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PubMed1988

Influence of kinins and angiotensin II on the regulation of papillary blood flow.

The influence of kinins and angiotensin II on the regulation of renal cortical and papillary blood flow and sodium and water excretion was examined in rats. Superficial cortical and papillary blood flows were measured using a laser-Doppler flowmeter. Papillary blood flow increased 50% after enalaprilat (60 micrograms/kg) and phosphoramidon (5.5 micrograms.kg-1.min-1) were given along with 0.3 M sodium bicarbonate solution to inhibit degradation of kinins and enhance urinary kallikrein activity. Infusion of a kinin antagonist, D-Arg-Hyp-Thi-D-Phe-bradykinin (5 micrograms/min), returned papillary blood flow to control levels. Urine flow and sodium excretion increased after the administration of the kininase inhibitors and sodium bicarbonate, while glomerular filtration rate (GFR) and outer cortical blood flow were unaltered. The kinin antagonist did not alter sodium and water excretion in rats receiving the kininase inhibitors and bicarbonate. Administration of the kinin antagonist alone lowered papillary blood flow by 20%, without affecting outer cortical blood flow or GFR. Urine flow decreased and urine osmolality increased after the rats received the kinin antagonist, but sodium excretion remained unaltered. To assess the role of angiotensin II in the control of papillary blood flow, kinin receptors were blocked by infusion of an antagonist, and the effects of enalaprilat and saralasin were studied. Papillary blood flow increased after blockade of the angiotensin II system in rats receiving the kinin antagonist. These results indicate that the kallikrein-kinin and renin-angiotensin systems participate in the regulation of papillary blood flow.

Angiotensin II↗
PubMed1992

Renal kinin antagonism does not impair pressure-induced natriuresis.

We studied the contribution of the renal kallikrein-kinin system to short-term electrolyte and water balance during baseline and during acutely elevated renal perfusion pressure (RPP) in the anesthetized dog. Renal blood flow, glomerular filtration rate, urine flow rate, renin secretion rate, and urinary excretion of sodium, potassium, prostaglandin E2 (PGE2), and kinins were measured at baseline RPP during intrarenal infusion of 0.9% saline or the competitive bradykinin analogue [D-Arg0,Hyp3,Thi5,D-Phe7,Thi8]bradykinin (50 micrograms/min), which blocks vascular and interstitial kinin receptors. RPP was then raised above baseline (control group 25%; kinin analogue group 22%) by ligating the celiac artery, the superior mesenteric artery, and the aorta distal to the renal arteries. Renal parameters were again measured during infusion of saline or the kinin analogue. The analogue had no effect on renal hemodynamic or excretory parameters at baseline perfusion pressures. Increasing RPP significantly increased urine flow rates and urinary sodium excretion rates (control group, 43 mumol/min; kinin analogue group, 55 mumol/min) in both groups of animals. Increasing pressure also tended to decrease renin secretion rate in both groups of animals; however, neither increased pressure nor infusion of the analogue affected urinary excretion of PGE2 or kinins. The results suggest that intrarenal kinins are not powerful short-term regulators of electrolyte and water balance and that an intact kallikrein-kinin system is not necessary to induce pressure diuresis and natriuresis.

Animals↗
PubMed1983

Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen.

Using a recently developed model of nasal challenge, we have obtained data that clearly demonstrate, for the first time, kinin generation during a local allergic reaction in vivo. Allergic individuals (n = 8) and matched nonallergic controls (n = 8) were challenged intranasally with the appropriate antigen and nasal washes were taken before and after challenge. Washes were assayed for kinin, histamine, and [3H]-N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase activity. Increased kinin generation was found by radioimmunoassay (RIA) in the nasal washes of all the allergics (5,560 +/- 1,670 pg/ml) but in none of the controls (38 +/- 16 pg/ml). The presence of kinin was highly correlated with that of histamine and TAME-esterase activity and with the onset of clinical symptoms (P less than 0.001). Serial dilutions of nasal washes produced RIA displacement curves that paralleled the standard curve, and recovery of standard kinins that were added to nasal washes was 100 +/- 4% (n = 14). Kinin recovery was identical in both allergics and controls and did not vary significantly with antigen challenge. The immunoreactive kinin in nasal washes was stable to boiling and not precipitated by ethanol, but completely destroyed by carboxypeptidase B. It was evenly distributed between the sol and gel phases of nasal washes. High performance liquid chromatography analysis of the immunoreactive kinin in nasal washes showed it to be a mixture of lysylbradykinin and bradykinin. We conclude that kinins are produced during local allergic reactions in the nose and may contribute to the symptomatology of the allergic response.

