Renal kinin-prostaglandin relationship: Implications for renal function

Transcription

1 Kidney International, Vol. 19 (1981), pp Renal kinin-prostaglandin relationship: Implications for renal function ALBERTO NASJLETTI and KAFAIT U. MALIK Department of Pharmacology, University of Tennessee, Center for the Health Sciences, Memphis, Tennessee In 1909, Abelous and Bardier described a bloodpressure-lowering substance in human urine [1], a finding that was confirmed by Frey in 1926 [2]. Kraut, Frey, and Werle believed the hypotensive principle of urine was of pancreatic origin and named it kallikrein a word derived from the Greek term for pancreas [3]. It is now known that kallikreins occur in plasma and in several glandular tissues, for example, kidney, pancreas, intestine, and salivary and sweat glands [4]. Kallikreins are a heterogeneous group of serine proteases that act on plasma protein substrates, kininogens, to liberate peptides termed kinins [4]. From kininogen, plasma kallikreins release the nonapeptide bradykinin, whereas glandular kallikreins release the decapeptide lysylbradykinin [4]. These peptides have a broad spectrum of biological activities, ranging from stimulation of sperm motility to inhibition of postjunctional events at the renal vascular neuroeffector junction. The discovery by Terragno et al [5] and McGiff et al [61 that bradykinin stimulates release of prostaglandins is a milestone in kinin research over the past decade, and led to the proposal that the kallikrein-kinin and arachidonateprostaglandin systems are related. It now appears that interactions of kinins and prostaglandins are a feature of biological processes as diverse as those involved in inflammation and in regulation of renal function. In this paper, we analyze the evidence for a relationship between the renal kallikrein-kinin and prostaglandin (PG) systems, and discuss the significance of such relationship with regard to renal hemodynamic and excretory functions. Figure 1 depicts the proposed relationship. Received for publication December 11, /81/ $ by the International Society of Nephrology The kallikrein-kinin system: Determinants of intrarenal activity In 1966, Carvaiho and Diniz found in homogenates of rat kidney a kinin-forming enzyme indistinguishable from urinary kallikrein [7]. Renal and urinary kallikrein resemble each other, and both differ markedly from plasma kallikrein in terms of physical and biochemical properties, immunologic characteristics, and profile of inhibition by several natural proteinase inhibitors [4]. From rat kidney slices that had been incubated with 3H-L-leucine, Nustad, Vaaje, and Pierce [8] isolated four species of radiolabeled kallikrein that were indistinguishable from corresponding species of the enzyme found in urine; they concluded that cellular elements of the kidney elaborate kallikrein and then release the enzyme into urine. Renal kallikrein is associated primarily with the plasma membraneenriched fraction of renal cortical tissue [91, and its activity decreases from the outer to the inner cortex with little activity occurring in the medulla and papilla of the kidney [101. In the rat kidney, kallikrein is localized in the apical region of cells of the distal nephron [11, 121, at which site it is released into the tubular fluid [14]. Release of the enzyme into the renal vascular compartment [14, 15], and interstitium [161 has also been suggested but is less well substantiated. Recently, Chao and Margolius [17] demonstrated that the active site of kallikrein faces the external environment in dispersed cortical cells, suggesting that renal kallikrein is an ectoenzyme. Interaction of renal kallikrein with kininogen within the kidney results in generation of lysylbradykinin. This event may be regulated by one or more kallikrein inhibitors found in the kidney and in urine [18, 19]. Scicli et al concluded from stop-flow studies in the dog that kinins are formed, and first 860

