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Background: For the early diagnosis of malignant biliary stricture due to biliary-pancreatic carcinoma, conventional biliary brush cytology with endoscopic retrograde cholangiopancreatography (ERCP; the conventional method) is not sensitive enough., Methods: Two hundred nine patients with biliary stricture who were admitted between September 2015 and June 2020 were enrolled in this study. Biliary brush cytology was performed on all patients. Samples were diagnosed independently by an expert pathologist and medical doctor with conventional cytology and photodynamic diagnosis (PDD) with 5-aminolevulinic acid., Results: The definitive diagnoses were 49 benign and 160 malignant diseases. The conventional method had a sensitivity of 77.5% (124/160) and specificity of 100% (49/49). The PDD method had a sensitivity of 77.5% (124/160) and specificity of 67.3% (33/49). The conventional method identified 36 malignant diseases as false negatives, while the PDD method enabled successful diagnoses of malignant diseases in 19 of these 36 patients. When PDD was combined with the conventional method, the sensitivity significantly increased to 89.4% (143/160, P = 0.006), and for biliary tract diseases only, the sensitivity increased to 95.6% (88/92, P = 0.001)., Conclusions: Malignant biliary stricture can be diagnosed effectively and safely with the in vitro PDD method. The sensitivity could be further increased by combining PDD with the conventional method., (Copyright © 2022. Published by Elsevier B.V.)

We have reported that the plasma zinc concentration gradually decreases with the progression of fibrosis and is related to hepatocellular carcinoma (HCC) development. The aim of this study was to examine the impact of the zinc concentration on HCC development (study 1) and the relationship between zinc intake and HCC development (study 2) in patients with hepatitis C virus (HCV) eradicated by direct-acting antivirals (DAAs). A total of 599 sustained virological response (SVR) patients treated with DAAs without a history of HCC were retrospectively analyzed in this study. Eighty patients received supplemental zinc (Zn treatment group), and 519 patients did not receive zinc (no Zn treatment group). In study 1, the cumulative incidence rate of HCC was compared between the Zn treatment group and the no Zn treatment group. In study 2, the risk factors for HCC development were examined in the no Zn treatment group. In study 1, in the Zn treatment group, HCC did not develop during follow-up, and the cumulative risk of HCC was significantly lower in the Zn treatment group than in the no Zn treatment group (P = 0.048). In study 2, the 1-year and 3-year cumulative incidence rates of HCC were 1.8% and 5.6%, respectively. The risk factors for HCC identified by multivariate analysis were male sex, cirrhosis, low platelet count before treatment, and low serum zinc concentration 12 weeks after the end of DAA therapy. Conclusion: The Zn concentration is related to HCC development in patients with HCV eradicated by DAA therapy. Oral zinc supplementation is recommended as a means of suppressing HCC development in patients who have achieved SVR., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

(1) Backgrounds and aim: Tolvaptan, a selective vasopressin type 2 receptor antagonist, was approved for ascites, and its short-term efficacy and safety have been confirmed. However, it is still unclear whether this novel drug may improve long-term survival rates in cirrhotic patients with ascites. (2) Patients and methods: A total of 206 patients who responded insufficiently to conventional diuretics and were hospitalized for refractory ascites for the first time were retrospectively enrolled in this study. Among them, the first 57 consecutive patients were treated with conventional diuretics (the conventional therapy group); the latter 149 consecutive patients were treated with tolvaptan in addition to the conventional therapy (the tolvaptan group). (3) Results: The exacerbation of renal function was significantly milder in the tolvaptan group than in the conventional therapy group. The prognostic factors for survival in the tolvaptan group were being male, having hyperbilirubinemia, having a high blood urea nitrogen (BUN), and receiving high-dose furosemide at the start of tolvaptan treatment. The one-year and three-year cumulative survival rates were 67.8 and 45.3%, respectively, in patients with low-dose furosemide (<40 mg/day) at the start of tolvaptan treatment. The prognosis was significantly better in the tolvaptan group with low-dose furosemide than in the conventional therapy group ( p < 0.001). (4) Conclusion: Tolvaptan can improve survival in patients with cirrhotic ascites, especially when tolvaptan is started before high-dose furosemide administration.

