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PubMed1981

Demonstration of a primary antidiuretic action of angiotensin II: effects of intrarenal converting enzyme inhibition in the conscious dog.

This study was designed to determine whether angiotensin II of renal origin physiologically mediates free water production by the kidney. The effect of renal arterial infusion of the angiotensin-converting enzyme inhibitor, teprotide, on renal function was studied under conditions of hydropenia and hydration in uninephrectomized conscious dogs after 5 days of equilibration on a normal or low sodium diet. In low sodium animals, intrarenal infusion of teprotide (0.25 microgram/kg.min) after 12 h of water restriction elicited marked increases in the glomerular filtration rate (GFR) and free water formation. After 24 h of water restriction, vasopressin (10 microU/min) was infused iv to achieve an effective maximal urine concentration. Under these conditions, the inhibitor again increased the GFR and free water formation. After the production of a state of stable hydration, intrarenal infusion of teprotide also increased the GFR and free water formation. In the normal sodium animals, intrarenal infusion of the converting enzyme inhibitor (2.5 microgram/kg.min) in 12-h hydropenic dogs failed to change the GFR but increased free water formation, while the inhibitor decreased effective renal plasma flow and free water formation in normal sodium, hydrated animals. These data suggest that angiotensin II of renal origin plays an important role in the control of free water production by the kidney.

Angiotensin II↗
PubMedDate not supplied

Adverse reactions with angiotensin converting enzyme (ACE) inhibitors.

Teprotide, a nonapeptide isolated from the venom of a Brazilian pit viper, Bothrops jararaca, was the first angiotensin converting enzyme (ACE) inhibitor to be discovered and tested. It was found to be an effective, non-toxic antihypertensive agent as well as an afterload-reducing agent for patients with congestive heart failure (CHF). The primary activity of teprotide resulted from blockade of the angiotensin I converting enzyme--the pivotal step in the renin-angiotensin-aldosterone system (RAAS), and consequent reductions in angiotensin II levels. There was limited clinical testing for teprotide because of: its scarcity; the need for parenteral administration; and the subsequent discovery and synthesis of captopril, the first orally active angiotensin converting enzyme inhibitor. Captopril is the prototype oral angiotensin converting enzyme inhibitor and has been extensively studied since the initiation of formal studies in 1976. Perhaps one of the most closely researched drugs in modern times, the experience with captopril now includes more than 12,000 patients studied in formalized trials and over 4,000,000 patients treated world-wide by physicians for hypertension and congestive heart failure. Enalapril (MK421) is the first of what appears to be a growing number of analogues which are structurally and pharmacodynamically different from captopril; yet, they possess the same capacity for inhibiting the activity of angiotensin converting enzyme. The side effect profile of enalapril (and presumably future) angiotensin converting enzyme inhibitors appears to be similar to captopril, though clearly more experience is needed with newer agents. The initial use of captopril was troubled by a relatively high incidence of side effects which will form the focus of this discussion. Partially the result of incomplete pharmacokinetic information, captopril was administered in early studies at dosages now recognised to be far in excess of those necessary for drug action. In addition, dosages were given without regard for deficiencies of renal function, now known to be the main excretory route of captopril. The population of those patients studied frequently had chronic, treatment-resistant hypertension, often associated with concomitant end-organ disease (especially renal disease); and many additional factors further complicating the clinical setting, e.g. a relatively high incidence of collagen vascular disease and immunosuppressive treatments.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1981

Prostaglandins mediate the vasodilatory effect of mannitol in the hypoperfused rat kidney.

