Masahide Seino

The kallikrein-kinin system and prostaglandins in the kidney: their relation to forosemide-induced diuresis and to the renin-angiotensin-aldosterone system in man.

The relations among the renin-angiotensin-aldosterone system, renal prostaglandin E, the renal kallikrein-kinin system, and furosemide diuresis were studied in 16 healthy volunteers. The diuretic and natriuretic effects of furosemide were accompanied by an increase in the excretion rates of urinary prostaglandin E (UPGEV), urinary kallikrein (UkaiiV), and urinary kinin (UkinV), in plasma renin activity (PRA) and plasma aldosterone concentration (PAC). However, the time courses of the increase in PRA and PAC following furosemide administration and assumption of an upright posture were different from those of UPCEV, UkaiiV, UkininV, urine flow (UV), and urinary sodium output (UNaV). In comparison with the early increase in UPCEV, UkaiiV, UkininV, UV and UNOV, the increases PRA and PAC were delayed. The augmentation of UPGEV, UkaiiV, and UkininV was closely related to the diuretic and natriuretic effects of furosemide. Highly significant correlations also were found between UPGE V and Ukaii V, UPGEV and Ukinin and UkininV. On the contrary, there were no significant correlations between UPGEV and PRA or PAC, between Ukaii V and PRA or PAC, or between UkininV and PRA or PAC before and after the furosemide injection. These results indicate that the augmentation of urinary prostaglandin E and urinary kallikrein-kinin system following furosemide administration is independent of the renin-angiotensin-aldosterone system but directly dependent on the effects furosemide. The possibility that renal prostaglandin E and the renal kallikrein-kinin system are involved in the diuretic and natriuretic effects of furosemide also is suggested by these experiments.

Attenuation of pressor responses to norepinephrine and pitressin and potentiation of pressor response to angiotensin II by captopril in human subjects.

The present study was conducted to investigate the influence of captopril on cardiohemodynamic responses in 38 normal volunteers (20- to 35-year-old men) to exogenously administered vasopressor substances. Norepinephrine (NE), 0.05, 0.1, and 0.2 μg/kg min−1; angiotensin II (AH), 5, 10, and 20 ng/kg min−1; and pitressin (2 mU/kg min−1) were infused for 10 minutes. Each infusion was repeated twice, and the responses were reproducible. Captopril (50 mg by mouth) significantly attenuated the pressor responses to NE and pitressin, but the decrease in heart rate in response to NE and pitressin was almost the same before and after captopril treatment, suggesting that captopril potentiates reflex slowing of the heart. Captopril significantly potentiated the pressor response to AIL Attenuation of pressor response and potentiation of reflex slowing of the heart, in response to NE and pitressin, disappeared when a subdepressor dose of AH (1 ng/kg min−1) was infused in addition to captopril. Infusion of a subdepressor dose of bradykinin (BK), 0.1 fig/kg min−1, had no influence on the pressor response to NE. In the subjects treated with indomethacin (225 μg/54 hrs), captopril still attenuated the pressor response to NE. These results suggest that captopril attenuates the pressor responses to NE and pitressin primarily by depletion of endogenous AH; decreased AH may desensitize the contraction of arterial smooth muscle and may potentiate the compensatory reflex mechanism. (Hypertension 4: 444–451, 1982)

Interaction of vasopressin and prostaglandins through calcium ion in the renal circulation.