Administration, Intranasal↗
PubMed2004

Stimulated human neutrophils form biologically active kinin peptides from high and low molecular weight kininogens.

Human neutrophils play a pivotal role in acute inflammation. However, their capacity to generate bioactive kinin peptides has not been established as yet. We have examined the ability of neutrophil enzymes to release biologically active kinins in vitro from purified human H- and L-kininogens. Neutrophils isolated from human blood were stimulated with f-Met-Leu-Phe, thrombin, or human immunoglobulin G adsorbed to silica particles. Supernatants were incubated with iodinated kininogens, and polyacrylamide gel electrophoresis analyzed aliquots taken after a range of incubation times. A time-course analysis demonstrated that supernatants from stimulated neutrophils caused a rapid hydrolysis of both substrates, resulting in an accumulation of fragments ranging from 20 to less than 10 kDa. Radioimmunoassay (RIA) revealed that all supernatants were able to generate kinins in vitro. High-performance liquid chromatography of the generated peptides indicated that they had a retention time similar to that of bradykinin and Met-Lys-bradykinin, clearly recognized as kinin peptides when the corresponding fractions were tested by RIA. The kinin-immunoreactive fractions produced lowering of blood pressure and a dramatic increase in venular permeability. Biological activity of the neutrophil-generated kinins was completely abolished by the B2 receptor antagonist HOE140, indicating that over the time-course of the experiments, only kinin B2 agonists appeared to have been generated and that cellular actions of these were mediated by kinin B2 receptors. Together, our results demonstrate that human neutrophil proteases can release kinins from both plasma kininogens, suggesting that these peptides may participate actively during acute inflammation.

Bradykinin↗
PubMed2003

Attenuated kinin release from human neutrophil elastase-pretreated kininogens by tissue and plasma kallikreins.

Components of kinin-forming systems operating at inflammatory sites are likely to interact with elastase that is released by recruited neutrophils and may, at least temporarily, constitute the major proteolytic activity present at these sites. The aim of this work was to determine the effect of kininogen degradation by human neutrophil elastase (HNE) on kinin generation by tissue and plasma kallikreins. We show that the digestion of both low molecular mass (LK) and high molecular mass (HK) forms of human kininogen by HNE renders them essentially unsusceptible to processing by human urinary kallikrein (tissue-type) and also significantly quenches the kinin release from HK by plasma kallikrein. Studies with synthetic model heptadecapeptide substrates, ISLMKRPPGFSPFRSSR and SLMKRPPGFSPFRSSRI, confirmed the inability of tissue kallikrein to process peptides at either termini of the internal kinin sequence, while plasma kallikrein was shown to release the kinin C-terminus relatively easily. The HNE-generated fragments of kininogens were separated by HPLC and the fractions containing internal kinin sequences were identified by a kinin-specific immunoenzymatic test after trypsin digestion. These fractions were analyzed by electrospray-ionization mass spectrometry. In this way, multiple peptides containing the kinin sequence flanked by only a few amino acid residues at each terminus were identified in elastase digests of both LK and HK. These results suggest that elastase may be involved in quenching the kinin-release cascade at the late stages of the inflammatory reaction.

Amino Acid Sequence↗
PubMed1988

[Kallikrein-kinin system, the kidney and arterial pressure].

