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PubMed2004

Putative roles of kinin receptors in the therapeutic effects of angiotensin 1-converting enzyme inhibitors in diabetes mellitus.

The role of endogenous kinins and their receptors in diabetes mellitus is being confirmed with the recent developments of molecular and genetic animal models. Compelling evidence suggests that the kinin B(2) receptor is organ-protective and partakes to the therapeutic effects of angiotensin 1-converting enzyme inhibitors (ACEI) and angiotensin AT(1) receptor antagonists. Benefits derive primarily from vasodilatory, antihypertensive, antiproliferative, antihypertrophic, antifibrotic, antithrombotic and antioxidant properties of kinin B(2) receptor activation. Mechanisms include the formation of nitric oxide and prostacyclin and the inhibition of NAD(P)H oxidase activity involving classical and novel signalling pathways. Kinin B(2) receptor also ameliorates insulin resistance by increasing glucose uptake and supply, and by inducing glucose transporter-4 translocation either directly or through phosphorylation of insulin receptor. The kinin B(1) receptor, which is induced by the cytokine network, growth factors and hyperglycaemia, mediates hyperalgesia, vascular hyperpermeability and leukocytes infiltration in diabetic animals. However, emerging data highlight reno- and cardio-protective effects mediated by kinin B(1) receptor under chronic ACEI therapy in diabetes mellitus. Thus, the Janus-faced of kinin receptors needs to be taken into account in future drug development. For instance, locally acting kinin B(1)/B(2) receptor agonists if used in a safe therapeutic window may represent a more rationale strategy in the prevention and management of diabetic complications. Because kinin B(2) receptor antagonists may further increase insulin resistance, the persisting dogma that restricts the development of kinin receptor analogues to antagonists (that is still relevant to abrogate pain and inflammation) needs to be revisited.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1988

A new kinin moiety in human plasma kininogens.

Recently, we isolated a new kinin from human urine and tentatively identified it as [Ala3]-Lys-bradykinin. However, there were inconsistencies between the properties of the naturally occurring new kinin and synthetic [Ala3]-Lys-bradykinin. In the present work, we determined whether the new kinin was released from human plasma kininogen, and further investigated the structure of the new kinin. After incubation of plasma (n = 6) with human urinary kallikrein, kinins were separated by HPLC and measured by RIA. The new kinin and Lys-bradykinin were found representing 23 +/- 3 and 76 +/- 6%, respectively, of total kinins released (2.0 +/- 0.4 micrograms/ml). The new kinin was also released from both purified low- and high-molecular-weight kininogens, representing 40-42% of total kinins released. Amino acid sequencing and composition analysis indicated that the structure of the new kinin was [Hyp3]-Lys-bradykinin (Lys-Arg-Pro-Hyp-Gly-Phe-Ser-Pro-Phe-Arg) and not [Ala3]-Lys-bradykinin. We conclude that an important proportion of human kininogens contain hydroxyproline instead of proline in position three of the bradykinin moiety.

Amino Acid Sequence↗
PubMed1997

Possible protective effects of kinins and converting enzyme inhibitors in cardiovascular tissues.

The main objective of this study was to determine if the components of the kallikrein-kinin system are released into the venous effluent from isolated perfused rat hearts. To assess the contribution of kinins and the vascular and cardioprotective effects of the ACE inhibitor ramipril, we determined the status of cardiac kallikrein (CKK), potent kinin-generating enzyme, in rats with right ventricular hypertrophy induced by chronic volume overload and left ventricular hypertrophy by aortic banding. CKK was measured as previously described (Nolly, H.L., Carbini, L., Carretero, O.A., Scicli, A.G., 1994). Kininogen by a modification of the technique of Dinitz and Carvalho (1963) and kinins were extracted with a Sep-Pak C18 cartridge and measured by RIA. CKK (169 +/- 9 pg Bk/30 min), kininogen (670 +/- 45 pg Bk/30 min) and immunoreactive kinins (62 +/- 10 pg Bk/30 min) were released into the perfusate. The release was almost constant over a 120 min period. Pretreatment with the protein synthesis inhibitor puromycin (10 mg i.p.) lowered the release of kallikrein (42 +/- 12 pg Bk/30 min, p < 0.001) and kininogen (128 +/- 56 pg Bk/30 min, p < 0.001). Addition of ramiprilat (10 micrograms/ml) increased kinin release from 54 +/- 18 to 204 +/- 76 pg Bk/30 min (p < 0.001). Aortic banding of rats increased their blood pressure (BP) (p < 0.001), relative heart weight (RHW) (p < 0.001) and CKK (p < 0.001). Ramipril treatment induced a reduction in BP (p < 0.05) and RHW (p < 0.005) while CKK remained elevated. Aortocaval shunts increased their ANF plasma levels (p < 0.05), RHW (p < 0.001) and CKK (p < 0.01). Ramipril treatment induced a reduction in RHW (p < 0.05), while CKK and ANF increased significantly (p < 0.05). The present data show that the components of the kallikrein-kinin system are continuously formed in the isolated rat heart and that ramipril reduces bradykinin breakdown with subsequent increase in bradykinin outflow. The experiments with aorta caval shunt and aortic banding show that cardiac tissues increase their kinin-generating activity and this was even higher in ramipril-treated animals. This may suggest that the actual level of kinins is finely tuned to the local metabolic demands. In this experimental model of cardiac hypertrophy. ACE inhibitors potentiate the actions of kinins and probably try to normalise endothelial cell function.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Facilitation of renal kallikrein-kinin system prevents the development of hypertension by inhibition of sodium retention.

