physiological role of renal kallikrein-kinin system in human is discussed by the three following topics. Localization of each component of renal kallikrein-kinin system: Kallikrein is localized in the apical site of the distal tubular epithelial cells and collecting ducts by the immunostaining method. Following the stop-flow method in dog kidney, kallikrein and kinin are recognized in the distal tubules. Kininase I, II and neutral endopeptidase (enkephalinase) are localized not only in the proximal tubules, but also in the distal tubules. The localization of kininases is further confirmed by the stop-flow method pretreated with specific inhibitors for each of the kininases. Sodium metabolism and renal kallikrein-kinin system: In normal subjects, fractional excretions of sodium and inorganic phosphorus which reflect the total and proximal sodium reabsorption, show significantly positive correlations for both urinary kallikrein and kinin excretions. In the case of 0.9% saline infusion, the activity of renal kallikrein-kinin system is augmented following the infusion as shown in the increases of urinary kallikrein and kinin excretions and the decreases of urinary kininases excretions. Relation to other renal depressor systems: The close relations among renal dopamine, kallikrein-kinin and prostaglandin systems have been suggested by a dopamine infusion study. Dopamine may augment the activity of the renal kallikrein-kinin system through both the increases of renal prekallikrein synthesis and kallikrein specific activity. From these studies reported up to the present, it is suggested that the renal kallikrein-kinin system produced in the distal nephron in the kidney may play a role in the sodium metabolism with other renal depressor systems in addition to its own action.
Amino Acid Sequence↗
Does kinin mediate the hypotensive action of angiotensin converting enzyme (ACE) inhibitors?
The lack of kinin formation in systemic circulation and in the renal system may lead to the pathogenesis of high blood pressure (hypertension). Angiotensin converting enzyme inhibitors are able to protect the kinin inactivation by kininase II, therefore, causing an accumulation of kinin. Although the concentrations of kinin in plasma after oral administration of ACE inhibitors are conflicting this is mainly due to methodological difficulties. Kinin receptor antagonists are becoming most reliable pharmacological probes for defining the molecular actions of kinin in several physiopathological states, and in the mechanism of actions of drugs which are dependent on the kinin system. The blood pressure lowering effect of ACE inhibitors can be antagonized by the pretreatment with kinin receptor antagonists. I have therefore proposed that the hypotensive action of ACE inhibitors may reflect the activation of kinin receptor. It is suggested that the development of compounds having protective properties on the kallikrein-kinin system might be therapeutically applicable as anti-hypertensive drugs.
Angiotensin-Converting Enzyme Inhibitors↗