Renal kallikrein is synthetized in the distal nephron and secreted in urine. Studies on the microdissected nephron and on the whole kidney using immunohistochemistry indicate that kallikrein is produced at the level of the distal part of the distal tubule and in some species in the cells of the initial part of the collecting duct. Urinary kinins are formed at these same sites. The renal tubule contains high levels of kininases, able to inactivate kinins, but the kininases are located mainly up-stream the sites of kinin production, i.e. in the glomerulus and in the proximal tubule. A kininase activity is however also found in the medullary collecting duct. This collecting duct kininase activity might contribute to the control of kinin levels in kidney and urine. The physiological role of the renal kallikrein kinin system is not completely understood. There is some evidence for a role of urinary kinins in water and solute transferrence in the distal nephron. Also kinin production in the renal interstitium and/or circulation may contribute to the control of renal blood flow. In the isolated perfused rat kidney vasoconstricted by angiotensin II for example, the high molecular weight kininogen is hydrolyzed to release kinins and induces a vasodilatation. The kallikrein-kinin system therefore might play a role in kidney function by antagonizing the vascular effect of angiotensin II in the renal circulation and the maintenance renal blood flow.

Animals↗
PubMed1979

The kinin-forming acid protease system in murine fibroblasts L-929.

Components of an acid protease kinin-forming enzyme system were isolated and purified from the murine fibroblast L-929 cell line grown in stationary cell culture. The enzyme, was purified from the 10,000 g supernatant cell fraction by sequential passage through G-200 Sephadex, hydroxylapatite, DEAE-A50 Sephadex and affinity chromatography columns. The specific activity was determined on a rat plasma kininogen purified on DEAE and G-100 Sephadex columns as assayed for kinin-forming activity on the isolated perfused rat uterus. Both enzyme and substrate showed a single band pattern by disc gel electrophoresis technique. Optimum protease activity was obtained at pH 3.8, and kinin release was both time- and enzyme-dependent at 37 degrees. The molecular weight of the protease and kininogen, estimated on a G-200 Sephadex column, was 39,000 and 115,000 respectively. Two fibroblast kinins were isolated from a mixture of 12,000 g fraction of fibroblast homogenate and rat plasma incubated at 37 degrees, pH 4.0 for 92 hours. The two fibroblast kinins (I, II) were separated and purified on G-25 Sephadex, CM-C50 Sephadex, and Biogel P-4 columns. The purity of the kinins was ascertained by thin layer chromatography. The molecular weight of fibroblast kinin I was estimated to be 1450 with a 14-amino acid composition consisting of AspThrSerProGluGlyAlaVal-LeuTyrPheLysHisArg. Fibroblast kinin II had an estimated molecular weight of 1000 with a 12-amino acid composition that included AspSerProGluGlyAlaLeuTyrLysHisArg. The kinins were relatively rich in arginine and did not contain the bradykinin sequence.

Amino Acids↗
PubMed1982

Blood kinins, their concentration in normal subjects and in patients with congenital deficiency in plasma prekallikrein and kininogen.

Kinins are potent vasodilator peptides that may participate in the regulation of local blood flow and blood pressure. Here we report a new method to measure kinins in blood. For this, 6 ml of blood are collected in less than 10 sec directly into 25 ml of ethanol. Kinins are further purified by extracting lipids with ether and by removing kininogen and other interfering substances by chromatography on QAE Sephadex and BioRex 70; then they are measured by a sensitive RIA. In 22 normal subjects, after correction for recovery (50%), the kinin concentration in peripheral venous blood was 25.2 +/- 2.6 pg/ml (mean +/- S.E.M.). To determine whether the circulating kinins are formed by plasma kallikrein or other kininogenases, the concentration of blood kinins was measured in the venous blood of three patients with congenital deficiency in plasma prekallikrein (Fletcher trait) and in one patient with congenital deficiency in the substrate of plasma kallikrein, high-molecular-weight kininogen (Fitzgerald trait). In the three subjects with Fletcher trait, blood kinins were 16, 21, and 31 pg/ml, whereas in the subject with Fitzgerald trait they were 26 pg/ml. Normal subjects had concentrations in the same range (9 to 55 pg/ml), indicating that the concentration of blood kinins in normal subjects is much lower than previously reported (70 to 5000 pg/ml). These results also suggest that kininogenases other than plasma kallikrein may generate circulating kinins.