2 Kinin-prostaglandin interaction 861 Knin? Kallikreiri Kinin Fig. 1. Relationship between renal kallikrein-kinin and prostaglandin systems. Kinins generated by kallikrein in the distal nephron and probably in the renal interstitium stimulate production of prostaglandins by the kidney. appear in the tubular fluid, in the most distal segments of the nephron [20]. Lysyl-bradykinin entering the tubular compartment is in part converted to bradykinin by an aminopeptidase that removes the N-terminal lysine from the decapeptide [211, and large quantities of both peptides are found in urine [22]. Methionyl-lysyl-bradykinin, a third kinin found in urine, is generated by uropepsin in urine acidified after voiding; as it does not occur in fresh frozen urine, or in specimens containing an inhibitor of pepsin, the undecapeptide is most likely an artifact [231. That urinary kinins originate intrarenally [241 in the distal nephron is well accepted, but information on the source of kininogen, and on the exact site(s) of kinin generation in the distal nephron, is scarce. Kininogen occurs in plasma [251, and in small amounts in urine [221, and possibly, in the kidney. Two types have been described in plasma, one having high molecular weight, the other low; renal kallikrein liberates kinin from both forms of kininogen but low-molecular-weight kininogen is the preferred substrate [25]. It is conceivable, but as yet unproven, that low-molecularweight kininogen is filtered in the glomeruli, and escapes tubular reabsorption in the proximal tubules, reaching sites in the distal nephron where it is acted on by urine kallikrein, or by kallikrein at the renal distal tubular cell surface. It is less likely that the interaction of kallikrein and its substrate occurs in the renal interstitium, and that the kinin subsequently escapes into the tubular fluid. Enzymes termed kininases are of major importance in determining the intrarenal level of kinins [26]. Probably the most abundant renal kininase is a peptidyl dipeptidase, kininase II, that inactivates kinins by cleaving C-terminal Phe-Arg. This enzyme, which also converts angiotensin I to angiotensin II, is associated primarily, but not exclusively, with cells of the proximal tubule [9, 261. That blockade of kininase II by specific inhibitors results in a substantial increase in the urinary excretion rate of kinins indicates that degradation of kinins by kininases is of major significance in determining the intrarenal level of kinins [24]. It follows, then, that the intrarenal activity of the kallikrein-kinin system, viz., the concentration of kinins at specific effector sites, depends on the balance between kinin generating and degrading processes within the kidney. In turn, these processes are regulated by many factors, including the availability of kininogen and the concentrations of kallikrein, kininases, and their respective inhibitors. The renal arachidonate-prostaglandin system as affected by kinins In 1965, Lee et a! [27] reported isolation from lapine renal medulla of a blood-pressure-lowering material that later work [28] revealed was a mixture of several prostanoids. Synthesis of PG's has since then been demonstrated in a variety of renal structures including glomeruli [29], collecting tubules [30], interstitial cells [31], and blood vessels [321. Arachidonic acid is released from membrane phospholipids by an acylhydrolase, presumably phospholipase A2, and then transformed by a cyclooxygenase to an endoperoxide intermediate that is the common precursor of thromboxane A2 and of PG's E2, F2, D2, and '2 [33, 34]. The predominant endproduct of PG endoperoxide metabolism differs among the different cells and regions of the kidney in relation to the distribution and activity of PG endoperoxide metabolizing enzymes, for example, PGI2 is a major derivative of arachidonic acid in the cortex but not in the medulla of the kidney [35]. The rate limiting step in overall PG biosynthesis is,

3 862 Nasjletti and Malik however, the deacylation reaction that makes available nonesterified arachidonic acid [361. In 1972, Terragno et al [51 and McGiff et a! [61 found that renal arterial infusion of bradykinin increases the release of renal prostaglandins; this finding has since then been confirmed by several investigators. As there is no appreciable storage of PG's in tissues, augmented release of PG's from an organ denotes either enhanced biosynthesis or diminished degradation [33]. But, the release of renal PG's elicited by bradykinin is caused by stimulation of synthesis rather than by inhibition of PG degradation. Several observations suggest that kinins augment renal PG synthesis by stimulating phospholipid deacylation and, consequently, making available free arachidonic for conversion to cyclic endoperoxides. (a) The release of PG's induced by bradykinin from the isolated perfused lapine kidney [36], and from lapine renomedullary interstitial cells grown in culture [31], is associated with release of arachidonic acid. (b) Renal arterial infusion of bradykinin causes augmentation of renal phospholipase activity in the rat [37]. And, (c) the phospholipase A inhibitor, mepacrine, inhibits the