We have previously reported that mannitol strikingly increases blood flow to rat kidneys hypoperfused at 35-40mm Hg. This vasodilator effect is not due to volume expansion or alterations in plasma osmolality. We have tested the hypothesis that the vasodilatory effect of mannitol in the ischemic rat kidney is mediated by one of the vasoactive renal hormone systems: renin-angiotension, kallikrein-kinin, or prostaglandins. Rats were infused with 5% mannitol in 0.9% saline to 3-5% of body weight. In agreement with our previous studies, RBF increased 1.3 +/- 0.1 ml/min despite maintenance of perfusion pressure at 35-40 mm Hg. The cyclooxygenase inhibitors, meclofenamate and indomethacin had no effect on renal blood flow (RBF) in hypoperfused kidneys. However, in rats pretreated with these inhibitors, expansion with mannitol increased RBF by only 0.37 +/- 0.02 ml/min, 28% of the response in the untreated group (p less than 0.001). Infusion of prostacyclin (PGI2) into the renal artery during reduced perfusion resulted in an increase in RBF of 1.0 +/- 0.1 ml/min. Subsequent expansion with mannitol increased RBF by only 0.5 +/- 0.1 ml/min more, less than one-half of the effect of mannitol in a concurrent group of rats not treated with PGI2. Unlike PGI2 prostaglandin E2 had only a minimal vasodilator effect during hyperperfusion. Imidazole, an inhibitor of thromboxane synthesis, did not alter RBF or renal vascular resistance during hypoperfusion. Treatment of rats during hypoperfusion. with the angiotensin-converting enzyme (kininase II) inhibitor teprotide increased RBF by 1.1 +/- 0.3 ml/min. However, teprotide did not alter the vascular response to mannitol: RBF increased 1.2 +/- 0.1 ml/min more when mannitol was infused into teprotide-treated rats. The renal vascular response to mannitol was not altered by treatment with aprotinin, an inhibitor of the kallikrein-kinin system. Aprotinin was ineffective whether given before or after the vascular response to mannitol was established. We conclude that the vasodilator response to mannitol in the ischemic rat kidney is mediated in large part by increased prostaglandin (PGI2) activity. The failure of converting enzyme inhibition and aprotinin to block the vasodilator response to mannitol is evidence against a role for the renin-angiotension or kallikreinkinin systems in mediating the vasodilator response.

Animals↗
PubMed1984

Effect of chronic angiotensin-converting enzyme blockade on pressor responses to exogenous angiotensin II, noradrenaline and vasopressin in deoxycorticosterone acetate salt (DOCA)-induced hypertensive rats.

Effect of chronic angiotensin converting enzyme blockade on the pressor response to exogenous angiotensin II, noradrenaline and vasopressin were evaluated in DOCA-salt induced hypertensive rats using teprotide. The blood pressure of rats receiving teprotide chronically was reduced markedly. The pressor responses to exogenous angiotensin II was accentuated, while that of noradrenaline and vasopressin were significantly reduced. It is concluded that besides the angiotensin converting enzyme blocking action, the decrease in sensitivity of the pressor response to noradrenaline and vasopressin may contribute towards the antihypertensive activity of teprotide given chronically.

Angiotensin II↗
PubMed1988

Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals?

The abilities of angiotensin converting-enzyme (ACE) inhibitors to suppress superoxide anion formation in vitro and to improve postischemic cardiac function in vivo were examined. Three sulfhydryl-containing ACE inhibitors, captopril, its stereoisomer SQ 14,534, and an analog, zofenopril (SQ 26,703) were compared with enalaprilat and teprotide, which lack the sulfhydryl group but inhibit ACE, and two compounds, N-2-mercaptopropionylglycine (MPG) and N-acetylcysteine (NAC), which contain a thiol moiety but are not ACE inhibitors, for suppression of free radical formation in vitro. The autooxidation of epinephrine to adrenochrome is mediated by superoxide anions and inhibited by captopril, SQ 14,534, and zofenopril, with similar IC50 values of 8 to 10 microM, but not by enalaprilat or teprotide (IC50 greater than 1000 microM). This reaction is also inhibited by MPG and NAC with IC50 values of 19 and 17 microM, respectively. In addition, captopril, MPG, or NAC, but not teprotide or enalaprilat, scavenge superoxide anion production by the purine-xanthine oxidase reaction and by canine neutrophils activated with phorbol myristate acetate. These results indicate that captopril scavenges superoxide anions in vitro independent of an action on ACE, which is probably related to the presence of a sulfhydryl moiety. Myocardial segmental function in the anesthetized, open-chest dog is altered during ischemia from active shortening to passive lengthening. Reperfusion after 15 min of ischemia does not restore active shortening within a 3 hr experimental period. Pretreatment of dogs with captopril intravenously (5 mg/kg) results in a 40% to 60% return to active shortening within 60 min of reperfusion. In contrast, equihypotensive doses of enalaprilat do not improve segmental function during reperfusion. Dogs given captopril immediately before restoring coronary blood flow show a similar return of function as that observed in animals treated with the drug before occlusion. SQ 14,534, the isomer of captopril, which is 100-fold less potent as an ACE inhibitor but equipotent in scavenging superoxide anions, also improves reperfusion-induced cardiac dysfunction when administered at reperfusion (5 mg/kg). Thus captopril improves postischemic contractile derangements by a mechanism independent of ACE inhibition. Restoration of blood supply to the ischemic myocardium provokes ventricular fibrillation in 37.5% of control dogs but in only 9% of those administered enalaprilat and 0% of captopril-treated animals. SQ 14,534 does not reduce the incidence of ventricular fibrillation (40%), indicating that the antifibrillatory actions may be related to ACE inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenochrome↗
PubMed1980

