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Equine angiotensin converting enzyme: a zinc metalloenzyme.

1. Angiotensin I converting enzyme from horse plasma has been extensively purified and shown to be homogeneous by disc-gel electrophoresis. 2. The metal ion involved in the catalytic reaction of the enzyme has been identified for the first time as zinc by atomic absorption spectrometry. 3. A number of other physicochemical properties of the enzyme are described and compared with results obtained by other investigators. The molecular weight was determined by gel filtration to be 113 000 daltons. The pH maximum was found to be 7-4. The chloride activation of the enzyme appears to act by facilitation of substrate binding to the enzyme. 4. By use of enzyme inhibitors, tyrosine has been implicated as a functional residue at the active site of the enzyme. 5. The enzyme shows a fairly high degree of specificity towards its substrates.

Angiotensin II↗
PubMed1975

Time course of changes in plasma renin after blockade of the renin-system. Studies of conscious and anaesthetized, normal, adrenalectomized and spontaneously hypertensive rats.

Inhibition of the angiotensin I converting enzyme with SQ 20.881 results in a 2 to 35 fold increase in plasma renin concentration in normal rats and in spontaneously hypertensive rats. The effect is transient, lasting for 1 to 3 hours even in the presence of prolonged blockade. The relative increase is independent of the pretreatment plasma renin concentration. The blood pressure is unchanged in conscious rats in which the effect of SQ 20.881 on plasma renin is believed to be due to a blockade of the negative feedback of angiotensin II on renin release. In anaesthetized rats, SQ 20.88) has an additional hypotensive effect which augments the increase in plasma renin. Saralasin is without effect on blood pressure and plasma renin in conscious normal rats and in spontaneously hypertensive rats, while it causes a transient 3 to 27 fold increase in plasma renin concentration in anaesthetized rats. It is suggested that this increase is hardly due to an interception of the feedback, but to the concomitant fall in blood pressure, as a similar hypotension and increase in plasma renin is produced by dihydralazine. It is furthermore found that Saralasin blocks renin release induced by SQ 20.881. This demonstrates that Saralasin is bound to the receptors in the juxtaglomerular cells and has slight, agonistic properties there. Both in conscious rats and in anaesthetized adrenalectomized rats substituted with DOCA and salt, SQ 20.881 as well Saralasin causes transient increases in plasma renin concentration. If such rats are only substituted with salt and not with DOCA, the effects of both blockers are in the form of severe hypotension and a permanent elevation of plasma renin.

Adrenalectomy↗
PubMed1975

Different effects on renal and submaxillary renin release after blockade of the renin system in mice.

Ingibition of the angiotensin I converting enzyme with SQ 20,881 results in a rapid marked increase in plasma renin concentration in mice. The maximum effect is short-lasting, but the values are still elevated 2 hours after the injection, the time course being similar to that previously found in rats. The relative increase is the same in normal and sialo-adenectomized mice. The plasma renin concentration of nephrectomized mice with their submaxillary glands intact is, however, totally uninfluenced by injection of the blocker. This finding indicates that renin release from the submaxillary glands is not controlled by the plasma angiotensin II concentration as is that of the renin release from the kidneys.

Angiotensin II↗
PubMed1976

The renin-angiotensin system and thirst: a reevaluation.

Systemic injections of renin that stimulate substantial amounts of drinking in nephrectomized rats can produce plasma renin activities that fall well above the physiological range. Furthermore, increases in plasma renin activities that occur in rats with intact kidneys during experimental hypotension appear to be too low to provide the basis for the observed elevations in water intake. These findings question the contribution of the renin-angiotensin system to thirst under normal physiological conditions.

Angiotensin II↗
PubMed1975

Effect of inhibition of peptidase activity on distribution of intrarenal blood flow.

Experiments were performed in dogs to determine the effects of the intravenous administration of the dipeptide hydrolase inhibitor SQ 20,881 on renal hemodynamics, intrarenal blood flow distribution, and renal function. Dipeptide hydrolase converts angiotensin I to angiotensin II and inactivates bradykinin. SQ 20,881 causes an inhibition of the vasoconstrictor response after angiotensin I and potentiation of the vasodilatory activity of bradykinin. Total renal blood flow, cortical distribution of blood flow, and glomerular filtration rate were determined. In seven animals administration of SQ 20,881 (1 mg/kg) resulted in a decrease in mean systemic blood pressure of 11 mmHg, an increase in total renal blood flow of 0.71 ml/min per g, and a significant fall in glomerular filtration rate. Fractional blood flow to the superficial cortex decreased and to the juxtamedullary cortex increased. Absolute flow was unchanged in the superficial cortex and increased significantly in the deep cortex. The findings are compatible with reported effects of bradykinin on intrarenal blood flow distribution, although the experiments do not distinguish between potentiation of bradykinin or inhibition of angiotensin I conversion.

