Angiotensin-converting Inhibitors Research Articles

Manejo del infarto de miocardio en España (1995-99). Datos del registro de infartos de la Sección de Cardiopatía Isquémica y Unidades Coronarias (RISCI) de la Sociedad Española de Cardiología

Limited information is available on how patients with myocardial infarction are treated in Spain. In order to make up for this deficiency, in October 1994, the Ischaemic Heart Disease Working Group of the Spanish Society of Cardiology initiated a myocardial infarction registry, which is currently active. Patients are recruited from hospitals with intensive coronary care facilities. Demographic characteristics coronary risk factors and previous conditions are collected, as well as clinical events, and diagnostic and therapeutic procedures performed during the stay in the coronary care unit. From 1995 to 1999, 28,357 patients were registered. During this period the mean age increased slightly (from 64.4 +/- 12.2 to 65.2 +/- 12.7; p < 0.001), although the male proportion remained stable (from 76.7% to 77.1%). The median "onset of symptoms-hospital arrival for 1st emergency" time fell from 135 min to 120 min, and the median "onset of symptoms-needle" time from 180 to 175 (NS). The use of thrombolytic therapy did not change (from 42.4 to 43.9%), but the use of aspirin (from 87.4 to 91.7%), beta-blockers (from 32.7 to 39.6%) and angiotensin-converting inhibitors (from 27.9 to 34.8%) increased significantly (p < 0.001). The Swan-Ganz catheter and the intra-aortic balloon counterpulsation were rarely placed during the five years (4.2% and 1.2% respectively in 1999). Both early mortality (11.4 to 9.3%) and the median duration of intensive coronary care stay declined, in these 5 years. In Spain, during the 1995-1999 period, the use of aspirin, beta-blockers, and angiotensin-converting inhibitors increased significantly during the acute phase of infarction in the coronary care unit. However, both the usage of thrombolytic therapy and the delay between the onset of symptoms and therapy initiation remained unchanged. At the same time, the length of stay in the coronary care unit and early mortality declined, although the clinical profile of the patients did not improve.

Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the U.S. from 1990 through 1999: The National Registry of Myocardial Infarction 1, 2 and 3

OBJECTIVESWe sought to determine trends in the treatment of myocardial infarction from 1990 through 1999 in the U.S. and to relate these trends to current guidelines.BACKGROUNDLimited data are available to show how recent clinical trials and clinical guidelines have impacted treatment of myocardial infarction.METHODSTemporal trends in myocardial infarction treatment and outcome were assessed by using data from 1,514,292 patients in the National Registry of Myocardial Infarction (NRMI) 1, 2 and 3 from 1990 through 1999.ResultsDuring this interval, the use of intravenous thrombolytic therapy declined from 34.3% to 20.8%, but the use of primary angioplasty increased from 2.4% to 7.3% (both p = 0.0001). The median “door-to-drug” time among thrombolytic therapy recipients fell from 61.8 to 37.8 min (p = 0.0001), primarily owing to shorter “door-to-data” and “data-to-decision” times. The prevalence of non–Q wave infarctions increased from 45% in 1994 to 63% in 1999 (p = 0.0001). From 1994 through 1999, there was increased usage of beta-blockers, aspirin and angiotensin-converting inhibitors, both during the first 24 h after admission and on hospital discharge (all p = 0.0001). Between 1990 and 1999, the median duration of hospital stay fell from 8.3 to 4.3 days, and hospital mortality declined from 11.2% to 9.4% (both p = 0.0001).CONCLUSIONSThe NRMI data from 1990 through 1999 demonstrate that the recommendations of recent clinical trials and published guidelines are being implemented, resulting in more rapid administration of intravenous thrombolytic therapy, increasing use of primary angioplasty and more frequent use of adjunctive therapies known to reduce mortality, and may be contributing to the higher prevalence of non–Q wave infarctions, shorter hospital stays and lower hospital mortality.