Alterations in responses to bradykinin, angiotensin I, and angiotensin II during the induction phase of one-kidney, one-wrapped hypertension and associated arterial disease in rabbits.

During the induction phase of low-renin, one-kidney, one-wrapped hypertension in rabbits,serum angiotensin converting enzyme (ACE) activity is depressed and correlates inversely with the degree of necrotic arterial disease that develops. Responses to the vasoactive polypeptides, bradykinin (BK), angiotensin I (AI), angiotensin II (AII), the ACE blocker teprotide, and the AII antagonist 1-sar-8-ile AII were studied. Responses to BK, AII, and AI showed significant changes in both magnitude and duration (recovery time). Recovery time for depressor responses to BK in hypertensive rabbits was approximately three times that in the control period. One-wrapped, two-kidney control rabbits without hypertension-associated arterial disease showed no change in BK recovery time, although serum ACE activity was significantly depressed. In the experimental period BK recovery time correlated directly with the degree of arterial disease and indirectly with the final serum ACE activity. Duration of the pressor responses after AII correlated directly with the degree of arterial disease and indirectly with final serum ACE activity. In untreated hypertensive rabbits the percentage of increases in blood pressure after AI relative to control animals were decreased, and for all hypertensive rabbits' the increase in blood pressure correlated directly with the final serum ACE activity. Long-term treatment with teprotide moderated the hypertension but had little effect on serum ACE activity or the responses to BK, AII, and AI. Short-term infusions of 1-sar-8-ile AII and teprotide caused significant decreases in blood pressure in both the control and experimental periods, although no change in response to either polypeptide occurred. These studies support other evidence that pressor components of the renin-angiotensin system do not sustain the elevation of blood pressure in this form of experimental hypertension. Alterations in response patterns following AII and AI suggest that a vasodepressor system may be altered. In addition, part of the altered response to BK, and possibly AII, appears related to the development of the hypertension-associated arterial disease.

Angiotensin I↗
PubMed1982

The effect of angiotensin converting enzyme inhibition of coronary blood flow and hemodynamics in patients without coronary artery disease.

We examined the role of the renin-angiotensin system in the regulation of systemic and coronary vascular tone by studying the effect of converting enzyme inhibition by teprotide on systemic and coronary hemodynamic parameters in 14 normal patients undergoing routine cardiac catheterization. Serial hemodynamic measurements were made before and up to 30 minutes after 1 mg/kg of intravenous teprotide. A significant rise in cardiac index and stroke volume index occurred with a fall in systemic vascular resistance. The increase in cardiac index was related to the level of resting plasma renin activity. Blood pressure, pulmonary artery and left ventricular end-diastolic pressures remained unchanged. Coronary sinus thermodilution blood flow also showed no significant change; however, some patients demonstrated dramatic increase in flow. The change in blood flow was highly correlated with the resting plasma renin activity (r = 0.939 P less than 0.001). The change in coronary vascular resistance and myocardial oxygen consumption were likewise related to the resting plasma renin level. Converting enzyme inhibition produces significant systemic hemodynamic changes in normal patients which implies that the renin-angiotensin system is important in normal cardiovascular homeostasis. The direct relationship between plasma renin activity and coronary blood flow suggests that the renin-angiotensin system may play an important role in coronary vasomotor regulation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Mechanism of the decreased renal blood flow in the potassium-depleted conscious rat.