We have previously reported that the renal kallikrein-kinin system suppressed the development of hypertension, using kininogen deficient Brown Norway Katholiek rats. Kinins were degraded in urine mainly by carboxypeptidase Y-like kininase (CPY). Blockade of renal kinin degradation may prevent the experimental hypertension through the facilitation of the renal kallikrein-kinin system. Daily administration of ebelactone B (EB), which is isolated from Actinomycetes and strongly inhibits CPY, from the first day of deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks completely blocked hypertension in Sprague-Dawley rats. This treatment reduced sodium levels in erythrocytes and cerebrospinal fluids (CSF) significantly. By contrast, an ACE inhibitor, lisinopril did not prevent hypertension. The development of hypertension in young spontaneously hypertensive rats was also blunted by EB with reductions in sodium levels in erythrocytes and in CSF. The arterial kinin levels in rats undergoing DOCA-salt treatment were 2.2 +/- 0.2 pg/ml, which were increased significantly to 4.6 +/- 0.4 pg/ml with captopril (10 mg/kg, s.c.). The increased kinin levels were less than those to show hypotension. EB did not increase the arterial kinin levels, with significant increase in urinary kinin secretion. These results suggested that facilitation of the renal kallikrein-kinin system by inhibition of kinin degradation on the luminal side of the renal tubules may effectively prevent hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Neurohumoral regulation of precapillary vessels: the kallikrein-kinin system.

Bradykinin and related kinins are potent vasodilators. Inhibition of peripheral vascular smooth-muscle tone may result from actions of kinins at different levels. These include the afferent nociceptive nerve endings (bradykinin being a potent algesic agent); the brain and the spinal cord; and the three basic structural components of resistance vessels, namely, endothelium, smooth-muscle fibers, and autonomic nerve endings. The relative roles and the importance of these various structures and the mechanisms for the vasodilator and hypotensive effects of the kinins are discussed. Attention is focused on data obtained in isolated vascular beds, perfused with physiological media, and in strips or segments of arterial and venous vessels, suspended in vitro. Bradykinin and related kinins are potent vasodilators in the majority of peripheral vascular beds of various species, although they contract some isolated arteries and all the veins. These opposite vascular effects of the kinins appear to be mediated by at least two different receptor types, which have been identified and characterized with a series of kinin agonists and some kinin antagonists. B1-receptors mediate the contraction of arterial and venous smooth muscles, while B2-receptors are involved in the relaxation of arteries, the contraction of veins, and the increase in vascular permeability produced by kinins. Hypotension generally results from activation of B2-receptors, B1-receptors intervening only in special conditions. The relaxing effect of kinins in isolated arteries (B2-receptors) occurs only in the presence of endothelium, whereas all the stimulations do not require endothelium and appear to be owing to the activation of B2- and B1-receptors in the membranes of vascular smooth-muscle cells. It is still unknown whether endothelium is involved in the hypotensive and peripheral vasodilator actions of kinins in vivo.

Animals↗
PubMed1989

Kinins as mediators of intestinal secretion.

