Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which the angiotensin converting enzyme inhibitor, teprotide (SQ 20881), lowers blood pressure was assessed in anesthetized normotensive and spontaneously hypertensive (SHR) rats. Teprotide always was administered at a maximally effective dose of 1 mg/kg. In six normal Wistar rats, teprotide lowered blood pressure only after sodium depletion, an effect which was abolished by bilateral nephrectomy. Saralasin infusion (5 microgram/kg/min) into salt-depleted normal rats induced a blood pressure effect similar to that of teprotide. When administered in addition to saralasin infusion, teprotide did not reduce blood pressure further in normal rats or in SHR. When blood pressure of normal rats was raised by angiotensin II infusion (200 ng/kg/min), teprotide did not affect the induced blood pressure increase. In contrast, the pressure rise induced by angiotensin I infusion (230 ng/kg/min) was reversed by saralasin, but again concomitant administration of teprotide did not induce further blood pressure reduction. Thus, under the particular conditions of the present study, teprotide did not appear to exert its hypotensive effect by any mechanism other than inhibition of the renin-angiotensin system. Furthermore, given at a maximally effective dose to the rat, it produced no greater vasodepressor effect than did saralasin.
 ...
PMID:Mechanism of blood pressure reduction by teprotide (SQ 20881) in rats. 65 Nov 28

A highly active angiotensin-producing enzyme (enzyme III) was obtained from the serum of bilaterally nephrectomized dogs by acid treatment and ammonium sulfate fractionation. An inactive precursor (proenzyme III) was converted to enzyme III during prolonged storage (or by treatment with acid or with cathepsin G or by incubation at 38 degrees C as described in the following paper). Enzyme III reacted maximally at pH 7.7 and it produced up to 400 ng of angiotensin II/mL serum/h (i.e., amounts 4000 times higher than that generated by the endogenous renin present in serum after bilateral nephrectomy). Enzyme III produced angiotensin II at identical rates when either dog angiotensinogen or angiotensin I was used as substrate, but the rate was 710 times higher with synthetic tetradecapeptide renin substrate. Enzyme III is not identical to renin, cathepsin G, tonin, enzyme I, enzyme II, the calcium-dependent angiotensin I-converting enzyme, or the calcium-independent carboxy peptidase, which acts by sequential cleavage of angiotensin I. Enzyme III was inhibited by alpha-1-antitrypsin, diisopropyl fluorophosphate, and lima bean trypsin inhibitor (hence it is a serine proteinase). It was not inhibited by Captopril, Teprotide, or Enalapril. It had been reported previously that cathepsin G released from neutrophil granulocytes, by producing high local concentrations of angiotensin II, may provide a mobile means for modulating blood flow in tissue microvasculature during the inflammatory response. The present study offers a new, additional pathway, by enzyme III, for a similar rapid formation of angiotensin II from serum protein substrate or angiotensin I.
 ...
PMID:Angiotensin II-producing enzyme III from acidified serum of nephrectomized dogs. 257 42

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)
 ...
PMID:Adverse reactions with angiotensin converting enzyme (ACE) inhibitors. 302 83

Effects of the pentapeptide renin inhibitor (RI-78; Phe(4Cl)-Phe-Val-Tyr-Lys-NH2) and the angiotensin converting enzyme (ACE) inhibitor (teprotide) on mean arterial pressure (MAP) were examined in conscious monkeys (M. fascicularis). In salt depleted normotensive monkeys with a MAP of 95 +/- 4 mmHg and plasma renin activity (PRA) of 15.9 +/- 2.7 ngAI/ml/h, a bolus injection of a dose of 375 micrograms/kg of RI-78 caused a prompt hypotensive effect. Maximal hypotensive action was seen within 1 min, and MAP returned to the basal level within 15 min. With this dose, MAP was reduced by 20 +/- 6 mmHg. Teprotide (1 mg/kg) decreased MAP and reached a nadir after 13 min. There was no significant difference between maximal hypotensive responses seen with RI-78 (375 micrograms/kg) and with teprotide (1 mg/kg). Hypotensive effects of RI-78 and teprotide were also examined in acute renal hypertensive monkeys with a MAP of 125 +/- 5 mmHg and a PRA of 27.1 +/- 5.7 ngAI/ml/h. Again, similar hypotensive effects were observed. We conclude that antihypertensive effect of RI-78 is comparable to that seen with teprotide.
 ...
PMID:Hypotensive effects of the renin inhibitor (RI-78) and the converting enzyme inhibitor (teprotide) in conscious monkeys. 303