Although chronic potassium deficiency is a common clinical problem, the hemodynamic consequences of chronic sustained potassium depletion have not been clearly delineated. In this study, the hemodynamic consequences of chronic potassium depletion were evaluated in the conscious rat. Potassium-depleted rats had a decrease in mean arterial pressure which was caused by a decrease in systemic vascular resistance. In association with these changes in systemic hemodynamics, renal blood flow (RBF) was also decreased. The decreased renal blood flow was caused by an increased renal vascular resistance (RVR). Because plasma renin activity was increased the role of angiotensin II as a renal vasoconstrictor was evaluated by utilizing two angiotensin antagonists. Although the administration of saralasin to potassium-depleted rats did not alter systemic hemodynamics, RVR was decreased and RBF was increased. Similar results were obtained with the converting enzyme inhibitor teprotide. Because products of endoperoxide metabolism may cause renal vasoconstriction, the role of prostaglandins and thromboxanes as renal vasoconstrictors were evaluated by utilizing cyclo-oxygenase and thromboxane synthetase inhibitors. None of these agents altered systemic hemodynamics. Following the administration of indomethacin, RVR was decreased and RBF was increased in potassium-depleted rats. Similar results were obtained with another cyclo-oxygenase inhibitor, meclofenamate, and with imidazole, an inhibitor of thromboxane synthetase. Because neither angiotensin II nor products of endoperoxide metabolism could alone account for the increased renal vascular resistance of potassium depletion, studies were performed in potassium-depleted rats treated with indomethacin plus either saralasin or teprotide. In these potassium-depleted animals, renal blood flow was restored to normal. In conclusion, the decrease in renal blood flow and the increase in renal vascular resistance in potassium depletion is mediated by angiotensin II and a product of prostaglandin endoperoxide metabolism, most likely, thromboxane.

Angiotensin II↗
PubMed1981

Complex competitive and non-competitive inhibition of rat lung angiotensin-converting enzyme by inhibitors containing thiol groups: captopril and SA 446.

1. The kinetics of the inhibitory action of four different angiotensin-converting enzyme inhibitors was evaluated in vitro with rat lung enzyme and the substrate hippuryl-histidyl-leucine. 2. Enzyme velocity against substrate concentration curves were fitted squares to hyperbolae by a weighted least squares iterative method to obtain apparent values of Km, Vmax. and K/V at each concentration of inhibitor. 3. The inhibitory constants Ki and Ki' were obtained by weighted linear regressions of K/V against i and 1/V against i respectively. 4. Teprotide was the least potent inhibitor with a Ki of near 20 nmol/l whereas captopril (SQ 14 225) and SA 446 were both approximately 10 times and MK 421 approximately 20 times more potent. 5. Two inhibitors which lacked thiol groups [teprotide or SQ 20 881 and N-(1-S-1-carboxy-3-phenylpropyl)-L-Ala-L-Pro or MK 421] produced a purely competitive pattern of inhibition with increased apparent Km but no change in apparent Vmax.. 6. Two inhibitors containing thiol groups [captopril or SQ 14 225 and 2-(2'-hydroxyphenyl)-3-(3-mercaptopropanoyl)-4-thiazolidine carboxylic acid or SA 446] both produced a mixed competitive and non-competitive pattern of inhibition with increased apparent Km and decreased Vmax.. 7. It is possible that thiol-containing inhibitors might produce non-competitive inhibition of converting enzyme by forming strong bonds with zinc near the active site of the enzyme.

3-Mercaptopropionic Acid↗
PubMed1985

Influence of blood gases, Ca2+-entry blockade and angiotensin converting enzyme inhibition on pressor responses to alpha-adrenoceptor agonists: evidence in vivo for subtypes of response independent of receptor subtype?