Kinins are small peptides that have diverse biological actions. Concentrations of kinins in the nanomolar or subnanomolar range induce intestinal smooth muscle contraction and evoke mucosal electrolyte secretion. Hyperkininemia is associated with effects on gastrointestinal motility and intestinal mucosal inflammation. Bradykinin and kallidin are the predominant kinins with effects on the gastrointestinal tract of mammals. Bradykinin stimulates chloride ion secretion by the guinea pig and rabbit ileum, rabbit colon, rat colon and monolayers of human HCA-7 cells. Kinins directly or indirectly stimulate phospholipase A2 and phospholipase C. Cells in the lamina propria of the mucosa (e.g., fibroblasts, mast cells, leukocytes), by liberating cyclooxygenase and lipoxygenase metabolites of arachidonic acid, are involved in the kinin response; direct effects on epithelial cells cannot be ruled out, however. Antagonists now exist for kinin receptors. Based on studies with these antagonists in smooth muscle preparations, two subgroups of kinin receptor have been identified. The B2-type receptor appears to be responsible for both the contraction of ileal muscle and ileal secretion. Kinins are probably more important as pathophysiological rather than as physiological mediators. They may amplify the effect of inflammatory products that induce intestinal secretion. The precise involvement of kinins in clinical mucosal secretory states and diarrhea will require quantitative assessment of their levels during each phase of mucosal inflammation. Additional studies on the mechanism of action of kinins will be essential in designing therapy to mitigate the symptoms associated with mucosal inflammation.

Animals↗
PubMed1983

Effect of pH and amiloride on the intrarenal formation of kinins.

Changes in urinary kallikrein excretion are assumed to reflect changes in intrarenal formation of kinins. Yet factors that alter the enzymatic activity of renal kallikrein and kininases may alter the concentration of kinins in the nephron independent of amount of kallikrein excreted. In anesthetized rats, we measured excretion of urinary kallikrein (kininogenase activity) and kinin excretion during altered urinary pH and after amiloride, which reportedly inhibits urinary kallikrein. In rats fed a low sodium diet, urine was acidified by intravenous 0.28 M sodium sulfate. This decreased urinary pH from 6.1 +/- 0.09 to 5.3 +/- 0.17 and urinary kinin excretion from 28.0 +/- 9.0 to 10.5 +/- 5.0 pg/min. Urinary kallikrein excretion doubled from 43.0 +/- 5.0 to 82.5 +/- 13.5 ng/min. The optimum pH of kallikrein is congruent to 8.5, so the decreased excretion of urinary kinins is probably secondary to decreased kininogenase activity at lower urinary pH. Amiloride decreased urinary kinins from 35.5 +/- 7.3 to 18.2 +/- 2.5 pg/min and kallikrein from 18.7 +/- 4.9 to 9.3 +/- 1.8 ng/min, while urinary pH increased from 6.7 +/- 0.07 to 7.3 +/- 0.07. The depressed excretion of kallikrein and kinins with amiloride may not have been due to inhibition of kallikrein, since amiloride (1 mM) did not inhibit the kininogenase activity of rat urinary kallikrein (congruent to 1.2 nM) on dog or rat kininogen in vitro. We conclude that changes in urinary kallikrein may not reflect changes in intrarenal formation of kinins. These data also indicate that kallikrein excretion increases and kinin formation decreases when urine is acidified in the distal nephron and that there may be a link between the kallikrein-kinin system and the renal mechanisms affected by amiloride.

Amiloride↗
PubMed1988

Effects of a kinin antagonist on mean blood pressure.

Administration of high doses of a kinin antagonist produces an increase in blood pressure. Thus, endogenous kinins may be involved in the regulation of blood pressure. Kinins can induce the release of vasoactive substances such as catecholamines, renin, vasopressin, histamine, and prostaglandins. To determine whether the blood pressure changes induced by high doses of kinin antagonist are due to agonistic activity mediated by these vasoactive substances, we studied the effect on blood pressure of a kinin antagonist (DArg0-Hyp3-Thi5,8-DPhe7-bradykinin) administered to control, nephrectomized, and adrenalectomized rats, and to rats treated with vasopressin V1-receptor antagonist, ganglionic and alpha- and beta-adrenergic receptor blockers (either separately or combined), histamine H1- and H2-receptor blockers, and indomethacin, a prostaglandin synthesis inhibitor. Blood pressure changes were monitored on awake, restrained rats. In the control rat, the kinin antagonist injected as a bolus (4 mg/kg) into the ascending aorta produced a transient biphasic blood pressure response, first a pressor effect (delta BP = 7 +/- 1 mm Hg; p less than 0.05), then a depressor effect (delta BP = -20 +/- 6 mm Hg; p less than 0.05). The pressor response to the kinin antagonist was not affected by any of the treatments; however, the depressor effect of the kinin antagonist appeared to be caused by the release of vasodilator prostanoids from the kidney, since it was not observed in the nephrectomized rats or in those treated with indomethacin. The pressor effect induced by the kinin antagonist suggests that kinins may contribute to the regulation of blood pressure.