We report a case of early gastric cancer in the remnant stomach after successful treatment with endoscopic submucosal dissection(ESD). A 64-year-old woman had undergone distal gastrectomy, D2 dissection, and Billroth Ⅰ reconstruction for advanced gastric cancer 11 years previously. During a routine upper gastrointestinal endoscopy, an elevated lesion was detected at the lesser curvature of the upper gastric body of the remnant stomach, and biopsy indicated a Group 4 tumor. Curative en bloc resection of the lesion was achieved via ESD, although there was severe fibrosis along the suture line. The pathological result was 0-I, pT1a, tub1, 3×3 mm, UL(－), ly(－), v(－), HM0(8 mm), VM0(800 μm), indicating curative resection. Surveillance of the upper gastrointestinal tract 5 years after gastric cancer surgery enabled the early detection of the gastric cancer and curative resection with ESD.

Here, we report a case of superficial-type gastric cancer with metastatic ovarian cancer(Krukenberg tumor)diagnosed by exploratory laparotomy. Chemotherapy was initiated at an early stage in this patient. A 43-year-old woman with superficialtype gastric cancer(0-Ⅱb plusⅡa), an ovarian tumor, and a solitary sclerotic bone lesion underwent exploratory laparotomy and bilateral salpingo-oophorectomy. Pathological findings showed that the resected ovarian tumor specimen contained the same type of signet ring cell carcinoma as the biopsy gastric cancer specimen; hence, the patient was diagnosed with superficial- type gastric cancer with metastatic ovarian cancer. She was treated with first-line chemotherapy(capecitabine plus oxaliplatin)15 days after exploratory laparotomy, followed by second-line chemotherapy(ramucirumab plus paclitaxel), thirdline chemotherapy(nivolumab), and fourth-line chemotherapy(irinotecan). Twenty-two months after the start of first-line chemotherapy, she finally died due to bone metastasis.

There is a growing need for home medicine in our graying society. New efforts are thus required to provide better treatment in the home. The Sakai Medical Association has established a new medical information system which uses the internet to increase the effectiveness of home medicine centered on the clinic and hospital cooperation.

A 24-yr-old male patient that suffered from chronic tetany since school age. At the age of 20 tetanic convulsions occurred due to hypocalcemia. His mother also had chronic tetany due to pseudohypoparathyroidism. At the age of 24, hypocalcemia caused by pseudohypoparathyroidism was noted. Hypopotassemia persisted even when the hypocalcemia improved with the administration of 1 alpha-hydroxycholecalciferol and calcium lactate. Other findings were normal blood pressure, high levels of plasma renin activity and serum aldosterone, a fall in blood pressure after angiotensin II antagonist infusion, blunted pressor response to angiotensin II infusion and hyperplasia of the juxtaglomerular cells. These results were compatible with Bartter's syndrome. Plasma prostaglandins E2 and F2 alpha in standing position were suppressed after indomethacin administration. To our knowledge this is thought to be the first report of a case of pseudohypoparathyroidism associated with probable Bartter's syndrome.

The present study was undertaken to evaluate the relationship between renin secretion from the denervated kidney and intrarenal distribution of blood flow during reductions in renal perfusion pressure by partial constriction of the aorta with and without ureteral occlusion in the anesthetized dog. In addition, renin contents in different zones of the kidney were measured. A reduction in renal arterial pressure from normal pressure (125-135 mmHg) to 77 mm Hg resulted in significant increase in renin secretion and redistribution of cortical blood flow. A further reduction of renal arterial pressure to 51 mmHg produced a marked increase in renin secretion rate (RSR) without further changes in the intrarenal distribution pattern of blood flow. The pressure reductions during ureteral occlusion increased RSR without any change in the distribution pattern of blood flow, and a decrease in the amounts of extractable renin was found in the outer cortex of the experimental kidney. These findings suggest that renin release occurs mainly in the outer cortex, and this process may be stimulated when the mechanism of autoregulation fails as the perfusion presure approaches to the lower range of autoregulation in the outer cortex.

Intravenous infusion of SA-446 (1 mg/min) decreased systemic blood pressure and increased renal blood flow in anesthetized dogs. These changes were accompanied by a slight natriuretic response. During the infusion of this dose of SA-446, the pressor response to angiotensin I was abolished and the depressor response to bradykinin was markedly potentiated. Administration of indomethacin (13 mg/kg i.v.) suppressed natriuresis and, to some extent, the renal vasodilation caused by SA-446. Before and after administration of SA-446, four arachidonate metabolites, prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2, were determined in plasma and urine by radioimmunoassay. There were no remarkable changes in levels of prostaglandins and thromboxane B2 in arterial and renal venous plasma. The urinary excretion of the metabolites varied little, but thromboxane B2 excretion did significantly decrease. Thus, reduction in the biosynthesis of thromboxane B2 in the kidney may relate to the effects of SA-446 on renal hemodynamics and urine formation.