Animals↗
PubMed1994

Kinins in the pathogenesis of human airway diseases.

1. Over the past decade, data have been obtained showing that the potent vasoactive peptides known as kinins are generated in airway secretions during a variety of inflammatory airway diseases, such as allergic rhinitis, viral rhinitis and asthma. Kinin generation involves release of tissue kallikrein from airway glands, as well as increased vascular permeability and activation of the plasma kallikrein system. The activity of generated kinins is regulated by a number of cell-associated, as well as plasma-derived, peptidases. 2. Kinins can induce relevant symptoms when applied to the surface of human airways. Moreover, the effects of kinins are more pronounced in the setting of chronic inflammation. In the upper airways, kinins can stimulate glandular secretion, increase vascular permeability and stimulate sensory nerves to produce symptoms of nasal obstruction, rhinorrhea, and nasal and throat irritation. In the lower airways of asthmatics, kinins are potent inducers of edema and cause bronchoconstriction by a mechanism that involves, at least in part, neural reflexes. 3. Definitive proof of a role for kinins in human airway diseases has been difficult to obtain because receptor antagonists that have been available to date have suffered from problems of potency or duration of action. Studies are continuing, however, to understand the mechanisms by which kinins exert their effects and to delineate their importance in airway diseases.

Asthma↗
PubMed1993

Kinins and respiratory tract diseases.

Bradykinin and related kinins are peptidic hormones, formed in tissues and fluids during inflammation. Various functional sites have been proposed as mediators of the biological effects of kinins, including the B1, B2 and B3 receptors. The existence of the B1 and the B2 receptor has largely been confirmed, whilst that of the B3 receptor is controversial and needs further confirmation. The role of bradykinin in the pathophysiology of asthma is not well understood, but bradykinin was proposed as a putative mediator of asthma, since asthmatic subjects are hyperresponsive to bradykinin, and since immunoreactive kinins are increased in the bronchoalveolar lavage fluids of asthmatic patients. Kinins could provoke bronchoconstriction by acting directly on smooth muscle and/or indirectly by their inflammatory properties. They may also contribute to the symptomatology of allergic and viral rhinitis, since they are the only mediators detected to date that are generated in nasal secretion during experimental and natural rhinovirus colds. Moreover, they can induce relevant symptoms when applied to airway mucosa. It has also been proposed that coughing during treatment with angiotensin-converting enzyme (ACE) inhibitors is linked to the action of kinins, since ACE is able to degrade kinins, and since the effects of ACE inhibitors are reduced by kinin antagonists. Due to their mitogenic properties, kinins have been proposed to regulate lung carcinoma growth. Their action remains speculative, but some findings are of great interest in order to define their role in these pathologies. Despite many studies in animals and in humans, the mode of action of kinins in airways is still poorly understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Kinin-enhancing drugs for unexplained subfertility in men.