release of both arachidonic acid and PGE2 elicited by bradykinm from rabbit renomedullary interstitial cells [31]. The deacylation reaction induced by bradykinin is highly selective in that it brings about release of arachidonic acid only [38]. This suggests that the kinin either activates a specific lipase that distinguishes different fatty acids in the 2-position of glycerophospholipids or, alternatively, that the Iipase activated by the kinin is compartmentalized with phospholipids containing arachidonic acid. The range of products of arachidonic acid metabolism released by kinins from the kidney has not yet been fully established. McGiff et al [61 found that renal arterial infusion of bradykinin in the dog stimulates release into renal venous blood of a material that has the chemical, chromatographic, and biological properties of PGE2. Others confirmed this finding and also reported elevation of urine PGE2 during infusion of the peptide [36, Recently, it was found that bradykinin also stimulates release of PGF2c. [41 43] and of PGI2 [44] from the canine kidney. Interestingly, bradykinin, previously believed to release only PGE2 from the isolated perfused rabbit kidney, was shown to release also thromboxane A2 from the hydronephrotic lapine kidney [451. Hence, considering that the predominant end-product of PG endoperoxide metabolism differs among different renal structures, kinin peptides may promote synthesis of dissimilar PG's in various cell types, and in the same cell type during varying experimental conditions. Relationship between the renal kallikrein-kinin and prostaglandin systems Evidence that the renal kallikrein-kinin system influences production of renal PG's was first provided by studies on the effect of kininogen, the inactive substrate of kallikrein, on PG release from the rabbit kidney perfused ex vivo with Krebs solution [40] (Fig. 2). Kininogen, like bradykinin, was found to increase the venous and urinary efflux of PG's, primarily of PGE2-like material. Aprotinin, a kallikrein inhibitor, reduced the release of PG induced by kininogen but not that by bradykinin. This implies that augmentation of renal PG production in response to kininogen requires conversion of kininogen to a kinin. A corollary of this conclusion is that kinins generated within the kidney cause stimulation of renal PG production. Additional evidence linking the renal kallikreinkinin and PG systems comes from studies on the effect of kallikrein inhibition on urinary PG excretion [46]. As PG's in urine arise within the kidney, their rate of excretion is considered an index of renal PG production. In the rat, daily administration of the kallikrein inhibitor aprotinin (100,000 U/day) reduced the urinary excretion of PGE2 by 63% and 67% after 1 and 3 days of treatment, and also decreased kallikrein activity in both urine and renal tissue (Fig. 3). Similarly, aprotinin reduced urine PGE2 excretion in rats that had been pretreated with DOCA to increase both renal kallikrein and basal renal PGE2 production; the decrease in PGE2 excretion caused by the enzyme inhibitor was correlated with reduction of kallikrein activity in both urine and the kidney. Aprotinin also reduced the urinary excretion rate of PGE2 in the rat during acute saline loading, which increases the basal excretion of PGE2, and in the nonvolume expanded animal [47]. Inasmuch as the effect of aprotinin in lowering urine PGE2 excretion is most likely related to reduction of intrarenal kinin formation, these observations suggest that a product of renal kallikrein activity promotes production of PGE2 by the kidney. Consonant with this conclusion are the results of a recent study on the effect of inhibition of peptidyl dipeptidase (kininase II or angiotensin I converting enzyme) on urine PGE2 excretion in the rat pretreated with DOCA [481. Inhibition of this enzyme reduces intrarenal kinin degradation, resulting in increased kinin levels within the kidney reflected by