Effects of calcium ionophore, A23187, on prostaglandin E2 and renin release, and the interrelationship were investigated in anesthetized dogs. PGE2 concentration in arterial and renal venous plasma was measured by radioimmunoassay, and secretion rate (pg/g-min) from the kidney was calculated. The renin secretion rate (ng/g-min) was calculated simultaneously. Intrarenal infusion of A23187 at a rate of 0.5 mg/min for 2 min resulted in a significant increase in RBF. PGE2 secretion rate increased from 61 +/- 26 to 1012 +/- 566 1222 +/- 500 and 388 +/- 125 at 5, 9 and 17 min. Renin secretion rate also increased rom 1.4 +/- 0.8 to 2.3 +/- 1.3, 5.8 +/- 2.7 and 5.9 +/- 1.6 at 5, 9 and 17 min. However, systemic administration of A23187 at a rate of 0.5 mg/min for 2 min did not alter the parameter. Thus, intrarenal infusion of A23187 affects RBF, renin release and PGE2 release directly within the kidney. In indomethacin treated dogs (5 mg/kg, i.v.) intrarenal infusion of A23187 significantly decreased RBF. The renin release with A23187 was also abolished with indomethacin as well as PGE2 release. These results suggest that calcium mobilization within the kidney plays an important role in PGE2 synthesis and release, and that the renal vasodilation and renin release are secondary effects of renal PGs synthesis and release.

Plasma levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolites of two prostanoids with opposing biological effects, TXA2 and prostacyclin, were measured by radioimmunoassay in normal pregnancy (controls) and pregnancy complicated by hypertension (PIH) from 32 to 36 (Period 1; P1) and from 36 to 40 (Period 2; P2) weeks of gestation. The plasma concentration of each compound in the control subjects was 265.6 +/- 58.4 (TXB2), 132.4 +/- 16.5 (6-keto-PGF1 alpha) for P1 (n = 10) and 142.6 +/- 11.8 (TXB2), 68.5 +/- 5.2 (6-keto-PGF1 alpha) for P2 (n = 10) respectively (pg/ml, mean +/- s.e). In the patients with PIH, TXB2 concentrations increased moderately for P1 (419.2 +/- 21.2; n = 7) and significantly (p less than 0.005) for P2 (452.8 +/- 31.0; n = 7) respectively (pg/ml, mean +/- s.e), while the plasma levels of 6-keto-PGF1 alpha revealed a slight to moderate decrease both for P1 (84.5 +/- 4.0; n = 7) and P2 (59.7 +/- 8.1; n = 7) respectively (pg/ml, mean +/- s.e). The physiological balance of TXB2 to 6-keto-PGF1 alpha was significantly greater (p less than 0.005) in the patients with PIH, where the TXB2/6-keto-PGF1 alpha ratio was 5.2 +/- 0.7 for P1 and 9.4 +/- 2.3 for P2 respectively (mean +/- s.e) compared with that of the controls, where it was 2.4 +/- 0.4 for P1 and 2.0 +/- 0.2 for P2 respectively (mean +/- s.e).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of nicardipine, classed as a calcium antagonist, on renal hemodynamics, renal function, and renin release were investigated in pentobarbital-anesthetized dogs. Intrarenal infusion of this drug at a rate of 5 micrograms/min in both hydrated and hydropenic dogs resulted in a significant increase in renal blood flow, glomerular filtration rate, urine flow, and renin release, with a significant fall in systemic blood pressure. The intrarenal blood flow as measured by the microsphere method indicated a greater increase in flow rate in the juxtamedullary than in the superficial area. During nicardipine infusion, free water reabsorption rate (TcH2O) in hydropenic dogs or free water production (CH2O) in hydrated dogs increased in proportion to the urine flow. Neither TcH2O/CH2O nor CH2O/osmolar clearance were significantly changed throughout the experiments. These data suggest that nicardipine did not inhibit sodium transport at the medullary portion of the ascending limb of Henle, and that the increase in GFR might induce an enhancement of the delivery of sodium to the Henle loop. In addition, an intrarenal hemodynamic alteration may be one possible mechanism involved in the diuretic action of nicardipine. Calcium-antagonistic actions of nicardipine may account for the changes in renal parameters.