Adrenal Glands↗
PubMed1999

Type 2 bradykinin-receptor antagonism does not modify kinin or angiotensin peptide levels.

Type 2 bradykinin (B2)-receptor antagonists have been used to define the role of endogenous kinin peptides. However, interpretation of the effects of B2-receptor antagonists has been limited by lack of information concerning the effects of these antagonists on endogenous kinin and angiotensin peptide levels. If kinin levels were subject to short-loop-feedback regulation mediated through B2 receptors, then a reactive increase in kinin levels might blunt the effects of B2-receptor antagonism and stimulate type 1 bradykinin receptors. Moreover, kinins have been implicated in the control of renin secretion. We investigated whether endogenous kinin levels are subject to short-loop-feedback regulation mediated by the B2 receptor and whether endogenous kinins acting through the B2 receptor influence plasma renin levels and circulating and tissue angiotensin peptide levels. The B2-receptor antagonist icatibant (1 mg/kg) was administered to rats by intraperitoneal injection, and circulating and tissue levels of angiotensin and kinin peptides were measured after 4 hours. Icatibant produced 75% occupancy of B2 receptors in the inner stripe of the renal medulla. Icatibant did not influence plasma levels of renin, angiotensinogen, angiotensin-converting enzyme, neutral endopeptidase, or circulating or tissue levels of angiotensin and bradykinin peptides. This study demonstrated that kinin levels are not subject to short-loop-feedback regulation mediated through B2 receptors and that endogenous kinin levels acting through the B2 receptor do not modulate the renin-angiotensin system.

Angiotensin II↗
PubMed1988

Mechanism of kinin release from human low-molecular-mass-kininogen by the synergistic action of human plasma kallikrein and leukocyte elastase.

We have investigated the kinin release from human L-kininogen, a poor substrate for plasma kallikrein, by the synergistic action of human PMN elastase and plasma kallikrein. Although PMN elastase alone failed to generate kinin activity from L-kininogen, combination of PMN elastase with plasma kallikrein was found to be effective for the generation of kinin activity from L-kininogen. Two kinds of kinin, bradykinin and Met-Lys-bradykinin, were found to be released from L-kininogen by the synergistic action of PMN elastase and plasma kallikrein. Pretreatment of L-kininogen with PMN elastase facilitated the kinin release by plasma kallikrein, whereas pretreatment of L-kininogen with plasma kallikrein did not allow kinin release by the action of PMN elastase. These results suggested that PMN elastase would act firstly on L-kininogen to form a kinin containing fragment, from which kinin is released by the action of plasma kallikrein. The kinin-containing fragment was isolated by gel filtration and high-performance liquid chromatography of the elastase digest of L-kininogen. The amino-acid analysis and N-terminal amino-acid sequence analysis revealed that the kinin-containing fragment consisted of 26 amino-acid residues and is formed by cleavage of an Ile-Ser and a Ser-His bond of L-kininogen.

Amino Acid Sequence↗
PubMed1989

Role of kinins and prostacyclin in blood pressure regulation.

The main vasodepressor hormone systems are the kallikrein-kinin systems and the vascular prostacyclin. Kallikreins release kinins which are the biological active compounds of the kallikrein-kinin systems. Kinins are one of the most potent vasodilators reducing systemic blood pressure by diminution of vascular resistance. The reduction in blood pressure is strongly dose related. Prostacyclin develops similar effects on blood pressure as kinins. There is a close relationship between kinins and prostacyclin since kinins stimulate prostacyclin synthesis very effectively. In arterial hypertension there is a lack in kallikrein-kinin and prostacyclin activity. This could also be shown under experimental conditions in spontaneously hypertensive and in Dahl salt-sensitive rats. In clinical studies these experimental results were confirmed in primary hypertension. The blood pressure response to exogenous vasodepressor hormones is increased in hypertensives suffering from reduced endogenous vasodilator activity. In the knowledge of reduced vasodilator activities in primary hypertension the stimulation of kinins by prostacyclin will be of major interest in the management of primary hypertension. In the last years some drugs have been investigated with regard to their kinin prostacyclin stimulating effect, but only angiotensin converting enzyme inhibitors, linolenic acid and cicletanin seemed to induce therapeutic prostacyclin stimulation. However, it remains unclear whether these drugs develop their blood pressure lowering effect by stimulation of the discussed vasodilators or by some other effect.