BACKGROUND: Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is felt by patients and doctors alike. As a result, a variety of empirical, non-specific treatments have been used in an attempt to improve semen characteristics and fertility. One suggested treatment for idiopathic oligo- and/or asthenospermia is the administration of kallikrein (kallidinogenase), a kinin-releasing enzyme (or kininogenase). The kinin biological system is complex and involves kininogen (the substrate), kininogenases (the activating enzymes), kinins (the effectors) and kininases (the inactivating enzymes). All four components of the kinin system have been found in the genitalia and in semen. Kallikrein releases 2 major kinins, kallidin and bradykinin, from seminal plasma kininogens. Activated kinins in semen affect sperm motility and metabolism. In vitro addition of kallikrein to semen has been shown to have a positive effect on sperm motility, sperm velocity, cervical mucus penetration, penetration of zona-free hamster eggs and post-thaw survival and motility rate after semen cryopreservation. The latter observation, however, was not confirmed in a more recent comparison of motility stimulants for cryopreserved semen using computerised sperm motion analysis. In vitro treatment of semen with kallikrein has been employed in a clinical context during sperm preparation prior to insemination. Although the kinin system may also be involved in the regulation of spermatogenesis in vivo, a clear mechanism of action is missing. Multiple suggestions on how an increase in kinin levels in the genital tract influences spermatogenesis at the testicular levels have been made by various authors. OBJECTIVES: To determine whether treatment of the male with drugs enhancing kinin levles increases pregnancy rates among couples where failure to conceive has been attributed to idiopathic oligo- and/or asthenospermia. Effects on sperm parameters and sex hormones were studied as secondary outcomes. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched". SELECTION CRITERIA: SIxteen RCTs on the therapeutic use of androgens (clomiphene citrate or tamoxifen) in subfertile men were identified. Six trials were excluded. DATA COLLECTION AND ANALYSIS: Methodological characteristics of trials Baseline characteristics of the studied groups Outcomes: Pregnancy rates, semen parameters (sperm concentration, motility and morphology), endocrinology (serum FSH, testosterone and oestradiol)

Fertility Agents, Male↗
PubMed1992

Measurement of T-kinin in rat plasma using a specific radioimmunoassay.

T-kinin (Ile-Ser-Bradykinin) has been isolated only from the plasma of the rat and it is unclear whether the peptide, or its biosynthetic precursor, T-kininogen, circulates in the human. An NH2-terminally directed antiserum to T-kinin was raised in rabbits using an immunogen prepared by coupling the free -SH group of T-kinin extended from its COOH-terminus by a cysteinyl residue to an -NH2 group on human serum albumin. A radioimmunoassay was developed using this antiserum and 125I-labelled [Tyr10]T-kinin as tracer that was sensitive (least-detectable concentration 3 fmol/tube) and relatively specific for T-kinin (cross-reactivity with bradykinin and kallidin less than 1%). Treatment of rat plasma with an excess of trypsin in the presence of a kininase inhibitor generated T-kinin immunoreactivity equivalent to 455 +/- 71 pmol/ml (mean +/- S.E.M.; n = 9) and this immunoreactivity was eluted from a reversed-phase HPLC column as a single peak with the same retention time as synthetic T-kinin. In contrast, treatment of plasma from healthy human subjects (n = 8) and from patients (n = 8) with inflammation due to acute or chronic gastrointestinal disease under the same conditions did not generate any detectable T-kinin immunoreactivity. It is concluded, therefore, that T-kininogen, the biosynthetic precursor of T-kinin in the rat, is either absent from the plasma of human subjects or is present in a concentration less than 30 fmol/ml. Similarly, T-kininogen is probably not an acute phase reactant in humans.

Adult↗
PubMed1997

Comparison of responses to T-kinin and bradykinin in the mesenteric vascular bed of the cat.

Responses to T-kinin and bradykinin were compared in the mesenteric vascular bed of the cat. Under constant-flow conditions, injection of T-kinin and bradykinin into the perfusion circuit induced similar dose-related decreases in perfusion pressure. Responses to T-kinin and bradykinin were inhibited by the kinin B2 receptor antagonist Hoe-140, but were not altered by the B1 receptor antagonist des-Arg9-[Leu8]-BK, the histamine H1 antagonist pyrilamine, the histamine H2 receptor antagonist cimetidine, or the H3 receptor antagonist thioperamide. Vasodilator responses to T-kinin and bradykinin were attenuated by the nitric oxide synthase inhibitor, N omega Nitro-L-arginine methyl ester (L-NAME), but were not altered by the cyclooxygenase inhibitor, sodium meclofenamate, or the K+ ATP channel antagonist, U37883A. These data suggest that vasodilator responses to T-kinin and bradykinin are mediated by kinin B2 receptor stimulated release of nitric oxide from the endothelium, but that the activation of kinin B1 receptors, the release of vasodilator prostaglandins, or the opening of K+ ATP channels are not involved in the response to T-kinin in the mesenteric vascular bed of the cat.