4 864 Nasfletti and Malik urine PGE2 excretion correlated positively with increased output of urinary kallikrein [50, 51]. Similarly, the excretion into urine of both PGE2 and kallikrein increases during the early phase following administration of ioop diuretics [52, 531; in one study the rise in urine PGE2 caused by furosemide (1 mg/kg, i.v.) in normal subjects was correlated positively with increments in urinary excretion of kinins and kallikrein [52]. DOCA (5 mg/day), or aldosterone (0.25 mg/day), after a few days of treatment, increases the urinary output of both kallikrein and PGE-like material in the rat [46]. Also, in the dog, the administration of DOCA resulted in elevation of kallikrein [541 and PGE2 [551 in urine. Another mineralocorticoid, fludrocortisone (0.2 mg/day), which causes elevation of urinary kallikrein, also was reported to increase urine PGE2 and PGF2 excretion in man [561. A positive relationship between urine PGE2 and kallikrein is not always apparent, however, despite evidence suggesting that a product of renal kallikrein promotes renal PG production. Normal subjects receiving DOCA (20 mg/day) for 10 days exhibit elevated urinary excretion of kallikrein but not of PGE2 1157]. Similarly, deprivation of dietary sodium for 12 days in the rat results in augmented kallikrein excretion, whereas the urinary output of both PGEand PGF-like material falls [581. It is possible that in such instances the renal kallikrein-kinin system influences renal production of arachidonic acid metabolites other than PGE2. The sites and regions where the renal kallikreinkinin and PG systems interact are not established nor is the route followed by lysyl-bradykinin to sites of PG synthesis (Fig. 1). Because renal kallikrein is a cortical enzyme, it is conceivable that its peptide product promotes PG synthesis in renal cortical structures. Also, it is possible that lysyibradykinin produced in the distal nephron travels via the tubule to the renal medulla where the peptide stimulates production of PG's in cellular elements associated with the collecting tubules, the medullary interstitium, and blood vessels. An additional possibility, suggested by the finding of small amounts of kallikrein in the medulla and papilla of the kidney, is that tubular fluid kallikrein crosses the collecting duct epithelium and enters the medullary interstitium to generate a kinin close to sites of PG synthesis in the renal medulla. An alternate route of transport of kallikrein and kinins via the blood stream to sites of PG synthesis in the renal medulla cannot be excluded. The kinin-prostaglandin relationship in relation to renal function Renal arterial infusion of bradykinin stimulates renal synthesis of PGE2 and PGI2, and this is associated with effects on renal hemodynamic and excretory functions similar to those of arachidonic acid, PGE2, and PGI2. Evidence that one or more products of arachidonic acid metabolism by the kidney contribute to the effects of kinins on renal function comes from work comparing such effects before and during inhibition of PG synthesis. Modification of the effects of kinins on renal function during PG synthesis blockade suggests involvement of PG's in those effects. Relation to prostaglandin synthesis of kinin effects on renal hemodynamics. Renal arterial infusion of bradykinin produces vasodilatation and increases the blood flow to the kidney [24, 39, 42, 431. In the canine kidney perfused ex vivo with blood, inhibition of PG synthesis was reported to reduce the vasodilatory action of the peptide [59]. But, several other studies indicate that PG synthesis inhibition does not reduce the elevation in blood flow to the kidney caused by bradykinin in the dog [39, 42, 431. It appears, then, that PG's produced by the kidney during infusion of bradykinin in vivo do not contribute to the renal circulatory actions of kinins. This is puzzling because two of the arachidonic acid metabolites released from the kidney by bradykinin, for example, PGE2 and PGI2, have a demonstrated capacity to produce renal vasodilatation [60, 611. Recent studies suggest that stimulation of renal PG synthesis by kinins results in reduction of renal vascular reactivity to sympathetic stimuli and All. Malik and Nasjletti [62] found that bradykinin (1 to 100 ng/ml) reduces the vasoconstrictor responses elicited by either norepinephrine or renal nerve stimulation and greatly enhances the renal output of a PGE-like material in the rabbit kidney perfused ex vivo with Tyrode's solution. They also found that indomethacin (1 ig/ml), an inhibitor of cyclooxygenase, causes reduction of the inhibitory action of bradykinin on adrenergically induced renal vasoconstriction. These findings have been confirmed in the pentobarbital-anesthetized dog [63], viz., bradykinin infused intrarenally (10 ngkg'min1) inhibits the lowering of renal blood flow caused by electrical stimulation of the renal nerves or by norepinephrine, an effect that is not apparent in the dog pretreated with the PG synthesis inhibitor sodium