Animals↗
PubMed1996

Expression and cellular localization of the kallikrein-kinin system in human ocular tissues.

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.

Base Sequence↗
PubMed1986

Urinary kininogen: a possible regulator of kinin formation in normal individuals and subjects with essential hypertension, end-stage renal and liver disease.

Most previous studies have not significantly correlated urinary kallikrein to urinary kinins. We investigated whether urinary kininogen might influence kinin formation within the urine. On an ad-lib diet the 24 hour excretion of total and intact kininogen, kinins and kallikrein was determined in 24 control subjects, 20 untreated essential hypertensives, 12 with end-stage renal disease and 8 subjects with liver disease. Kallikrein and kinins were measured by a direct radioimmunoassay. Total kininogen was determined from the sum of preformed kinins and kinins generated after trypsin (intact kininogen). Cross reactivity between purified human low molecular weight kininogen and bradykinin antiserum was 3%. Total and intact kininogen were significantly correlated with kinins in controls, essential hypertension and liver disease. In essential hypertension, end-stage renal and liver diseases kinins were significantly decreased. This was associated with a reduction in kininogen but not kallikrein in essential hypertension and liver disease, and a reduction in kallikrein but not kininogen in end-stage renal disease. Thus, renal kinin generation in various states may be affected by either or both kininogen and kallikrein.

Humans↗
PubMed1978

The role of kininogenases, kinin formation and kininogenase inhibition in post traumatic shock and related conditions.

The kinin system has for a long time been considered to play a role in the pathophysiology of trauma, particularly in blood pressure changes and in inflammatory effects. Recent findings necessitate a revision of this view. It is now necessary to differentiate between two kinin systems: 1. the plasma kallikrein-HMW kininogen-kinin-system, which besides forming kinin acts decisively in Hageman Factor activation, clotting and fibrinolysis; 2. the glandular and tissue kallikrein-LMW kininogen-kinin-system which is to our present day knowledge primarily involved in kinin formation. Kinins exert a variety of actions. By interfering with angiotensin II formation, kinins may contribute to blood pressure regulation. By enhancing cellular glucose uptake and/or metabolism, they regulate partly energy production. In post traumatic states death is preceded by a severe depletion of various factors of the system and an almost total loss of kinin forming capacity. Severity and time course of these phenomena suggest that early institution of direct (Trasylol) or indirect (heparins, cortocosteroids) proteinase inhibition, and if necessary a replacement of the lost factors, should be considered.

Blood Pressure↗
PubMed1992

Kinins--key mediators in inflammatory arthritis?

Recent evidence suggests an important role for kinins in the generation of pain, swelling and the cellular damage associated with inflammatory joint disease. Kinins are considered to be pro-inflammatory peptides for a variety of reasons. They stimulate c fibres in the synovium to cause pain and increase extravasation of fluid to produce swelling. Kinins possess the capacity to release neurotransmitters (substance P, acetylcholine) and a second wave of mediators (interleukin-1, tumour necrosis factor, interleukin-8, prostaglandins, leukotrienes). The steady levels and turnover of kinins is regulated by formation (enzymic action of kininogenases on endogenous substrates called kininogens) and by metabolism (kininases, peptidases that hydrolyse kinins). These components of the kinin system can enter the synovial joint space either by transudation from the plasma or from degranulating neutrophils chemotactically attracted into the synovium from which they migrate into the synovial fluid. If kinins are involved, one would expect neutrophil derived mediators of the system to dominate in rheumatoid arthritis and psoriatic arthritis and plasma derived products to be more important in osteoarthritis and gout. But, the question whether any of the functions attributed to each component of the system can be considered to be a primary factor in the cellular pathology of inflamed joints remains to be established. Future investigations, including therapeutic trials with kinin antagonists and kallikrein inhibitors, will need to address the differential role of the kallikreins and kinins in the different types of synovitis, on symptoms of inflammation and on any remedial effects on the progression of tissue damage within the joint.

Amino Acid Sequence↗
PubMed1987

Antihypertensive and renal effects of captopril in spontaneously hypertensive rats: evidence against a role of the kallikrein-kinin system.