The pressor responses in the pithed rat to alpha-adrenoceptor agonists can be modified by alterations in arterial blood gas levels or by drugs which interfere with excitation-contraction coupling processes in the vascular smooth muscle, e.g. Ca2+-entry blockers or angiotensin converting enzyme (ACE) inhibitors. However, the extent of these influences depends on which agonist is used. The pressor response to intravenous injection of alpha-adrenoceptor agonists consists of two phases: an initial rapid but transient response (phase I) is followed by a response of slower onset but longer duration (phase II). We have examined the effects of manipulation of arterial blood gases, a Ca2+-entry blocker, nifedipine, and an ACE inhibitor, teprotide, on the pressor responses to a series of alpha-adrenoceptor agonists. In each case, the effects showed selectivity for one or other of the two phases and the differences in susceptibility between agonists could be explained by the relative sizes of the two phases in their responses. In general, phase II was more susceptible to alkalosis, nifedipine and teprotide, so that drugs in which this component predominated were more susceptible to these factors. In contrast there was no direct correlation with the receptor subtypes activated by the agonists.

Adrenergic alpha-Agonists↗
PubMed1980

Specific inhibition of renin by an angiotensinogen analog: studies in sodium depletion and renin-dependent hypertension.

The angiotensin substrate analog Pro-His-Pro-Phe-His-Phe-Phe-Val-Tyr-Lys has no significant effect on blood pressure in sodium-replete monkeys (Macaca fascicularis) but blocks the pressor response to infused human renin. Pressor responses to angiotensin I and angiotensin II are not attenuated. In five studies in sodium-depleted monkeys, an infusion of 2 mg of the peptide per kg of body weight resulted in a reduction of mean arterial pressure (MAP) from 105 +/- 4 to 79 +/- 3 mm Hg, which is not significantly different from the response to 1 mg of the angiotensin I-converting enzyme inhibitor teprotide per kg. In uninephrectomized monkeys, inflation of a suprarenal aortic cuff caused an increase in MAP from 107 +/- 3 to 131 +/- 3 mm Hg. Infusion of 0.6 mg of the renin-inhibitory peptide per kg was followed by a return of blood pressure to 107 +/- 4 mm Hg--a depressor response similar to that observed with teprotide. This specific in vivo inhibitor of renin can now be applied to a wide variety of physiologic studies.

Angiotensin I↗
PubMed1990

A new experimental model for measurement of pulmonary arterial haemodynamic variables in conscious rats before and after pulmonary embolism and during general anaesthesia.

STUDY OBJECTIVE: The aim of the study was to develop a new animal model of pulmonary arterial hypertension allowing direct measurement of pulmonary artery pressure in conscious chronically instrumented rats. DESIGN: Pulmonary artery pressure was measured via a pulmonary artery catheter, and cardiac output by thermodilution with a thermistor probe in the aortic arch, allowing determination of stroke volume and total pulmonary arterial resistance. Pulmonary hypertension was induced by fractionated injections of latex microspheres into pulmonary circulation, causing an increase in mean pulmonary pressure of 13.7 mm Hg (p less than 0.001). To test the regulatory influence of the renin system on the pulmonary vascular bed, one group of rats received an intravenous bolus injection of the angiotensin converting enzyme inhibitor teprotide 1 mg x kg-1 24 h after pulmonary embolism. The effect of general barbiturate anaesthesia was also investigated. SUBJECTS: Experimental animals were male Wistar rats, 300-350 g weight. They were studied in groups of 6-8. MAIN RESULTS: Following pulmonary embolism there was no significant difference in haemodynamic variables between control and teprotide treated rats. General anaesthesia caused an 11% fall in mean pulmonary artery pressure (p less than 0.01) and a 32% decrease in cardiac index (p less than 0.01). CONCLUSIONS: (1) The renin-angiotensin system has no important role in the regulation of pulmonary resistance vessels 24 h after pulmonary embolism; (2) the negative inotropic effect of anaesthesia has major implications for interpretation of results obtained in animals under general anaesthesia; and (3) the results emphasise the need to study haemodynamic variables in conscious chronically instrumented, fully recovered, animals.

Anesthesia, General↗
PubMed1984

Blood pressure effects of renin inhibition by human renin antiserum in normotensive marmosets.