The relationship between the renin-angiotensin system (RAS) and prostacyclin (PGI2) biosynthesis was studied in experimental diabetic rats. The group with diabetes induced by streptozotocin (STZ, 3.3 mmol/kg i.v.) showed prolonged hypertension, and plasma renin activity decreased markedly from 8.4 +/- 0.7 to 2.4 +/- 0.3 and 1.2 +/- 0.3 ng angiotensin I/ml per h at 2 and 8 weeks after STZ treatment. Plasma PGI2, determined as 6-keto-PGF1 alpha, decreased significantly at 8 weeks, with the values for the STZ-treated and control groups being 1490 +/- 99 and 2210 +/- 90 pg/ml, respectively. Significant suppression of renin release from renal cortical slices was observed at 8 weeks in the diabetic group, although no significant change was found in the renal renin content when compared with that of the controls. The release of PGI2 from the renal medullary slices of the diabetic group was suppressed at 2 and 8 weeks, with the suppression in aorta and renal cortical slices being apparent only at 8 weeks. These results indicate that suppression of the RAS may be related to PGI2 biosynthesis in diabetes mellitus.

The present study was designed to examine the interrelationship between the intrarenal vascular receptor and the sympathetic nerve, beta-adrenergic system, for renin secretion in the anesthetized dog. 1) A reduction in renal arterial pressure from a control pressure to 100 mmHg changed neither ther flow rates of all cortex zones nor renin secretion. Further reduction of renal arterial pressure to 75 mmHg resulted in a significant increase of renin secretion and a decrease of blood flow in the outer cortex. Intrarenal arterial infusion of norepinephrine at a control pressure increased a renin secretion. However, norepinephrine infusion at a reduced pressure suppressed the renin release with a recovery of the vascular resistance to the control level. These results suggest that the changes in the degree of blood flow and pressure in the renal afferent arterioles are not essential for the renin secretion,but renin secretion by the pressure reduction might be related to the autoregulatory capacity of afferent arterioles in the outer cortex. 2) At 5 min of hemorrhagic period (75 mmHg) arterial PRA elevated in control, and phenoxybenzamine and propranolol treated groups and any significant difference in responses was not observed among groups. However, at 60 min of hemorrhagic hypotensive period PRA in control and phenoxybenzamine treated groups further increased, but PRA in propranolol treated group was not alter from its 15 min value. These results indicated that the roles of vascular receptor and renal sympathetic nervous sytem in receptor and renal sympathetic nervous system in renin secretion might be separated, and that the renal sympathetic nervous system did not relate to the early response of renin release, but related to the late response. 3) Intrarenal arterial infusion of cAMP and DbcAMP resulted in a significant increase of renin release. In addition, CaC12 solution was infuesed into the renal artery and a significant rise in renal venous PRA was observed within 5 min of infusion. These data suggested that a beta-adrenergic receptor-adenyl cyclase-cAMP system was involved in the control of renin secretion, and that since the intracellular effect of cAMP was partly related to the change of intracellular Ca distribution, its change resulted in an increase in renin secretion.

1. Effects of 4-pentenoic acid (4-PA), an inhibitor of fatty acid oxidation, on renal fatty acids (FFA) were investigated using mongrel dogs, and the results compared with findings in the case of furosemide. 2. Continuous infusion of 4-PA at a rate of 0.66 mumoles/kg.min into the renal artery resulted in a marked reduction of glomerular filtration rate after 45 min. Sodium reabsorption rate tended to decrease at 30 min and a significant decrease was seen after 45 min. With decrease in the renal sodium reabsorption rate, the urine flow increased about 3 times, and there was a marked natriuresis. 3. Concentrations of individual FFA in the arterial and renal venous plasma were determined by gas-liquid chromatographic analysis. In the control period, data from 25 dogs showed renal uptake of palmitic, stearic, oleic, and linoleic acids to be approximately 40, 15, 25, and 10 nmoles/g.min, respectively, and the uptake of palmitic and oleic acids was depressed during the natriuresis following administration of 4-PA and furosemide. 4. These results suggest that fatty acids play an important role in the energy supply in renal tubular sodium transport.