5 Kinin-prostaglandin interaction 865 meclofenamate. These observations suggest that the kinin acts at postjunctional sites to reduce adrenergically-induced renal vasoconstriction through a mechanism involving PG's. The effect of bradykinin in reducing reactivity of the renal vasculature to vasoconstrictor stimuli is not restricted to norepinephrine only. Renal arterial infusion of bradykinin (10 ngkg'min') also reduces the vasoconstrictor effect of All in the canine kidney [64]. That the inhibitory action of the kinin on All-induced renal vasoconstriction is dependent on the synthesis of PG is inferred from the observation that such an action is not apparent in the dog pretreated with an inhibitor of cyclooxygenase [64]. Collectively, these observations suggest that bradykinin reduces the reactivity of the renal vasculature to pressor hormones by a mechanism related to PG synthesis. Consonant with this interpretation are observations that the major PG's released from the kidney by bradykinin, PGE2, and PGI2, also attenuate All and norepinephrine-induced vasoconstriction in the kidney [64, 651. From this it may be inferred that one or more PG's produced by the kidney during infusion of bradykinin mediate the action of the peptide in reducing the reactivity of the renal vasculature to All and adrenergic stimulation. Relation to prostaglandin synthesis of kinin effects on renal excretory functions. Renal arterial infusion of kinins increases, like PGE, and PGI2, the volume of urine and the excretion of sodium [24, 391. Inhibition of PG synthesis by sodium meclofenamate in the dog during water diuresis was found to suppress both the bradykinin-induced output of PGE2 and the associated natriuresis, suggesting contribution of a PG or PG's to the effect of the kinin in increasing urinary sodium [39]. Both brad y- kinin and PGE2 increase urinary sodium excretion by inhibiting sodium reabsorption by the distal nephron. Injection of either PGE2 or bradykinin into surface convolutions of later proximal tubules in the rat inhibits the efflux of sodium 22 in distal nephron segments [66, 67], which is consistent with reduction of tubular reabsorption. PGE2 also inhibits sodium transport in isolated perfused segments of lapine cortical and medullary collecting tubules [681. It is possible, then, that PGE2 mediates the kinin-induced natriuresis by reducing sodium reabsorption in the distal nephron. The effect of bradykinin infused intrarenally in increasing urine volume in the dog during water diuresis appears unrelated to PG synthesis, that is, it is not affected by PG synthesis blockade [39]. But, the diuretic action of bradykinin in the isolated blood-perfused canine kidney was significantly reduced following inhibition of cyclooxygenase by indomethacin [59]. PGE2 antagonizes the tubular actions of vasopressin. As bradykinin augments renal synthesis of PGE2, failure to detect the contribution of the PG to the diuretic effect of the peptide may relate to the particular experimental conditions. For example, in the dog during water diuresis, the effect on urine volume of PGE2 synthesis stimulation by a kinin is likely to be less apparent because plasma vasopressin levels are low. Physiological sign jfi cance of the relationship between the renal kallikrein-kinin and arachidonateprostaglandin systems The physiologic significance of the relationship between the renal kallikrein-kinin and PG systems is uncertain. Inasmuch as kinins stimulate renal synthesis of arachidonic acid metabolites that increase urinary sodium excretion and reduce the reactivity of the renal vasculature to pressor hormones, it is reasonable to propose that the relationship between the renal kallikrein-kinin and PG systems is a feature of mechanisms influencing renal hemodynamic and excretory functions. That the renal kallikrein-kinin system influences the function of the kidney is inferred from reports that the administration of inhibitors of kininase II, or of an inhibitor of kallikrein, causes distinct alterations of renal function. The rise in intrarenal kinin levels following inhibition by teprotide of kinin degradation is associated with renal vasodilatation, diuresis, and natriuresis [241. In contrast, inhibition of kallikrein by aprotinin decreases renal plasma flow, glomerular filtration rate, urine volume, and urinary excretion of sodium and potassium in the saline-expanded rat, without affecting blood pressure [47]. In another study, administration of aprotinin for 4 days to normal rats, or to rats pretreated with DOCA, resulted in reduced sodium excretion during the first 24 to 48 hours of treatment but not thereafter [46]. Furthermore, bradykinin antibodies, which are capable of blocking the biological actions of the peptide, were reported to reduce the natriuretic response to saline loading in the rat [69]. Collectively, the foregoing observations suggest that the renal kallikrein-kinin system influences renal hemodynamic and excretory functions by promoting vasodilatation and natriuresis.