The effects on blood pressure of an antiserum against pure human kidney renin were studied in conscious and anesthetized (pentobarbital, 24 mg X kg-1 i.p.) small new world monkeys (common marmosets). The antiserum inhibited the enzymatic activity of renin by 50% in a dilution of 1:45,000 in marmoset and 1:50,000 in human plasma. The antiserum (0.2 ml i.v.) decreased blood pressure in conscious marmosets on normal sodium intake by 15 +/- 5 (SD) mmHg and after salt depletion by 31 +/- 13 mmHg. A converting enzyme inhibitor (teprotide, 2 mg X kg-1 i.v.) induced a comparable fall in blood pressure: -16 +/- 10 and -30 +/- 10 mmHg, respectively. Similar effects were observed on blood pressure of anesthetized marmosets. The correlation between pretreatment plasma renin concentration and the maximum fall in blood pressure was significant and identical for the experiments with antiserum and teprotide. These results demonstrate that antisera against human renin can be used for the specific blockade of the renin-angiotensin system in primates. In normotensive marmosets the renin-angiotensin system participates in the maintenance of blood pressure, to a degree depending on the state of sodium balance.

Anesthesia, General↗
PubMedDate not supplied

Decreased vascular responsiveness produced by angiotensin-converting enzyme inhibitors in the rat isolated kidney.

The effects of three angiotensin converting enzyme (ACE) inhibitors - captopril, MK-421 diacid, and teprotide - on renal vascular responses to graded (50, 100, 200 ng) injections of norepinephrine (NE) were examined in rat isolated perfused kidneys, having a mean basal perfusion pressure of 78 +/- 10 mm Hg. The minimum dose of captopril (0.05 microgram/ml, low dose) that abolished the vasoconstrictor responses to 100 and 200 ng angiotensin I did not affect NE-induced renal vasoconstriction, whereas a dose 100 times greater (high-dose captopril, 5 micrograms/ml) reduced the vasoconstrictor action of NE. MK-421 diacid also at high dose (1 microgram/ml), caused similar reduction in renal vasoconstrictor responses to NE. In contrast, a high dose of teprotide (50 micrograms/ml) did not affect renal vascular responsiveness to NE. The threshold dose of NE that released prostaglandins, measured by bioassay, was 50 ng. Indomethacin (1 microgram/ml) prevented NE-induced release of prostaglandins but did not affect the ability of captopril to attenuate NE-induced vasoconstriction. We conclude that captopril and MK-421 diacid decreases vascular reactivity in the rat isolated kidney by a mechanism independent of ACE inhibition and unrelated to a prostaglandin-dependent vascular mechanism. Moreover, the presence of mercapto function in the ACE inhibitor is not essential since captopril, which has a sulfhydryl group, and MK-421 diacid, which lacks this group, have similar effects on renal vascular responsiveness.

Angiotensin I↗
PubMed1984

The inhibition of rat renin in sodium depleted and renal hypertensive rats. Comparison of purified antibodies or Fab fragments against mouse submaxillary renin with SQ 20881, and the effect on blood pressure homeostasis.

Studies were undertaken in order to demonstrate the role of the renin-angiotensin system for blood pressure homeostasis in sodium depleted and renal hypertensive (acute and chronic) rats. Purified antibodies and Fab fragment against mouse submaxillary were able to complete inhibited plasma activity in rats. The depressor response was compared with the converting enzyme inhibitor teprotide SQ20881. Teprotide, showed an additional depressor response indicating that effect of converting enzyme blockade is due to factors other than renin-angiotensin blockade.

Animals↗
PubMed1983

Purification and characterization of enkephalinase, angiotensin converting enzyme, and a third peptidyldipeptidase from rat brain.