We investigated the effects of leukotrienes (LTs) C4 and D4 on renal function and hemodynamics of dogs. LTC4 (0.5 microgram/min, infused into the renal artery), but not LTD4 (1 microgram/min), caused an increase in renal blood flow, urine flow, urinary excretion of sodium and potassium, and rate of free water reabsorption, with a concomitant rise in systemic blood pressure. Intrarenal infusion of LTC4 under conditions of constant renal perfusion pressure induced no significant effect on renal blood flow or urine formation. Infusions or LTC4 and LTD4 into the renal artery induced no change in the release of prostaglandins, PGE2, PGF2 alpha, 6-keto-PGF1 alpha or thromboxane B2 into renal venous blood. From these findings, we concluded that the renal effects of LTC4 were secondary responses to a rise in systemic blood pressure.

The release of prostaglandin(PG) and thromboxane(TX) was examined in the six different areas of the normal dog kidney, i.e., renal arterial and venous strips(RA and RV), superficial and deep cortical slices(SC and DC) and outer and inner medullary slices(OM and IM). These tissues were incubated in Krebs-bicarbonate buffer(pH 7.4, 37 degrees C), and the released PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2(as stable metabolites of PGI2 and TXA2, respectively) were determined by radioimmunoassay. In RA, RV, SC and DC, 6-keto-PGF1 alpha was predominant, however, there were no quantitative differences between RA and RV, or SC and DC. The release of 6-keto-PGF1 alpha reached a maximum in IM, similar to findings on the release of PGE2 and PGF2 alpha. The release of TXB2 was uniform in OM and IM. The amount of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 released from IM was 2800, 400, 60 and 50 times higher, respectively, than the extent of the release from the cortical slices. These results suggest that PGI2 as well as PGE2 and PGF2 alpha, may be involved in renal PG, and that TXA2 is biosynthesized in the normal dog kidney.

The effects of alpha-hANP on systemic hemodynamics and regional blood flow were examined in conscious WKY and SHR. An intravenous infusion of alpha-hANP (3 micrograms/kg per min) resulted in a rapid and marked fall of blood pressure and of total peripheral resistance but with no change in cardiac output in both strains. alpha-hANP decreased vascular resistance in most organs and there was a redistribution of renal blood flow. Thus, the acute hypotensive effect of alpha-hANP is probably related to a vasodilator action.

The effects of PGI2 and PGE2, given in the same doses were compared as to renal hemodynamics and functions and renin release. The same experimental conditions were used for both compounds and experiments were carried out in pentobarbital anesthetized dogs. Adrenergic influences were excluded by renal denervation. Given intrarenally at doses at 0.1 microgram/min and 1 microgram/min, PGE2 caused significant increase in RBF, UF and UNaV, but had no effect on BP and GFR. Intrarenal infusion of PGI2 at a rate of 1 microgram/min resulted in a significant increase of RBF and in a marked fall of BP, but only little change in GFR, UF and UNaV. With a dose of 0.1 microgram/min, the parameters remained the same. Intravenous infusion of PGI2 (1 microgram/min) caused a significant fall in BP with no change in the other parameters. Both PGI2 and PGE2 had a similar effect on intrarenal hemodynamics, i.e., caused a progressively greater proportional vasodilation from superficial to deep cortex. Given intrarenally in a dose of 1 microgram/min, PGI2 and PGE2 increased renin release. But with a dose of 0.1 microgram/min and 1 microgram/min, i.v., renin secretion was not influenced. The effect of PGI2 on systemic blood pressure was more potent than that of PGE2, however, with regard to renal vasodilating action and tubular effects, PGE2 was the more potent. Present data indicate that PGI2 and PGE2 stimulate renin secretion through a direct action on the juxtaglomerular cells.

A reduction of renal arterial pressure in mongrel dogs to 70 mmHg resulted in marked increases in plasma renin activity and plasma levels of angiotensin I (AI) and angiotensin II (AII). Production of renin and AI but not AII in the kidney was observed. A reduction of renal arterial pressure also resulted in a redistribution of blood flow from the outer to inner cortex. An arterial infusion of AII (200 ng/min), however, failed to affect the intrarenal distribution of the blood flow. An intrarenal infusion of AII rather restored the normal pattern of the distribution of intrarenal blood flow altered by the pressure reduction. These results indicate that the renin-angiotensin system is probably not involved in the control of renal hemodynamics through the intrarenal formation of AII, and that the intrarenal hemodynamic changes caused by pressure reduction is due to the intrinsic differences in myogenic force in different cortical zones.

