The inhibitory effect of pepstatin A, an isovaleryl pentapeptide isolated from streptmyces, was studied. Pepstatin A inhibited the action of dog renin on homologus substrate. The Ki value was 7.7 × 10^-7M and the mode of the inhibition was non-competitive. Pestatin A suppressed angiotensin I generation in dog plasma. Dose-dependent hypotensive effect of pepstatin A was observed in rats with sustained increase in blood pressure during continuous infusion of dog renin. It is concluded that pepstatin A inhibits the dog renin activity in vitro and in vivo.

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A normal size form of renin, which seems to be a storage form in renin granules, changed neither in molecular weight nor activity by acidification to pH 3.0. High molecular weight (HMW) renin fractionated by gel chromatography from crude renal extract prepared with thiol group blockers was converted into normal size renin by acidification, accompanied with an increase in renin activity by about 5%. The molecular weight conversion by acidification appeared due to destruction or loss of binding ability of the renin binding substance which was present in the cytosol of renal cortical tissue. Renin and renin binding substance could combine into HMW renin at neutral pH in the presence of thiol group blockers and renin activity decreased.

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The mechanism of the increase in renin activity in human plasma which had been kept -5°C for 4 days (cryoactivation) was investigated. From the results of clinical studies, it is likely that the controling mechanism of inactive renin has some thing in common with that of active renin. The experimental data showed that the increase in renin activity of human plasma by cryoactivation was closely correlated to the increase obtained by incubation with trypsin (r=0.88, p < 0.001, n=10). Soybean trypsin inhibitor, aprotinin and di-isopropylfluorophosphate (DFP) inhibited cryoactivation, indicating that the cryoactivation is due to the action of a trypsin-like serine enzyme. Trypsin which had no effect on plasma renin activity in the presence of the same amount of soybean trypsin inhibitor at 37°C, activated the renin activity during cold incubation, suggesting that the dissociation of the trypsin-inhibitor complex may have taken place at a low temperature. Endogenous trypsin inhibitor is also likely to lose its affinity to endogenous trypsin-like enzyme at a low temperature.

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The effects of isoproterenol, dibutyryl cyclic AMP, theophlline, and angiotensin II upon tonin release were examined by incubation of rat submaxillary gland slices. Isoproterenol, dibutyryl cyclic AMP, and theophylline stimulated tonin release. Propranolol inhibited the effect of isoproterenol. Angiotensin II by itself did not inhibit tonin release, but it suppressed the increase in tonin release produced by isoproterenol. These results suggest that the tonin stimulating effect of isoproterenol is due, at least in part, to a direct stimulation of β-receptor upon the submaxillary glands and that cyclic AMP system may play a role as an intracellular mediator of this action. Angiotensin II, which is formed directly from a natural protein substrate by tonin, is suggested to inhibit tonin sectetion in some situations.

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Sodium intake reciprocally influences adrenal and vascular responses to angiotensin II. The modulating action of sodium could occur at the receptor level of these organs. In he present study, we characterized the angiotensin II receptors from the rabbit adrenal cortex and aorta at the subcellular level and examined the effects of sodium balance on these receptor sites. ¹²⁵I-angiotensin II bindings to rabbit adrenal and aortic membrane fractions were demonstrated to have features consistent with those of biologically relevant receptors with high affinity, limited capacity and specificity for angiotensin II. The binding affinities and capacities of these adrenal and aortic receptors were compared between rabbits maintained on high and low sodium diets for 6 weeks. The binding capacity of adrenal receptors from low sodium intake animals, which had higher levels of plasma angiotensin II, was 45% significantly increased than that from high sodium intake animals, Affinity constants of adrenal receptors from high and low sodium intake groups were not significantly varied. On the other hand, either the affinity constant or the binding capacity of aortic receptors between these two groups was not significantly different. The variation of the binding capcity of adrenal receptors during alterations of sodium intake did not seem to be related to changes of other membrane constituents. These results suggest that during changes of sodium intake altered adrenal angiotensin II receptor content might be responsible for the control of adrenal sensitivity to angiotensin II, but the changes in vascular responsiveness to angiotensin II need not be accompanied by alterations of the aortic angiotensin II receptor itself.

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Plasma catecholamine levels have been used experimentally and clinically as the indices of the sympathetic nerve activity. We measured plasma catecholamines using high pressure liquid chromatography in rats to assess the significance of plasma catecholamines as an index of the sympathetic nerve activity and its role in hypertension. Pentobarbital anesthesia depressed plasma catecholamine levels, especially plasma adrenaline. Sodium loading for 5 weeks suppressed plasma noradrenaline, while administration of furosemide (1 mg/kg) produced the elevation of plasma noradrenaline. Experimental hypertension, one-kidney and two-kidney types of Goldblatt hypertension and DOCA-salt hypertension, raised plasma noradrenalines both in acute and chronic phases. The infusion of pressor doses of angiotensin II suppressed plasma noradrenaline by the reflex mechanism. Sar¹, Ile⁸-angiotensin II and SQ 14, 225 did not suppress plasma catecholamine elevation due to hemorrhage. 6-Hydroxydopamine produced elevation of plasma catecholamines in experimental hypertension and controls in rats. After adrenal demedullation, plasma noradrenaline was decreased by the administration of 6-hydroxydopamine. Acute reduction of circulating blood volume and blood pressure fall produced the elevation of plasma catecholamine, especially plasma adrenaline. In rats, the adrenal medulla plays an important role in the regulation of blood pressure.