6 866 Nasj/etti and Malik Positive evidence that PG's participate in such mechanisms is lacking as yet. An increasing body of evidence suggests, however, that renal PG's are involved in the regulation of renal function. Depending on the experimental conditions, the activity of vasoconstrictor systems, and the state of sodium balance, PG's produced intrarenally influence renal blood flow, its intrarenal distribution, the excretion of water and electrolytes, and renal vascular reactivity. This is inferred primarily from observations that blockade of renal PG synthesis is associated with: (a) lowering of renal blood flow during conditions that cause elevation of All levels or of renal sympathetic activity [70, 71]; (b) augmentation of renal vascular reactivity to All and adrenergic stimuli 72]; (c) increased sensitivity to vasopressin [731; and (d) reduction of urinary sodium excretion [731. These findings are taken as evidence that PG's produced by the kidney influence its function by promoting vasodilatation, opposing the vasoconstrictor actions of All and norepinephrine, antagonizing the actions of vasopressin on water reabsorption, and interferring with sodium reabsorption. It is apparent from these considerations that relationships between the renal kallikrein-kinin and PG systems may be an integral part of mechanisms regulating the function of the kidney. Implicit in this is the assumption that the product of renal kallikrein activity stimulates renal production of arachidonic acid metabolites that affect renal hemodynamic and excretory functions. But, the available information does not permit definite conclusions about the physiologic significance of the relationship between the renal kallikrein-kinin and PG systems. Acknowledgments This work was supported by USPHS grants HL and HL A. Nasjletti and K. U. Malik are the recipients of the USPHS Career Research Development Awards lk04 H and 5 K04 HL-99142, respectively. We thank B. Chandler for assistance and Dr. L. Cagen for suggestions. Reprint requests to Dr. A. Nasjletti, Department of Pharmacology, UTCHS, 800 Madison Avenue, Memphis, Tennessee 38163, USA References 1. ABELOUS JE, BARDIER E: Les substances hypotensives de l'urine humaine normale. CR Soc Biol 66: , FREY EK: Zusammenhange zwischen Herzarbeit und Nierentatigkeit. Arch Kim Chir 142:663, KRAUT H, FREY EK, WERLE E: Der Nachweis eines Kreislaufisormons in der Pankreasdruse: IV. Mitteilung uber dieses Kreislauthormon. Hoppe-Seylers Z Physiol Chem 189:97 106, SCHACI-ITER M: Kallikreins (kininogenases): A group of serine proteases with bioregulatory actions Pharmacol Rev 31:1 17, TERRAGNO AA, LONIGRO AJ, MALIK KU, MCGIFF JC: The relationship of the renal vasodilator action of bradykinin to the release of prostaglandin E-like substances. Experientia 28: , MCGIFF JC, TERRAGNO NA, MALIK KU, L0NIGR0 AJ: Release of a prostaglandin E-like substance from canine kidney by bradykinin. Circ Res 31:36 43, CARVALHO IF, DINIz CR: Kinin-forming enzyme (kininogenin) in homogenates of rat kidney. Biochem Biophys Acta 128: , NUSTAD K, VAAJE K, PIERCE JV: Synthesis of kallikreins by rat kidney slices. Br J Pharmacol 53: , WARD PE, ERDOS EG, GEDNEY CD, DOWBEN RM, REYN- OLDS RC: Isolation of membrane bound renal enzymes that metabolize kinins and angiotensins. Biochem J 157: , SCICLI AG, CARRETERO OA, OZA NB: Distribution of kidney kininogenase. Proc Soc Exp Biol Med 151:57 60, OR5TAvIK TB, NU5TAD K, BRADNTZAEG P, PIERCE JV: Cellular origin of urinary kallikrein. J Histochem Cytochem 24: , SIM5ON JAV, SPICER SS, CHAO J, MARGOLIUS HS: Kallikrein localization in rodent salivary glands and kidney with immunoglobulin-enzyme bridge technique. J Hisrochem Cytochem 27: , SCICu AG, CARRETERO OA, HAMPTON A, CORTE5 P, OZA NB: Site of kininogenase secretion in the dog nephron. Am J Physiol 230: , ROBLERO J, CROXATTO H, GARCIA R, CORTHORN J, DE VITO E: Kallikrein-like activity in perfusates and urine of isolated rat kidneys. Am J Physiol 23 1: , RABITO SF, SCICLI AG, CARRETERO OA: Glandular kallikrein in plasma and urine: Evaluation of a direct RIA for its determination. Adv Exp Med Biol I 20A: , MILLS IH: Kallikrein, kininogen, and kinins in control of blood pressure. Nephron 23:61 67, CHAO