To determine whether the effects of arginine vasopressin (AVP) on the renal and systemic vessels are modulated by prostaglandins (PGs), AVP (10, 20, and 50 mU/kg/min) was infused into the renal artery before and after treatment with indomethacin (8 mg/kg) in anesthetized rabbits. Arginine vasopressin elicited a dose-dependent increase in systemic arterial pressure and renal vasoconstriction. However, after cessation of the infusion, significant renal vasodilation was observed. Indomethacin potentiated the systemic and renal vasoconstrictor actions and attenuated the renal vasodilator reaction induced by AVP. These results suggest that endogenously produced PGs buffer the vasoconstrictor action of AVP, and the renal vasodilator reaction induced by AVP could be mediated through PGs. Further, to investigate whether the effects of AVP on the systemic and renal vessels are mediated by calcium ion (Ca++), the Ca++ entry blocker nifedipine was used. Intravenous administration of nifedipine (50 micrograms/kg) attenuated the systemic and renal vasoconstrictor action of AVP. The renal vasodilator reaction induced by AVP was also diminished after treatment with nifedipine. These results indicate that the systemic and renal vasoconstrictor actions of AVP are mediated through Ca++ influx into the vascular smooth muscle cells. The present study suggests that Ca++ participates in the AVP-induced vasodilator reaction, itself probably mediated by PGs.

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.

Sex and age-related differences in the urinary excretion of TXB2 in normal human subjects: a possible pathophysiological role of TXA2 in the aged kidney

Urinary excretion of thromboxane B2 (TXB2), a stable metabolite of TXA2, was measured by radioimmunoassay in 58 normal subjects (17 males and 41 females) aged from 19 to 98 years. The basal level of urinary TXB2 in normal subjects was 100 +/- 6.7 ng/day (mean +/- SEM). In young males, contamination of urine specimens with seminal fluid, which is known to contain large amounts of prostaglandin E, did not change the level of urinary TXB2. Urinary excretion of TXB2 was significantly higher in male subjects than in female (124 +/- 12.6 vs 90 +/- 7.4 ng/day, p less than 0.05). There was no significant age-related difference in 24-h urinary excretion of TXB2 in normal subjects. However, when urinary excretion of TXB2 was expressed as a function of urinary creatinine excretion, it was significantly higher in the elderly (60-93 years old) than in the younger subjects (19-59 years old)(141 +/- 15.7 vs 99 +/- 7.7 ng/g creatinine, p less than 0.02). Renal TXA2 may have a pathophysiological role in the functional impairment of the kidney in elderly people.

Nifedipine enhances the vasodepressor and natriuretic effects of atrial natriuretic peptide.

We examined a possible interaction between the calcium entry blocker nifedipine and atrial natriuretic peptide on blood pressure and natriuresis in anesthetized rabbits. The administration of atrial natriuretic peptide (0.05 micrograms/kg/min) produced a significant decrease in mean arterial pressure. Similar reductions in blood pressure were obtained during the administration of nifedipine (1.0 micrograms/kg/min). Atrial natriuretic peptide produced a consistent increase in glomerular filtration rate that was higher than the increase in renal blood flow; hence, the filtration fraction was significantly elevated. Atrial natriuretic peptide also elicited a significant increment in urine volume and urinary sodium excretion, while nifedipine was devoid of any significant effects on renal hemodynamics and renal excretory function during the experimental period. The administration of atrial natriuretic peptide superimposed on an ongoing infusion of nifedipine resulted in a greater fall of blood pressure than that seen during the administration of atrial natriuretic peptide or nifedipine alone. Sodium excretion was also potentiated, but there were no changes in renal hemodynamics or in the filtration fraction. These results suggest that calcium entry blockers potentiate the vasodepressor and the natriuretic effects of atrial natriuretic peptide but prevent its renal hemodynamic effects.

Metabolism of PG in man: Effect of furosemide on the excretion of the main metabolite of PG F2α

The excretion rates of main urinary metabolite of PG F2alpha were measured radioimmunologically in 4 healthy persons and in 13 essential hypertensives. The resting values were 9.3+/-0.73 in the former and 10.4+/-2.17 ng/min in the latter. There was no significant differences between them. The excretion of the metabolite decreased prominently after the administration of furosemide. The percent decrease was 57% in healthy persons and 70% in essential hypertension. The percent result supports that furosemide inhibit the catabolism of PG F2alpha.