Adamantane↗
PubMed1997

T-kinin has endothelium-dependent vasodilator activity in the cat.

Responses to T-kinin, a peptide formed from the acute-phase substrate T-kininogen, were investigated in the hindlimb vascular bed of the cat. Under constant-flow conditions, injections of T-kinin into the perfusion circuit in doses of 0.03-1 nmol induced rapid dose-related decreases in perfusion pressure. Responses to T-kinin were similar in time course and magnitude to responses to bradykinin and kallidin and were inhibited by the kinin B2-receptor antagonist, Hoe-140. Responses to T-kinin were attenuated by an inhibitor of nitric oxide synthase and by tetraethylammonium chloride and were enhanced in duration by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor zaprinast. Responses to T-kinin were not altered by inhibitors of K+(ATP) channels, by the cyclooxygenase pathway, or by muscarinic or beta-adrenergic-receptor antagonists. These data suggest that vasodilator responses to T-kinin are mediated by kinin B2-receptor-stimulated release of nitric oxide from the endothelium and increased smooth muscle cGMP levels. These results indicate that activation of K+(ATP) channels and muscarinic or beta-adrenergic receptors and the release of vasodilator prostaglandins are not involved in mediating the response to T-kinin in the hindlimb circulation of the cat.

Acetylcholine↗
PubMed1989

Role of endogenous brain kinins in the cardiovascular response to intracerebroventricular melittin.

Intracerebroventricular infusion of the peptide melittin increases immunoreactive kinins in the cerebrospinal fluid of anesthetized dogs, probably secondary to activation of brain or cerebrospinal fluid kininogenases. Intracerebroventricular melittin also increases blood pressure and heart rate, possibly mediated by brain kinins, since intracerebroventricular bradykinin also increases blood pressure and heart rate. We tested whether the effects of centrally administered melittin on blood pressure and heart rate could be blocked by simultaneous infusion of a kinin receptor antagonist, [DArg0]Hyp3-Thi5,8[DPhe7]bradykinin, in normotensive awake rats. In the controls, intracerebroventricular infusion of kinin receptor antagonist given for 1 hour at a rate of 10 micrograms/hr blocked bradykinin-induced increases in blood pressure and heart rate by 80%. Basal blood pressure and heart rate were not affected by the kinin receptor antagonist alone. After a 30-minute infusion of melittin (8 micrograms/30 min), cerebrospinal fluid kininogenase activity (n = 17) rose from 0.13 +/- 0.05 to 0.43 +/- 0.1 ng/ml/min (p less than 0.02). Although cerebrospinal fluid kinins increased from below sensitivity (0.02 ng/ml, n = 12) to 0.19 +/- 0.1 ng/ml (n = 17), this change was due to drastic increases in three rats, whereas in 12 of them kinins were below sensitivity. Incubation of bradykinin (10 ng) with 0.1 ml rat cerebrospinal fluid for 5 minutes destroyed 70% of kinins, suggesting that rapid destruction may have made detection of increased CSF kinins difficult.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Antagonizing and measurement: approaches to understanding of hemodynamic effects of kinins.