J, MARGOLIUS HS: Studies on rat renal cortical cell kallikrein II: Identification of kallikrein as an ecto-enzyme. Biochem Biophys Acta 570: , GEIGER R, MANN K: A kallikrein-specific inhibitor in rat kidney Tubules. Hoppe-Seylers Z Physiol Chem 357: , RYAN JW, OZA NB, MARTIN LC, PENA GA: Components of the kallikrein-kinin system in urine. Adv Exp Med Biol 120A: , SCICLI AG, GANDOLFI R, CARRETERO OA: Site of formation of kinins in the dog nephron. Am J Physiol 234:F36 F40, BRAND! CMW, PRADO ES, PRADO MJBA, PRADO JL: Kinin-converting aminopeptidase from human urine partial purification properties. mt j Biochem 7: , PIsAN0 JJ, CORTHORN J, YATES K, PIERCE, JV: The kallikrein-kinin system in the kidney. Contrib Nephrol 12: , HIAL V, KEISER HR, PISANO JJ: Origin and content of methionyl-lysyl-bradykinin, lysyl-bradykinin and, bradykinm in human urine. Biochem Pharmacol 25: , NASJLETTI A, COLINA-CHOURIO J, MCGIFF JC: Disappearance of bradykinin in the renal circulation of dogs: Effects of kininase inhibition. Circ Res 37:59 65, 1975

7 Kinin-prostaglandin interaction CARRETERO OA, ScicLi AG: The renal kallikrein-kinin system. Am J Physiol 238:F247 F255, ERDOS EG: Inhibitors of kininases. Fed Proc 38: , LEE JB, CoviNo BG, TAKMAN BH, SMITH ER: Renal medullary vasodepressor substance, medullin: Isolation, chemical characterization, and physiological properties. Circ Res 17:57 77, LEE JB, CROWSHAW K, TAKMAN BH, ATRREP KA, GOUGOUTAS JZ: The identification of prostaglandins E2, F2, and A2 from rabbit kidney medulla. Biochem J 105: , HASSID A, KONIECZKOWSKI M, DUNN JJ: Prostaglandin synthesis in isolated rat kidney glomeruli. Proc Nat! Acad Sci USA 76: , SMITH WL, WILKIN GP: Immunochemistry of prostaglandin endoperoxide-forming cyclooxygenase: The detection of the cyclooxygenases in the rat, rabbit, and guinea pig kidneys by immunofluorescence. Prostaglandins 13: , ZUSMAN RM, KEISER HR: Prostaglandin E2 biosynthesis by rabbit renomedullary interstitial cells in tissue culture: Mechanism of stimulation by angiotensin II, bradykinin, and arginine vasopressin. J Biol Chem 252: , TERRAGNO NA, TERRAGNO A, EARLY JA, ROBBERT5 MA, MCGIFF JC: Endogenous prostaglandin synthesis inhibitor in the renal cortex: Effects on production of prostacyclin by renal blood vessels. Clin Sci Mo! Med 55:l99s 202s, MCGIFF JC, WONG PYK: Compartmentalization of prostaglandins within the kidney: Implications for renal function. Fed Proc 38:89 93, MONCADA 5, VANE JR: Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 30: , WHORTON AR, SMIGEL M, OATES JA, FROLICH JC Regional differences in prostacyclin formation by the kidney: Prostacyclin is a major prostaglandin of renal cortex. Biochem Biophys Acta 529: , IsAKsoN PC, RAZ A, DENNY SE, WYCHE A, NEEDLEMAN P: Hormonal stimulation of arachidonate release from isolated perfused organs: Relationship to prostaglandin biosynthesis. Prostaglandins 14: , ANTONELLO A, TREMOLADA C, BAGGIO B, BUIN F, FAVARO S, PICCOLI A, BORSATTI A: In vivo activation of renal phospholipase activity by bradykinin in the rat. Prostaglandins 16:23 29, HSUEH W, IsAKsoN PC, NEEDLEMAN P: Hormone selective lipase activation in the isolated rabbit heart. Prostaglandins 13: , BLASINGHAM MC, NASJLETTI A: Contributions of renal prostaglandins to the natriuretic action of bradykinin in the dog. Am J Physiol 237:F182 Fl87, COLINA-CHOURIO J, MCGIFF JC, MILLER MP, NASJLETTI A: Possible influence of intrarenal generation of kinins on prostaglandin release from the rabbit perfused kidney. Br J Pharmacol 58: , DUNN Mi, LIARD JF, DIY F: Basal and stimulated rates of renal secretion and excretion of prostaglandins E2, F,,, and l3,14-dihydro-15-keto F, in the dog. Kidney ml 13: , LONIGRO AJ, HAGEMAN MH, STEPHENSON AH, FRY CL: Inhibition of prostaglandin synthesis by indomethacin augments the renal vasodilator response to bradykinin in the anesthetized dog. Circ Res 43: , FLAMENBAUM W, GAGNON J, RAMWELL P: Bradykinininduced renal hemodynamic alterations: Renin and prostaglandin relationships. Am J Physiol F433 F440, MULLANE KM. MONCADA 5, VANE JR: Prostacyclin release induced by bradykinin may contribute to the antihypertensive action of angiotensin-converting enzyme inhibitors, in Advances in Prostaglandin and Thromboxane Research, edited by SAMMUELSON B, RAMWELL PW, PAOLETTI R, New York, Raven Press, 1980, pp MORRISON AR, MISHIKAWA K, NEEDLEMAN P: Thromboxane A2 biosynthesis in the ureter obstructed isolated perfused kidney of the rabbit. J Pharmacol Exp Ther 205: NASJLETTI A, MCGIFF JC, COLINA-CHOURIO J: Interrelations of the renal kallikrein-kinin