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Reserpine was administered in purpose to determine the "Noradrenaline store" in sympathetic nerve endings. The marked increase of urinary noradrenaline excretion was observed by reserpine 0.4 mg/day administration. Total amount of noradrenaline in urine for first three days of 0.4 mg/day of reserpine administration was considered as a good indicators of "Noradrenaline store". There was no difference of "Noradrenaline store" between normal and hypertensive subjects. The increase % of urinary noradrenaline was higher in labile hypertension than in established hypertension as well as in normal subjects. Though the relationship between "Noradrenaline store" or the increase % of noradrenaline and sympathetic nerve activity was not clear, it is suspected that the releasable noradrenaline in sympathetic nerve granule was higher in labile hypertension than in established hypertension or normal subjects.

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In order to clarify the properties of sympathetic nerve activity in low renin essential hypertension, plasma catecholamines (CA), dopamine-β-hydroxylase (DBH) activity and urinary CA were measured and the changes of these variables induced by 60° head-up tilt or i.v. injection of tyramine (0.1 mg/kg) were also measured in in-patients with low renin (LRH) and normal renin essential hypertension (NRH). IN addition, blood pressor response to tyramine, i.v. infusion of 0.3 μg/kg/min. of noradrenaline (NA Response) and 0.015 μg/kg/min. of angiotensin-II (ANG-II Response) were determined before and after salt restriction (Na 35, K 75 mEq) for 7 days or salt loading (Na 390, K 75 mEq) for 14 days. The basal values of plasma noradrenaline (NA), plasma DBH, and 24 hour urinary excretion of NA in LRH were significantly lower than in either NRH (p < 0.01, 0.05 and 0.01, respectively) or normotensive subjects (p < 0.05, 0.05 and 0.001, respectively). Plasma NA, plasma DBH and urinary output of NA clearly rose after 30 min. to two hours of the tilt in both LRH and NRH, and the maximal values of plasma NA (p 0.05) during tilting was significantly lower in LRH compared with those in NRH, while no significant difference was observed in the changes of plasma DBH and urinary NA between LRH and NRH. Following i.v. injection of tyramine, the maximal value of plasma NA and blood pressure rise was significantly lower (p 0.05) and significantly higher (p 0.05) than those in NRH, respectively. Following salt restriction, significant reduction of mean arterial pressure (MAP), pressor response to NA and ANG-II and a marked augmentation of PRA and urinary NA were observed. LRH showed a more marked reduction of MAP (p 0.01) and of NA Response (p 0.05) and a significantly higher augmentation of urinary NA excretion (p 0.05) than those in NRH. The increase of PRA (p 0.02) and the decrease of ANG-II Response (0.05 p 0.1) were less in LRH than in NRH. On the other hand, following salt loading, LRH exhibited a significant elevation of MAP and diminution of urinary NA, which differed markedly (p 0.01 and p 0.001) from those in NRH, in whom no significant changes were observed. No significant difference was observed between LRH and NRH in the other variables. These findings suggest that, in LRH, there exists a reduced sympathetic nerve activity at rest and a suppressed sympathetic responsiveness to the postual and tyramine stimulation, and these reduced sympathetic activity might be not primary but rather secondary to the changes in water-sodium balance.

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Plasma volume (PV), extracellular fluid volume (ECFV) and total exchangeable sodium (Nae) were measured by the dilution methods of ¹³¹RISA and ²²NaCl in the patients with low-(LRH), normal-(NRH) and high-renin essential hypertension (HRH). In addition, fractional excretion of sodium (FENa) and inorganic phosphorus (FEP) and free water (FEW), urinary Na/K ratio after oral water ingestion of 400 ml/m² body surface area, and fractional potassium excretion (FEK) after intravenous injection of 80 ml of 10% sodium thiosulfate, estimated by clearance method, were compared between LRH and NRH. PV, ECFV and Nae, which inversely correlated with logarithm of supine plasma renin activity (log PRA), were significantly higher in LRH than each of NRH and of HRH. FENa and FEP, which are assumed to reflect the renal tubular and proximal tubular sodium reabsorption, were positively correlated with age, severity of hypertension (VA score), mean arterial pressure (MAP) and correlated inversely with endogenous creatinine clearance (Ccr). FENa was also correlated positively with log PRA and negatively with ECFV and Nae in the whole patients with essential hypertension. Twenty-four hour urinary kinins excretion and plasma levels of antidiuretic hormone (ADH) measured by radio immunoassay were compared between LRH and NRH. LRH had significantly lower FENa and FEP than age-, MAP- and Ccr-matched NRH and lower urinary excretion of kinins than age-matched NRH. The mean values of these variables in LRH are almost similar to those in normotensive subjects. Plasma ADH levels and FEW were significantly lower and tended to be lower than those in NRH, respectively. Urinary Na/K ratio and FEK which may reflect the mineralocorticoid action on the renal tubule were not significantly different among these three renin sub-groups.

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