Reduction of cardiac endothelin-1 by angiotensin II type1 receptor antagonist in viral myocarditis of mice

Renin angiotensin system contributes to activation of circulating endothelin in congestive heart failure. To investigate the effects of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitors (ACEI) on the levels of endothelin-1 (ET-1), we administered orally angiotensin II type1 receptor (AT1) antagonist, L-158,809 (ATA) (6, 1.2 and 0.12 mg/kg/day), enalapril (1 mg/kg/day) and captopril (7.5 mg/kg/day) for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus (500 pfu/mouse) inoculation. Plasma ET-1, cardiac ET-1, heart weight (HW) and HW/ body weight (BW) ratio were examined and compared with infected untreated mice. Moreover, the HW (mg) and HW/BW (×10 −3) ratio were significantly (P<0.05) reduced in mice treated with ATA and ACEIs in comparison with infected control. ACEIs and higher dosed of ATA reduced myofiber hypertrophy. Both of plasma and cardiac ET-1 proteins were significantly elevated in infected control compared with uninfected normal mice. Plasma ET-1 was significantly (P<0.01) reduced in mice with three different concentrations of ATA but were not decreased in mice with captopril or enalapril compared with infected control. The expression of endothelin-1 mRNA was significantly reduced in mice with ATA in comparison with infected untreated mice by competitive RT-PCR. ATA reduced ET-1 protein and mRNA in the myocardium of mice with myocarditis, improving congestive heart failure and myofiber hypertrophy. We suggest the effect of ATA on the reduction of endothelin has a different pathway from angiotensin converting inhibitor and that ATA seems to be a useful agents for congestive heart failure due to viral myocarditis.

Angiotensin II attenuates renal cortical cyclooxygenase-2 expression.

We have previously shown that in rat renal cortex, cyclooxygenase-2 (COX-2) expression is localized to cTALH cells in the region of the macula densa, and that dietary salt restriction increases COX-2 expression. Administration of the angiotensin converting inhibitor, captopril, further increased COX-2 mRNA and renal cortical COX-2 immunoreactivity, with the most pronounced expression in the macula densa. Administration of an AT1 receptor antagonist, losartan, also significantly increased cortical COX-2 mRNA expression and COX-2 immunoreactivity. Mutant mice homozygous for both Agtr1a and Agtr1b null mutations (Agtr1a-/-,Agtr1b-/-) demonstrated large increases in immunoreactive COX-2 expression inthe cTALH/macula densa. To determine whether increased COX-2expression in response to ACE inhibition mediated increases in renin production, rats were treated with captopril for one week with or without the specific COX-2 inhibitor, SC58236. Plasma renin activity increased significantly in the captropril group, and this increase was significantly inhibited by simultaneous treatment with SC58236. Thus, these studies indicated that angiotensin II inhibitors augment upregulation of renal cortical COX-2 in states of volume depletion, suggesting that negative feedback by the renin-angiotensin system modulates renal cortical COX-2 expression and that COX-2 is a mediator of increased renin production in response to inhibition of angiotension II production.

Differential action of angiotensin II and activity of angiotensin-converting enzyme in human bypass grafts

Objective: The activity of the renin-angiotensin system may be important in determining the performance of coronary artery bypass grafts. We have examined the activity of tissue angiotensin-converting enzyme and the effects of angiotensin II in vessels used as bypass grafts. Methods: Organ bath studies were used to determine the vasoactive effect of angiotensin II. The activity of the angiotensin-converting enzyme was assessed by metabolism of a specific synthetic substrate. Results: The saphenous vein produced greater maximum responses to angiotensin II than did the internal thoracic artery. This response was not modified by inhibition of nitric oxide synthase, cyclooxygenase, or by an endothelin receptor antagonist in either vessel. Losartan, an AT 1 receptor antagonist, inhibited the vasoconstrictor response in both blood vessels. Homogenates of saphenous vein and internal thoracic artery displayed tissue angiotensin-converting enzyme activity, which was inhibited by captopril. Enzyme activity was threefold greater in the vein. Both the contractile response to angiotensin II and the enzyme activity were retained in venous grafts removed up to 20 years after coronary bypass surgery. Conclusions: These data demonstrate that marked differences exist in angiotensin-converting enzyme activity and AT 1 receptor responses in the saphenous vein compared with the internal thoracic artery. These findings may have important implications for the performance of the vein when used as a coronary artery bypass graft and may have clinical implications for the use of angiotensin-converting inhibitors and AT 1 receptor antagonists in the prevention and treatment of vein graft disease. (J Thorac Cardiovasc Surg 1998;116:206-12)