Three distinct peptidyldipeptidases (exopeptidases releasing carboxyl terminal dipeptide residues) can be solubilized from nerve terminal membrane fractions from whole rat brain or striatum, and separated by ion exchange chromatography. Brain angiotensin-converting enzyme (PDP-1) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin, and is markedly inhibited by several specific inhibitors such as captopril, teprotide, and MK-422. Enkephalinase (PDP-2) cleaves 80 nM [3H-Tyr1, Leu5]-enkephalin, but not Hip-His-Leu; it is not inhibited by any of the standard competitive inhibitors of angiotensin-converting enzyme (all analogs of carboxyl-terminal peptide sequences Phe-Ala-Pro or Ala-Pro), but is strongly inhibited by captopril analogs such as thiorphan (Phe-Gly analog). A third peptidyldipeptidase (PDP-3) cleaves Hip-His-Leu, but not 80 nM [3H-Tyr1, Leu5]-enkephalin; it is inhibited by dipeptide analog inhibitors such as captopril and thiorphan, but not by longer peptides such as teprotide or tripeptide analog inhibitors such as MK-422. Both PDP-2 (enkephalinase) and PDP-3 are apparently present in nerve terminal membranes predominantly as inactive proenzyme precursors, which elute from DEAE-cellulose at high salt concentration, and are activated very slowly by a process involving one or more trypsin-like enzymes. Rechromatography of activated PDP-2 and PDP-3 achieves a nearly complete separation of the two enzymes, both markedly purified, since each is much less acidic than its proenzyme precursor. Purified enkephalinase does not appear to have any significant endopeptidase activity. It cleaves Hip-Phe-Arg 200 times more effectively than Hip-Phe-Arg-NH2, and appears to be quite selective for cleaving the terminal dipeptide residue, Phe-Arg, from bradykinin, with no release of the second dipeptide and no cleavage of the Gly4-Phe5 interior peptide bond.

Animals↗
PubMed1982

Determinants of acute and long-term response to converting enzyme inhibitors in congestive heart failure.

In 42 patients with moderate-to-severe congestive heart failure (CHF), the acute hemodynamic and neurohumoral response to the converting enzyme inhibitors (CEIs) captopril (CPT) and teprotide were measured. Plasma renin activity (PRA) was elevated and correlated with control plasma norepinephrine (PNE) but not with any of the control hemodynamics. Acutely after CEIs, significant (p less than 0.001) decreases in right atrial pressure, pulmonary artery pressure (PAP), capillary wedge pressure (PCWP), mean arterial pressure (MAP), total systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), and heart rate (HR, p less than 0.002), as well as an increase in cardiac index (p less than 0.001), were observed. Control PRA correlated with the degree of hemodynamic change for PAP (r = -0.64), PCWP (r = -0.66), SVR (r = -0.61), and PVR (r = -0.61). Long-term CPT therapy in 12 of these patients resulted in symptomatic improvement and a marked increase in exercise tolerance (7.4 to 10.4 minutes, p less than 0.009). These data suggest that CEIs effect beneficial acute hemodynamic improvements in depressed left ventricular function, leading to substantial reduction in disabling symptomatology and augmentation of exercise capacity in patients with stable severe CHF. Thus, CPT appears to provide well-tolerated, effective long-term ambulatory vasodilator therapy for advanced cardiac dysfunction.

Adult↗
PubMed1982

Renal response to angiotensin-converting enzyme inhibition.

Angiotensin-converting enzyme inhibitors, both teprotide and captopril, induce a potentiated renal vascular response in patients with essential hypertension, and with that a consistent increase in sodium excretion and occasionally an increase in glomerular filtration rate. In patients with advanced congestive heart failure resistant to other vasodilators, a similar triad occurs. It is not yet clear in which settings the renal response to angiotensin-converting enzyme inhibition reflects a reduction in angiotensin II formation--thus implicating the renin-angiotensin system in the pathogenesis--or an additional action, such as a potentiation of the local actions of bradykinin or enhanced prostaglandin formation. Under some circumstances, especially where a qualitatively and quantitatively similar response occurs to angiotensin antagonists and angiotensin-converting enzyme inhibitors or where an angiotensin antagonist prevents an additional response to a converting enzyme inhibitor, it is clear that the specific action of the converting enzyme inhibitor on angiotensin II formation is responsible. Unfortunately, for most responses in animal models and all responses in patients, such rigorous evidence is not yet available.

Angiotensin-Converting Enzyme Inhibitors↗