Angiotensin II↗
PubMed1975

Angiotensin and the hemodynamics of chronic salt deprivation.

Salt deprivation has been shown to cause fluid volume contraction and marked renin release; it is not clear whether angiotensin-induced vasoconstriction adds to low volume in compromising circulatory function or whether there are additional facets to the salt-deprived state. Mature Wistar rats were fed a low-salt diet for 1 mo and then, under pentobarbital anesthesia, compared to normals. Arterial pressure (is congruent to 125 mmHg), cardiac output (is congruent to 200 ml/min per kg), and total peripheral resistance were nearly identical in both groups. The influence of angiotensin was estimated by injecting converting enzyme inhibitor (SQ 20881, 1 mg/kg), and then observing the immediate hemodynamic response. Salt-deprived rats responded with a large (-47 mmHg) fall in pressure and total peripheral resistance indicating that, although total peripheral resistance was normal in salt deprivation, an increased fraction (30% vs. 11%) of the resistance was supported by angiotensin. Cardiac output decreased (-8%) in contrast to the increase that would be expected during marked arterial dilation; elevated angiotensin levels may have caused a moderate, beneficial decrease in venous compliance. These results suggest that circulatory function is adequately maintained during salt deprivation by a combination of normal total peripheral resistance and decreased venous compliance.

Angiotensin II↗
PubMed1976

Response to angiotensins I and II and to AI-converting-enzyme inhibitor in a shark.

The spiny dogfish shark, which does not have renal juxtaglomerular cells, exhibits a strong pressor response to both angiotensin I and II. A nonapeptide, angiotensin I-converting-enzyme inhibitor, blocks the pressor response to angiotensin I in this fish. The pressor response to both angiotensin II and norepinephrine is completely blocked by the adrenergic blocking drug phentolamine.

Adrenergic alpha-Antagonists↗
PubMed1976

The role of the renin-angiotensin-aldosterone system in cardiovascular homeostasis in normal human subjects.

To examine the role of angiotensin II in the maintenance of blood pressure and the control of aldosterone secretion in man, eight normal subjects were studied on a tilt table in sodium replete and sodium depleted states prior to and subsequent to the intravenous infusion of an angiotensin converting enzyme inhibitor (CEI). In both the sodium replete or sodium depleted state, upright tilting resulted in an increase in heart rate and a narrowing of pulse pressure. None of the sodium replete or depleted subjects fainted. Tilting was accompanied by a rise in plasma renin activity with an associated rise in plasma aldosterone concentration. When converting enzyme inhibitor was administered, which blocked the generation of angiotensin II, sodium replete subjects were able to compensate for an upright tilt, despite the absence of angiotensin II, without significant hemodynamic change when compared to control state. In sodium depleted subjects, after the administration of converting enzyme inhibitor, there was a sharp and significant decrease in systolic and diastolic blood pressure associated with a significant rise in heart rate. All but one sodium depleted subject fainted within seven minutes. Both plasma aldosterone concentration and plasma renin activity rose on tilting in both sodium replete and sodium depleted subjects. After the administration of converting enzyme inhibitor, plasma aldosterone failed to rise in association with a rise in plasma renin activity. In supine subjects, after the administration of converting enzyme inhibitor, plasma renin activity rose but plasma aldosterone concentration fell. In sodium depleted subjects, after the administration of CEI, aldosterone fell to a level significantly lower than that in supine controls and to a level no different from the supine sodium replete subject. These results indicate that angiotensin II is essential for blood pressure maintenance in sodium depleted individuals, that angiotensin II exerts a direct feedback control on renin secretion, and that angiotensin II is the primary stimulus to aldosterone secretion in response to both sodium depletion and to posture.

Adult↗
PubMed1977

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.

Angiotensin II↗
PubMed1976

The renin-angiotensin-aldosterone system in congestive failure in conscious dogs.

The role of the renin-angiotensin-aldosterone system in the development of congestive failure has been assessed in the conscious dog by use of the nonapeptide converting enzyme inhibitor. Constriction of the pulmonary artery or thoracic inferior vena cava was maintained for 2 wk while daily measurements were made of plasma renin activity, plasma aldosterone, plasma volume, hematocrit, serum sodium and potassium concentrations, sodium and water balance, body weight, and arterial, caval, and atrial pressures. The initial response to constriction was a reduction in blood pressure, a rise in plasma renin activity, plasma aldosterone, and water intake, and nearly complete sodium retention. In the days after moderate constriction plasma volume and body weight increased (with development of ascites and edema); blood pressure, sodium excretion, plasma renin acvitity, and plasma aldosterone returned to normal. In animals in which blood pressure was not restored, plasma renin activity and plasma aldosterone remained elevated throughout the period of constriction. Single injections of converting enzyme inhibitor reduced blood pressure when plasma renin activity was elevated. Chronic infusion of the inhibitor in dogs with thoracic inferior vena caval constriction prevented the restoration of blood pressure and suppressed the rise in plasma aldosterone; sodium retention and volume expansion were less than in control experiments. Thus the renin-angiotensin-aldosterone system plays an essential role in the maintenance of blood pressure during the genesis of congestive failure. Initially, the restoration of blood pressure is dependent upon circulating angiotensin II; in the later stages, blood pressure is dependent upon the increase in plasma volume.