Hemodynamic effects of the kallikrein-kinin system can be investigated by experimental administration of specific kinin antagonists and by measurement of kinin levels in the circulating blood. In conscious normal rats, the bradykinin analog B4162 blunts the hypotensive effect of exogenous bradykinin. This kinin antagonist has no blood pressure effect in control rats, but it enhances the pressor effect of vasoconstrictor substances such as vasopressin or angiotensin II when they are infused at subpressor doses. Endogenous kinins may therefore participate in blood pressure regulation by antagonizing pressor substances. Plasma levels of endogenous kinins are normally in the low picomolar range. They are rapidly generated and destroyed in biological fluids. Thus, measurement of plasma kinins requires sensitive assays based on high-affinity antibodies and careful sample-handling techniques. Nonpolar solid-phase extraction on phenylsilylsilica provides a rapid, reliable, and easy extraction of kinins from plasma with constant and high recoveries.

Amino Acid Sequence↗
PubMed1998

Release of endothelial-derived kallikrein, kininogen and kinins.

The endothelial cell should be regarded as a highly active metabolic and endocrine organ interacting with the blood streak and the interstitium. Kinins are vasodepressor hormones that may participate in local blood flow regulation as part of an autocrine-paracrine system. We have previously reported that tissue kallikrein, its mRNA and kininogen are present in vascular tissue. The present study was undertaken to examine the release of the components of this system from isolated perfused rat vessels. These vessels were perfused at 4 ml/min with physiological saline solution containing 3% Ficoll and 0.1% BSA. Kallikrein was released into the perfusate at a rate of 75 +/- 5 ng Bk/100 g bw/30 min (n = 10). Kininogen was released at a rate of 55 +/- 5 pg Bk/100 g bw/30 min. Pre-treatment with puromycin, a protein synthesis inhibitor, significantly reduces kallikrein and kininogen release. Vascular derived kinins were released at a constant rate of 38 +/- 6 pg Bk/100 g bw/30 min for at least 120 min. This basal kinin release was increased 3-fold when perfused with the angiotensin converting enzyme inhibitor ramiprilat (p < 0.05). When purified kininogen was added to the physiological saline solution, immunoreactive kinins in the perfusate increased from 42 +/- 7 to 3140 +/- 210 pg Bk/100 g bw/30 min (n = 6; p < 0.002). Increase in flow rate (from 2 ml/min up to 4 ml/min and 8 ml/min) causes a parallel increase in the release of kinins (from 32 +/- 4 up to 48 +/- 6 and 62 +/- 8 pg Bk/100 g bw/30 min, respectively; p < 0.01); the increase may be due to the effect of shear stress upon the endothelial cells. The present data confirm that vascular tissue synthesizes and releases continuously kallikrein, kininogen and kinins. Vascular kinins induce potent vasodilatation through the release of prostacyclin, nitric oxide and endothelium-derived hyperpolarization factor, and some of the converting enzyme inhibitors effect may be explained by potentiation of vascular-derived kinins.

Animals↗
PubMed1997

The kallikrein-kinin system in post-myocardial infarction cardiac remodeling.

Angiotensin converting-enzyme (ACE) inhibitors attenuate cardiac hypertrophy and prolong survival in animal models and patients after myocardial infarction (MI). Considering the dual function of the ACE, the therapeutic efficacy of ACE inhibitors after MI implicates the renin-angiotensin system and/or the kallikrein-kinin system in the pathophysiology of postinfarction cardiac remodeling. We evaluated the role of kinins, and their potential contribution to the antiremodeling effects of ACE inhibition in this setting. Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant (HOE 140). Additional groups of MI rats were treated with the ACE inhibitor lisinopril, alone or in combination with icatibant. B2 kinin receptor blockade enhanced the deposition of collagen (morphometric analysis) in the left ventricular interstitial space after MI, whereas markers of cardiomyocyte hypertrophy (left ventricular weights and prepro-atrial natriuretic factor [ANF] expression) were not affected. Chronic ACE inhibition reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition on cardiomyocyte hypertrophy. In conclusion, kinins inhibit the interstitial accumulation of collagen, but do not modulate cardiomyocyte hypertrophy after MI. Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition; however, the effects of ACE inhibition on cardiomyocyte hypertrophy are related to reduced generation of angiotensin II.

Adrenergic beta-Antagonists↗