Inhibition of the kallikrein-kinin system with aprotinin, and measurements of urinary kallikrein and kinin excretion, were used to examine a possible involvement of endogenous kinins in mediating the acute antihypertensive and renal actions of captopril in conscious, unstressed spontaneously hypertensive rats (SHR). Captopril, 30 mg/kg + 300 micrograms/kg/min, caused an acute significant decrease in mean arterial pressure. Urinary kallikrein excretion tended to decrease, while kinin excretion tended to decrease, while kinin excretion tended to increase after captopril, without reaching statistical significance. Renal water and electrolyte excretion remained practically unchanged. Aprotinin, 1,000 KIU/kg/min, had no effect on mean arterial pressure, whereas it decreased urinary kallikrein activity to undetectable levels and lowered kinin excretion by 21% (p less than 0.05). Urine flow remained unchanged, but sodium/potassium excretion ratio increased significantly during aprotinin infusion. When captopril and aprotinin were infused in combination, the decrease in mean arterial pressure was not significantly different from that seen when captopril was given alone. Although urinary kallikrein activity decreased below the detection limit of our assay, urinary kinin, as well as water and electrolyte excretion, remained relatively stable during the combined infusion. The present results provide direct evidence that the acute antihypertensive effect of captopril in conscious SHR is probably not due to an increased kinin accumulation secondary to the inhibition of kininase II. Our findings also suggest that under basal conditions intrarenal renin-angiotensin and kallikrein-kinin systems may play a minor role, if any, in the regulation of renal water and electrolyte excretion.

Animals↗
PubMed1987

Afferent vagal stimulation, vasopressin, and nitroprusside alter cerebrospinal fluid kinin.

The effects of afferent vagal stimulation, cerebroventricular vasopressin, and intravenous nitroprusside on cerebrospinal fluid (CSF) kinin levels, mean arterial pressure (MAP), and heart rate (HR) were determined in anesthetized dogs in which a ventriculocisternal perfusion system (VP) was established. Following bilateral vagotomy, stimulation of the central ends of both vagi for 60 min significantly increased MAP and CSF perfusate levels of kinin and norepinephrine (NE). MAP was increased a maximum of 32 +/- 4 mmHg, and the rates of kinin and NE appearance into the CSF perfusate increased from 4.2 +/- 1.4 to 22.1 +/- 6.9 and from 28 +/- 5 to 256 +/- 39 pg/min, respectively. A significant correlation was found between CSF kinin and NE levels in these experiments. In other experiments the addition of arginine vasopressin to the VP system caused a significant increase in CSF perfusate kinin without affecting MAP or HR. Intravenous infusion of nitroprusside lowered MAP without affecting kinin levels in the CSF. However, on cessation of nitroprusside infusion, CSF kinin increased significantly in association with the return in MAP to predrug level. Collectively the data are consistent with the hypothesis that central nervous system kinins have some role in cardiovascular regulation, and furthermore that this role may involve an interaction between brain kinin and central noradrenergic neuronal pathways.

Afferent Pathways↗
PubMed1998

Determinants of kinin release in isolated rat hindquarters.

We studied the determinants of kinin release into the venous effluent of rat hindquarters perfused with Krebs bicarbonate buffer. Kinin release in preparations perfused with control media (14.6 +/- 2.5-20.7 +/- 6.7 pg/15 min) was surpassed by that in preparations perfused with media containing kininase inhibitors (243 +/- 53 to 276 +/- 78 pg/15 min). Kinin release increased when purified kininogen (from 242 +/- 43 to 3,365 +/- 725 pg/15 min) or kallikrein (from 270 +/- 49 to 30,649 +/- 8,040 pg/15 min) was added to the perfusate. Conversely, kinin release fell when the kallikrein inhibitor aprotinin (from 272 +/- 58 to 122 +/- 27 pg/15 min) or soybean trypsin inhibitor (from 273 +/- 52 to 195 +/- 25 pg/15 min) was added. Both basal and kininogen-induced kinin release were attenuated in preparations perfused with media containing cycloheximide, a protein synthesis inhibitor, but kallikrein-induced kinin release was not. These data suggest that kinin release from perfused rat hindquarters reflects the activity of both the kinin-degrading and kinin-generating pathways and that the latter is sustained by a kallikrein manufactured de novo and by preexistent kininogen(s).

Animals↗