Aldosterone↗
PubMed1977

Endocrine and cardiovascular consequences of angiotensin converting enzyme inhibition.

One of several novel peptidic inhibitors of angiotensin converting enzyme (CEI) has been studied intravenously both in normal male volunteers and severely hypertensive patients without any clinically significant adversity or intolerance. Hypertensive patients experienced a significant yet gradual reduction in resting arterial pressure without hypotension. The addition of a diuretic agent was observed to potentiate this antihypertensive effect. Normal, sodium replete volunteers received this nonapeptide intravenously in doses up to 2-0 mg/kg without any significant cardiovascular effect. Both patients and normal subjects exhibited reversible dose related increases in angiotensin I and renin levels after receiving the peptide. The plasma renin response to tilting was also potentiated by CEI. These findings suggest that intravenous CEI may be of value in the treatment of severely elevated hypertension and as a tool to evaluate vasoconstrictor and volume factors in hypertension.

Aldosterone↗
PubMed1977

(Des-Asp1) angiotensin I: a study of its pressor and steroidogenic activities in conscious rats.

The steroidogenic and pressor activities of the nonapeptide (des-Asp1) angiotensin I [(des-Asp)-AI] were tested in conscious rats. (des-Asp)-AI caused dose related increases in mean arterial pressure (MAP), serum aldosterone, and serum corticosterone in doses between 3 and 3,000 ng/kg/min. (des-Asp)-AI was 14% as potent as angiotensin I and angiotensin II and 60% as potent as (des-Asp1) angiotensin II [des-Asp)-AII] in raising MAP. (des-Asp)-AI was less active than AI, AII, or (des-Asp)-AII in causing increased release of aldosterone, possessing only 8%, 11%, and 17% of the potency of AII, (des-Asp)-AII, and AI, respectively. Each of these angiotensin peptides was equally potent in elevating serum corticosterone levels. Infusions of a nonapeptide inhibitor of converting enzyme (CEI, 0.5 mg/kg/min iv) did not alter control MAP or blood pressure responses to AII or (des-Asp-)-AII but inhibited equally the blood pressure effects of AI and (des-Asp)-AI. CEI also inhibited the ability of (des-Asp)-AI (67% inhibition) and AI (34% inhibition) to increase the serum aldosterone concentration, but had no effect on basal aldosterone levels. These data indicate that (des-Asp)-AI has pressor and steroidogenic effects, but requires conversion to (des-Asp)-AII for a major portion of its activity. These results further substantiate the hypothesis that (des-Asp)-AII, recently recognized as a hormone of the renin-angiotensin system, may be produced without the formation of AII as an intermediate and provide in vivo evidence for the conversion of (des-Asp)-AI to (des-Asp)-AII.

Aldosterone↗
PubMed1975

Differentiation of nephrotensin from the renin angiotensin system.

An investigation of the relationship between nephrotensin and the renin angiotensin system was carred out. Nephrotensin was found in the plasma of rats with renal clip hypertension and with chemically induced kidney damage. There was no demonstrable correlation between presence of nephrotensin and plasma renin activity, and the pressor activity of nephrotensin was not altered by previous immunization of test animals with angiotensin II nor by pretreatment with angiotensin I converting enzyme inhibitor. These results indicate that nephrotensin is different from the components of the renin-angiotensin system.

Angiotensin II↗
PubMed1975

The inhibition of angiotensin converting enzyme in chronic renal hypertension by a synthetic peptide.

Renal hypertension was produced in 14 Sprague-Dawley rats by ligating both poles of one kidney followed in one week by unilateral nephrectomy. Biweekly subcutaneous injections of SQ 20858 reduced the blood pressure in the chronic renal hypertensive animals. Upon discontinuing the injections the blood pressure rose to pretreatment levels. No angiotensin II activity was seen in seven of the renal group treated with SQ indicating a complete block in serum converting enzyme activity. Likewise, serum with only angiotensin I activity when added to normal serum containing converting enzyme, continued to show angiotensin I activity. It is concluded that SQ 20858 is effective in lowering blood pressure in chronic renal hypertensive rats presumably by partially inhibiting converting enzyme.

Angiotensin II↗