system and renal prostaglandins in the conscious rat. Circ Res 43: , KRAMER Hi, MOCH T, VON SICHERER L, DUSING R: Effects of aprotinin on renal function and urinary prostaglandin excretion in conscious rats after acute salt loading. Gun Sci 56: , BARR JG, DIZ D, KAUKER ML, NASJLETTI A: Effect of the converting enzyme inhibitor SQ-2088l on urinary excretion of PGE2 in the rat: Influence of pretreatment with deoxycorticosterone. J Pharmacol Exp Ther 215: , OLSEN UB, ARRIGONI-MARTELLI E: The effects of kininase II inhibition by SQ on kidney kallikrein-kinin and prostaglandin systems in conscious dogs. Eur J Pharmacol 54: , HALUSHKA PV, WHOLTMANN H, PRIVITERA PJ, HURWITZ G, MARGOLIUS HS: Bartter's syndrome: Urinary prostaglandin E-like material and kallikrein; indomethacin effects. Ann Intern Med 87: , VINcI JM, GILL ir, BOWDEN RD, PISANO JJ, Izzo il, RADFAR N, TAYLOR AA, ZUSMAN RM, BARTTER FC, KEISER HR: The kallikrein-kinin system in Bartter's syndrome and its response to prostaglandin synthetase inhibition. J Gun Invest 61: , ABE K, IROKAWA N, YASUJIMA M, SEIN0 M, CHIBA 5, SAKURAI Y, YOSHINAGA K, SAITO T: The kallikrein-kinin system and prostaglandins in the kidney: Their relationship to furosemide-induced diuresis and to the renin-angiotensinaldosterone system in man. Circ Res 43: , OLSEN UB, AHNFELT-RONE I: Bumetanide induced increase of renal blood flow in conscious dogs and its relation to local renal hormones. Acta Pharmacol Toxicol 38: , MARIN-GREZM, OZA NB, CARRETERO OA: The involvement of urinary kallikrein in the renal escape from the sodium retaining effect of mineralocorticoids. Henry Ford Hosp Med J 21:85 90, BARTTER FC: Role of prostaglandins in potassium-depletion nephropathy. Adv Prostaglandin Thromboxane Res 7: , DURR i, MARON H, FAVRE L, VALLOTTON ME: Is the renal escape to mineralocorticoid mediated by prostaglandins in man? Acta Endocrinol (Suppl.) 225:383, ZIPSER RD, ZIA P, STONE RA, HORTON R: The prostaglandin and kallikrein-kinin systems in mineralocorticoid escape. J Gun Endocrinol Med 47: , NASJLETTI A, MALIK KU: Interrelationship of the renal kallikrein-kinin and prostaglandin systems, in Enzymatic Release of Vasoactive Peptides, edited by GROSS F, VOGEL G, New York, Raven Press, 1980, pp MCGIFF JC, ITSKOVITZ HD, TERRAGNO NA: The actions of bradykinin and eledoisin in the canine isolated kidney:

8 868 Nasfletti and Malik Relationship to prostaglandins. Clin Sci Mo! Med 49: , BOLGER PM, EISNER GM, RAMWELL PW, SLOTKOFF LM: Renal actions of prostacyclin. Nature 271: , TANNENBAUM J, SPLAWTNSKI JA, OATES JA, NIEs AS: Enhanced renal prostaglandin production in the dog: Effects on renal function. Circ Res 36: , MALIK KU, NASJLETTI A: Attenuation by bradykinin of adrenergically induced vasoconstriction in the isolated perfused rabbit kidney: Relationship to prostaglandin synthesis. Br J Pharmacol 67: , Suic H, NASJLETTI A, MALIK KU: Inhibition by bradykinm of the vasoconstrictor responses to sympathetic nerve stimulation and norepinephnne in the canine kidney: Relationship to prostaglandin synthesis (abst). Fed Proc 39(3):997, Sulic H, NASJLETTI A, MALIK KU: Inhibition by bradykinm of the vascular effects of pressor hormones in the canine kidney: Relationship to prostaglandins. Clin Sci 59: 145s l48s, HEDQUIST P: Actions of prostacyclin (PGI2) on adrenergic neuroeffector transmission in the rabbit kidney. Prostag!andins 17: , KAUKER M: Prostaglandin E2 effect from the luminal side on renal tubular 22Na effiux: Tracer microinjection studies. Proc Soc Exp Biol Med 154: , KAUKER ML: Bradykinin action on the efflux of luniinal 22Na in the rat nephron. J Pharmacol Exp Ther 214: , STOKES JB, KoKico JP: Inhibition of sodium transport by prostaglandin E2 across the isolated, perfused rabbit collecting tubule. J Clin Invest 59: , MARIN-GREZ M: The influence of antibodies against bradykinin on isotonic saline diuresis in the rat: Evidence for kinin involvement in renal function. Pfluegers Arch 350: , SATOH S, ZIMMERMAN BG: Influence of the renin-angiotensin system on the effect of prostaglandin synthesis inhibitors in the renal vasculature. Circ Res 36, 37 (suppl. l): , BLASINGHAM MC, NASJLETTI A: Differential renal effect of cyclooxygenase inhibition in the sodium replete and deprived dog. Am J Physiol 239:F360 F365, AIKEN JW, VANE JR: Intrarenal prostaglandin release attenuates the renal vasoconstrictor activity of angiotensin. J PharmacolExp Ther 184: , FEJES-TOTH G, MAGYAR A, WALTER J: Renal response to vasopressin after inhibition of prostaglandin synthesis. Am J Physiol 232:F416 F423, 1977