Effects of a competitive antagonist of bradykinin on blood pressure and renal blood flow in anesthetized rats

To examine a possible role of endogenous bradykinin in the regulation of blood pressure (BP) and renal blood flow (RBF), a newly synthesized competitive antagonist of bradykinin (B4147) was studied in anesthetized rats. Also, the question of whether the hypotensive effect of the converting enzyme inhibitor, captopril, is mediated partly by an accumulation of endogenous bradykinin was considered. The intravenous infusion of B4147 (25 micrograms/min) inhibited the depressor effect of exogenous bradykinin (0.5 microgram, i.v.) by 69%. After an intravenous injection of B4147 at doses of 25, 50 and 100 micrograms, BP increased and RBF decreased in a dose-dependent fashion. The increase in BP was not blocked by pretreatment with an angiotensin II antagonist (1-Sar-8-Ile angiotensin II; 20 micrograms/kg per min) or an alpha 1-blocker (prazosin; 0.1 mg/kg). The administration of captopril (1 mg/kg) decreased mean BP from 110 +/- 3.5 to 71 +/- 1.9 mmHg (P less than 0.001). However, the injection of B4147 (50 micrograms) after the administration of captopril elicited an increase in BP of 43% of the initial decrease induced by captopril. These results suggest that the effects of B4147 on BP and RBF are not mediated through angiotensin II or sympathetic alpha 1-stimulation. Endogenous bradykinin could contribute to the maintenance of BP and RBF in anesthetized rats, probably counter-balancing the vasoconstrictor mechanisms. It is also suggested that bradykinin may partly participate in the acute hypotensive effect induced by the converting enzyme inhibitor captopril.

Contribution of bradykinin to maintenance of blood pressure and renal blood flow in anaesthetized spontaneously hypertensive rats

We used a newly synthesized competitive antagonist of bradykinin (B 4147) to determine whether bradykinin contributes to the maintenance of blood pressure and renal blood flow in anaesthetized Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The injection of B 4147 (50 μg, intravenously) caused an increase in blood pressure and a decrease in renal blood flow in both strains. However, the magnitude in the change in blood pressure was significantly lower in SHR than in WKY. The reduction of renal blood flow was greater in WKY than in SHR, but there was no significant difference in the basal renal blood flow. These results indicate that bradykinin contributes to the maintenance of blood pressure and renal blood flow in both strains. However, bradykinin antagonist produced a more prominent systemic effect in WKY than in SHR. This suggests that a deficiency in the bradykinin system in SHR contributes to the development or the maintenance of hypertension.

Role of bradykinin in the regulation of blood pressure and renal blood flow in DOCA-salt hypertensive rats

We examined the role of bradykinin in the onset and/or the maintenance of blood pressure and renal blood flow in deoxycorticosterone acetate (DOCA)-salt hypertensive rats by using a competitive antagonist of bradykinin [Arg-Pro-Hyp-Gly-Thi-Ser-Dphe-Thi-Arg; Hyp, L-4-hydroxyproline; Thi, beta-(2-theinyl-L-alanine)]. The intravenous injection of the bradykinin antagonist (25, 50 and 100 micrograms) produced an increase in mean arterial pressure in all rats treated with tap water, 1% NaCl and DOCA + 1% NaCl. However, the magnitude of the increase in mean arterial pressure was significantly lower in the DOCA-hypertensive rats than in the two groups of rats drinking tap water and 1% NaCl after 4 and 6 weeks, but there was no significant difference after 2 weeks. The bradykinin antagonist induced a decrease in renal blood flow in all rats. However, the extent of the fall in renal blood flow was reduced in the DOCA-hypertensive rats compared with the control rats drinking tap water. These results suggest that endogenous bradykinin is depressed in the established phase of hypertension in DOCA-hypertensive rats. It is also suggested that endogenous bradykinin may counteract the elevation of vascular resistance in the early stages of this model.