Control mechanisms for total renal blood flow (RBF) or regional blood flow were reviewed. Physiological and experimental conditions will usually cause simultaneous activation of several control mechanisms. The many interactions and secondary effects through release of intrarenal hormones, i.e., the renin-angiotensin system, prostaglandins and the kallikrein-kinin system, complicate the picture even more; but they also make it easy, and tempting, to construct various feedback control systems for renal hemodynamics. 1. There is no functional evidence for renal vasodilator nerves, while both pre- and postglomerular resistance vessels are supplied by adrenergic constrictor nerves. Nervous vasoconstrictor tone is absent or low under basal conditions, but may be activated by a number of afferent stimuli. 2. Intrarenal distributions of adrenergic alpha- and beta-receptor are homogeneous and beta-receptor may be selectively located in the afferent arterioles. On the other hand, the distribution of dopamine and acetylcholine receptor is not uniform, and they are distributed more in the inner cortex than in the outer cortex. 3. The renal arterioles are highly sensitive to the vasoconstrictor action of angiotensin II and to the vasodilator action of prostaglandin E2 and bradykinin. Under basal conditions, there seems to be no resting "angiotensin vasoconstrictor tone" and "bradykinin vasodilator tone", whereas salt depletion and certain types of renal hypertension may be associated with sustained renal vasoconstriction caused by angiotensin II. 4. Autoregulation tends to keep RBF and GFR constant at varying arterial pressure. There is no direct evidence for a metabolic autoregulation of RBF and for a contribution of intrarenal humoral factors for autoregulation. Thus, in spite of only indirect evidence, a Bayliss mechanism is still an attractive hypothesis, and would in fact seems to satisfy more experimental observations than any other mechanism.

Prostaglandin E2 (PGE2), thromboxane B2 (TXB2; as a stable metabolite of TXA2), prostaglandin F2 alpha (PGF2 alpha) and 6-keto-PGF1 alpha (as a stable end product of prostacyclin) have been measured by using specific radioimmunoassay in the plasma of the cord artery immediately after delivery before the cord was clamped. Plasma prostanoid concentrations in normal deliveries (n = 8, as controls) were 24.8 +/- 2.6 (PGE2), 246.8 +/- 37.0 (TXB2), 122.2 +/- 13.3 (PGF2 alpha) and 82.1 +/- 7.7 (6-keto-PGF1 alpha) respectively (pg/ml, mean +/- s.e). On the other hand, in fetal distressed deliveries showing continuous bradycardia (n = 6), they increased significantly to 275.4 +/- 20.1 (PGE2), 948.6 +/- 102.5 (TXB2), 218.0 +/- 21.4 (PGF2 alpha) and 1498.6 +/- 298.4 (6-keto-PGF1 alpha) respectively (pg/ml, mean +/- s.e, p less than 0.005). However, both PGF2 alpha/PGE2 and TXB2/6-keto-PGF1 alpha ratios declined significantly from 4.70 +/- 0.33 to 0.68 +/- 0.05 and from 3.07 +/- 0.37 to 0.68 +/- 0.12 respectively (mean +/- s.e, p less than 0.005) in the fetal distressed group compared with those of the controls. From these results, it may be concluded that the cord artery, which is known as the patent source for the production of PGE2 and prostacyclin, did exert a sufficiently strong reaction to overcome the undesirable haemodynamic changes to maintain the fetal well-being in utero.

EDTA or verapamil was infused into the renal artery of the anesthetized dog, and the effects on renin release and renal function were examined in an attempt to elucidate the role and action site of calcium ion in the renin secretory system. Both EDTA (25 mg/min) and verapamil (50 micrograms/min) increased RSR and RBF with a concomitant increase of urine flow, although there was no change in systemic arterial pressure. An infusion of verapamil in combination with ouabain produced a significant increase in RBF which was similar to that seen with verapamil alone. Urine flow and urinary excretion of electrolytes were also increased, but these changes did not differ from those seen with ouabain infusion alone. Ouabain alone did not affect RSR, but its infusion combined with verapamil resulted in a significant increase in RSR. Therefore, the effects of EDTA and verapamil on renin release may reflect the action of both drugs on the vascular component of the juxtaglomerular apparatus. If a change in calcium movement similar to the one in vascular smooth muscle occurs in the juxtaglomerular cells, the altered concentration of calcium may be considered to induce, in part, the stimulation of renin release by EDTA or verapamil.

The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (PSA) and the urine concentration was 726 +/- 200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (CSA) was 2.24 +/- 0.34 ml/g X min and was significantly higher than GFR. The clearance ratio (CSA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in PSA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. CSA decreased significantly from 2.24 +/- 0.34 to 0.71 +/- 0.14 ml/g X min. The inhibitory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog. Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.