Toshiaki Haruyama

Indomethacin (IND) inhibits an enhanced renin release following the captopril, SQ 14225, administration.

Abstract The present study was done to investigate the role of endogenous prostaglandins in the mechanism of renin release stimulated by angio-tensin I-converting enzyme inhibitor, SQ 14225 in 9 hypertensive patients and 3 normotensive subjects. Plasma renin activity was significantly i increased after the administration of SQ 14225 and decreased to control levels after the addition of indomethacin. Pre-treatment with indomethacin also inhibited the augmentation of renin release following the SQ 14225 administration. Urinary excretion of prostaglandin E was not significantly increased after the SQ 14225 administration but significantly decreased after the administration of indomethacin. The present data that the augmented renin release due to the suppression of the negative short feedback mechanism of renin release by SQ 14225 was inhibited by indomethacin suggest that endogenous prostaglandin system may contribute to the short feedback mechanism of renin release.

Captopril attenuates pressor responses to norepinephrine and vasopressin through depletion of endogenous angiotensin II

The influence of captopril on pressor responses to exogenously administered vasopressor substances was investigated in normal subjects. Norepinephrine (0.05, 0.1 and 0.2 micrograms/kg . min -1; n = 5), angiotensin II (5, 10 and 20 ng/kg . min -1; n = 5) and vasopressin (2 mU/kg . min -1; n = 5) were infused each for 10 minutes; each infusion was repeated twice. Captopril (50 mg orally) significantly attenuated the pressor response to norepinephrine (0.1 [p less than 0.05], 0.2 [p less than 0.01] micrograms/kg . min -1; n = 7) and to vasopressin (p less than 0.01, n = 5), but not to angiotensin II; these responses were reproducible. Attenuation of the pressor responses to norepinephrine did not occur when a subpressor dose of angiotensin II (ng/kg . min-1) was infused in addition to captopril (n = 5). Infusion of a subpressor dose of bradykinin (0.1 ng/kg . min-1) had no influence on the pressor responses to norepinephrine (n = 5). In the five subjects treated with indomethacin (225 mg/54 hours) captopril still attenuated the pressor responses to norepinephrine. These results suggest that the attenuation by captopril of the pressor responses to norepinephrine and vasopressin might have been due to reduction of endogenous angiotensin II.

Estimation of Urinary Kininogenase Activity Using Bovine Serum Low Molecular Weight Kininogen

Estimation of urinary kininogenase activity by radioimmunoassay of generated kinin was studied. Bovine serum low molecular weight kininogen was proved not to cross-react with kallidin antibody and also bradykinin antibody. This kininogen was used as substrate measuring urinary kininogenase activity. Separation of released kinin from the kininogen was not required in the present method. Urinary kallikrein activity was found to be significantly decreased in essential hypertension, in chronic glomerulonephritis and in patients who had received renal transplantation. On the contrary, an increase in urinary kallikrein was found in primary aldosteronism and in Bartters syndrome. The present method was very useful for measuring kininogenase activity.

Evaluation of the chronotropic property of captopril in hypertensive patients

Captopril was administered (50 mg orally) to 88 untreated hypertensive patients (70 with essential hypertension, eight with renal arterial disease, 10 with renal parenchymal disease) and to 25 hypertensive patients treated with sympatholytic or beta-blocking agent (20 with essential hypertension, five with renal arterial disease). In the former group, captopril caused a decrease in heart rate (HR) in 18 patients and an increase in only two. As a whole, captopril caused significant decreases in blood pressure without increase in HR. Significant negative correlation was observed between change in HR and plasma renin activity obtained before captopril administration (n = 79, r = -0.425, p less than 0.0001). Hypotensive and chronotropic effects of captopril were almost identical in untreated and treated patients. Hypotensive effects caused by captopril and nifedipine (20 mg orally) were almost identical. Nifedipine caused reflex tachycardia, while captopril caused slight bradycardia. Absence of compensatory tachycardia appears to be related to reduction of endogenous angiotensin II by captopril.U

Effect of dietary sodium intake on the metabolism of prostaglandins in the kidney in hypertensive patients

To investigate the role of renal prostaglandins (PGs) in the renal handling of sodium, urinary excretion of PGE, PGF2 alpha and PGF2 alpha MUM (main urinary metabolite of PGF2 alpha) were measured after various manipulations of dietary sodium intake in 8 hypertensive patients. A low sodium intake increased urinary excretion of PGF2 alpha MUM (p less than 0.05), but failed to change urinary excretion of PGE and PGF2 alpha. In contrast, a high sodium intake increased urinary excretion of PGE (p less than 0.01) and decreased urinary excretion of PGF2 alpha MUM (p less than 0.02). A low sodium intake decreased the ratio of urinary PGE/PGF2 alpha MUM and high sodium increased it (both p less than 0.001). There was a significant positive correlation between urinary excretion of sodium and that of PGE (p less than 0.001). Additional oral administration of potassium chloride did not change urinary excretion of PGs. These results may suggest that dietary sodium intake may be one of the regulators of the metabolism of PGs in the kidney, supporting the hypothesis that renal PGE has a natriuretic action in humans.