Endopeptidase-24.11 (EC 3.4.24.11), purified to homogeneity from pig kidney, was shown to hydrolyse a wide range of neuropeptides, including enkephalins, tachykinins, bradykinin, neurotensin, luliberin and cholecystokinin. The sites of hydrolysis of peptides were identified, indicating that the primary specificity is consistent with hydrolysis occurring at bonds involving the amino group of hydrophobic amino acid residues. Of the substrates tested, the amidated peptide substance P is hydrolysed the most efficiently (Km = 31.9 microM; kcat. = 5062 min-1). A free alpha-carboxy group at the C-terminus of a peptide substrate is therefore not essential for efficient hydrolysis by the endopeptidase. A large variation in kcat./Km values was observed among the peptide substrates studied, a finding that reflects a significant influence of amino acid residues, remote from the scissile bond, on the efficiency of hydrolysis. These subsite interactions between peptide substrate and enzyme thus confer some degree of functional specificity on the endopeptidase. The inhibition of endopeptidase-24.11 by several compounds was compared with that of pig kidney peptidyldipeptidase A (EC 3.4.15.1). Of the inhibitors examined, only N-[1(R,S)-carboxy-2-phenylethyl]-Phe-p-aminobenzoate inhibited endopeptidase-24.11 but not peptidyldipeptidase. Captopril (D-3-mercapto-2-methylpropanoyl-L-proline), Teprotide (pGlu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) and MK422 [N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro] were highly selective as inhibitors of peptidyldipeptidase. Although not wholly specific, phosphoramidon was a more potent inhibitor of endopeptidase-24.11 than were any of the synthetic compounds tested.
 ...
PMID:The metabolism of neuropeptides. The hydrolysis of peptides, including enkephalins, tachykinins and their analogues, by endopeptidase-24.11. 614 47

Administration of Teprotide (SQ 20881), an angiotensin I-converting enzyme inhibitor for up to 10 weeks at a dose of 3 mg. per kg., subcutaneously, twice a day in the rat, effected no change in the ultrastructure of the adrenal cortex nor in the concentration of serum aldosterone. A significant increase (p less than 0.05) in renin granulation indices which was already apparent after 3 weeks of treatment with Teprotide was even more definitive after 10 weeks (p less than 0.01). Moderate renal hypertrophy was present in rats receiving the drug for 3 weeks. Findings pertaining to aldosterone production differed from those reported following acute administration of Teprotide wherein a decrease in the production of serum aldosterone and an increase in plasma renin activity was observed. It has been suggested that decreased aldosterone production following acute administration of Teprotide is a consequence of decreased stimulus of the zona glomerulosa due to diminished synthesis of angiotensin II. If this is the case, mechanisms other than angiotensin II stimulation of the zona glomerulosa must control aldosterone synthesis, perhaps through hormones of the adrenal cortex. Another possibility could be that angiotensin II synthesis may be obtained, after an interval, through an alternative pathway.
 ...
PMID:Failure of chronic administration of the angiotensin I-converting enzyme inhibitor, Teprotide (SQ 20881), to affect the ultrastructure of the adrenal cortex and the aldosterone secretion in the rat. 617 61

Experiments were carried out in anaesthetized rats to compare the abilities of angiotensin II (A II) and angiotensin III (A III) to reverse the effects of angiotensin converting enzyme inhibition (Teprotide) on salt and water excretion. In rats infused with Teprotide, significant increases in urine flow and sodium excretion were observed and arterial blood pressure decreased. Addition of A II (10 pmol min-1) to the Teprotide infusion reduced renal excretion of sodium and water to control values and excretion of potassium to below control. Blood pressure increased to a value significantly higher than that during the control period. In a separate group of rats the natriuretic and diuretic effects of Teprotide were reversed by a similar dose of A III (10 pmol min-1). A primarily angiotensin-mediated action is indicated for the renal effects of Teprotide. Although angiotensins II and III appeared to be equipotent in their abilities to reverse the renal responses to Teprotide, A II caused an increase in arterial blood pressure that was not seen with A III. In a third group of rats A II (10 pmol min-1) was added to the Teprotide infusion and an aortic snare located between the renal arteries was tightened to prevent any increase in left renal perfusion pressure. During this period the rate of sodium excretion from the left kidney was significantly lower than from the right kidney. It is concluded that in the absence of any accompanying 'pressure natriuresis' A II is more potent than A III in its ability to reverse the natriuretic action of Teprotide. The elevation of blood pressure to above control values by a dose of A II only just sufficient to reverse the Teprotide-induced natriuresis suggests that the concentration of angiotensin in the kidney is higher than in plasma and supports the concept of an intrarenal renin-angiotensin system. In the rat both A II and A III may affect renal salt and water excretion by a combination of mechanisms involving glomerular, vascular and tubular receptors. The possibility is raised that differential effects of the active angiotensins on these mechanisms may participate in the regulation of sodium excretion.
 ...
PMID:Reversal by angiotensins II and III of the effects of converting enzyme inhibition on renal electrolyte excretion in rats. 620 44