Effect of propranolol on the urinary excretion of prostaglandin E and plasma benin activity in hypertensive patients

To investigate the role of the renin-angiotensin (R-A) system in the release of renal prostaglandin E (PGE), urinary excretion of PGE, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured before and after the manipulation of the R-A system in hypertensive patients. After 7 days of the control sodium diet, the R-A system was stimulated by a combination of low sodium diet and oral administration of furosemide for 7 days. From the 4th day of sodium restriction, 40 mg/day of propranolol was administered per os for 2 days, and the dose was doubled for the following 2 days. PRA and PAC were significantly increased after the sodium restriction, but no change in urinary excretion of PGE was observed. Additional administration of propranolol for the following 4 days suppressed PRA significantly and PAC moderately, but it also failed to change urinary excretion of PGE. These results may suggest that renal medullary PGE synthesis, as reflected in urinary excretion of PGE, is not strongly dependent on the R-A system in these hypertensive patients.

Reduced urinary excretion of prostaglandin E in essential hypertension.

To ascertain whether renal prostaglandin (PG) E synthesis is decreased in patients with essential hypertension (EH), urinary PGE excretion (UPGEV) was measured in 47 normal females and 62 female patients with EH. In order to avoid contaminations of urine by seminal fluids, only female subjects were studied. UPGEV was also measured in female patients with renovascular hypertension (RVH) as well as primary aldosteronism (PA) or idiopathic hyperaldosteronism (IHA). As a whole, UPGEV was lower in patients with EH (226.9 +/- 13.7 ng/day) than that in normal females (317.3 +/- 22.1 ng/day, p less than 0.001). Younger patients (15 to 39 years) had significantly lower UPGEV than normal females of corresponding ages. However, there was no significant difference in UPGEV between older patients (over 40 years) with EH and normal females of the same age range. There were no significant differences in UPGEV among patients with low renin EH, normal renin EH, RVH, PA and IHA. We reconfirmed the decrease in UPGEV in patients with EH as compared with normal controls by studying female subjects. Further, it is suggested that renal PGE synthesis is not influenced by the renin-angiotensin system in these hypertensive states.

The Role of Renal Prostaglandin E in the Mechanism of the Exaggerated Fractional Na Excretion in Hypertensive Patients with Advanced Renal Disease

Prostaglandin E (PGE) is a vasodilatory and natriuretic substance which is synthesized in the renomedullary interstitial cell and collecting tubule.1–3 Previous experimental and theoretical studies have shown a reduced clearance of sodium and water in renal hypertension.4 On the other hand, it is well known that sodium excretion per nephron varies inversely with the number of constituent nephrons, and that reduction of renal excretory function due to renal parenchymal disease is associated with exaggerated fractional sodium excretion.5 Since PGE can induce natriuresis, there is a possibility that renal PGE may contribute to the mechanism of exaggerated fractional sodium excretion in hypertensive patients with end-stage renal disease. The present study was performed to investigate this possibility.

Prostaglandin e synthesis in the kidney in renin subgroups of essential hypertension

To assess the pathophysiological role of renal prostaglandin E (PGE) in renin subgroups of essential hypertension, urinary excretion of PGE before (24 hours urine) and after the administration of furosemide (1 mg/kg, iv) and 2 hours upright posture was estimated in 66 essential hypertensives, classified into high, normal and low renin subgroups. In each renin subgroup, the administration of furosemide and 2 hours upright posture induced marked increases in urinary excretion of PGE and sodium, and in plasma renin activity. However, there were no significant differences in basal values of urinary excretion of PGE among the 3 subgroups, nor in the values after the administration of furosemide and 2 hours upright posture. The present data do not support the hypothesis that the difference in renin level in essential hypertensives is dependent on the synthesis of renal PGE.

STUDIES ON KALLIKREIN-KININ SYSTEM IN ESSENTIAL HYPERTENSION

尿kininと尿kallikreinの簡便なradioimmunoassay法を確立させ,これを用いて本態性高血圧症の病態生理と腎kallikrein-kinin系との関係を研究した.本態性高血圧症では尿中kinin排泄量と尿中kallikrein排泄量とが正常者のそれに比し明らかに減少していた. kallikrein-kininの尿中排泄量と血漿renin活性或いは血漿aldostorone濃度との間には有意の相関々係がみられた.減塩食やfurosemide立位のrenin分泌刺激負荷後には尿中kallikrein排泄量が増加し, angiotensinII阻害薬投与や抗aldosterone薬投与により尿中kallikrein排泄量が減少したことから, renin-angiotensin-aldosterone系が腎kallikreinの産生を調節していると考えられた.一方,尿中prostaglandin E排泄量はfurosemide立位負荷後に増加したが,減塩食摂取後には減少し,腎kallikrein産生能と腎prostaglandin E産生能との間に解離がみられた. renin-angiotensin-aldosterone系を作動させた際の腎kallikreinの産生遊離の反応性は,本態性高血圧症で正常者に比し明らかに低下していた.腎kallikrein-kinin系は腎性減圧系物質の一つであるので,本態性高血圧症では腎性減圧系の機能低下があると考えられた.