Renoprotection in diabetes: genetic and non-genetic risk factors and treatment.

Keywords Type I and Type II diabetes, microalbuminuria, diabetic nephropathy, antihypertensive treatment, angiotensin converting inhibition, renal progression promoters, insertion/deletion polymorphism of angiotensin converting enzyme gene, end stage renal failure, glycaemic control.

Cilazapril and Dietary Gamma-Linolenic Acid Prevent the Deficit in Sciatic Nerve Conduction Velocity in the Streptozotocin Diabetic Rat

Young adult male Hooded Wistar rats were rendered diabetic by administration of streptozotocin and maintained for 5 weeks on a diet containing either 6% olive oil as the total source of fat (OO diet), or purified gamma-linolenic acid (GLA) at a concentration of 0.5% with the remaining 5.5% provided by olive oil (GLA diet). Rats were treated with the angiotensin converting inhibitor, cilazapril, administered in the drinking water at a dose of 20 mg kg −1 body weight day −1. For the OO diet groups, sciatic nerve conduction velocity (NCV) in diabetic rats was reduced by 32% ( p < 0.01) in comparison with nondiabetic (vehicle-treated) rats and 27.5% ( p < 0.05) in comparison with diabetic rats treated with cilazapril. Diabetic, cilazapril-treated rats showed no reduction in NCV. For the nondiabetic, diabetic, and diabetic plus cilazapril groups fed GLA, the NCV was not significantly different, indicating that dietary GLA also prevented the deficit in the NCV induced by the diabetic state. Analysis of the sciatic nerve endoneurial phospholipid fatty acids revealed a significant reduction in the proportion of GLA and an elevation in the proportion of linoleic acid in the diabetic groups compared with the nondiabetic groups and this was independent of the cilazapril treatment or the dietary lipid supplement. Sciatic nerve myo-inositol content was unaltered while mannose, fructose, glucose, and sorbitol levels were elevated in the diabetic groups and these changes were independent of the cilazapril treatment or the dietary lipid supplement. These results indicate that in the rat, cilazapril treatment or dietary GLA, at the doses tested, are effective in preventing the deficit in the NCV induced by diabetes.

Presence and biochemical properties of a molluscan invertebrate angiotensin-converting enzyme

A soluble 65582.9 Da (in MALDI-TOF) angiotensin converting (ACE)-like enzyme has been purified by a captopril-Sepharose affinity column chromatography from the mollusk Mytilus edulis. This glycosylated peptidyl dipeptidase, with an N-terminal sequence of LDPELSPGCFVANQAGGQLF, hydrolyses the Phe8–His9 bond (at pH 8.4 and 37°C) of angiotensin I with a high catalytic activity i.e. Km: 168 μM and Kcat/Km: 262 s−1 mM−1. The hydrolysis of angiotensin I is inhibited by the specific ACE inhibitors captopril and lisonopril (Ic50=50 nM). This activity is increased by Cl− (optimal Cl− concentration 400 mM) and by Zn2+. This zinc metallopeptidase also attacks peptides having a Gly–His, Gly–Phe or a Phe–His bond in their sequence e.g. leucine–enkephalin (Kcat/Km: 1200 s−1 mM−1) or bradykinin (Kcat/Km: 2500 s−1 mM−1). Mytilus ACE displays properties of the C-domain of human ACE, indicating a high degree of conservation during evolution. These results are consistent with an ACE activity implicated in metabolism of several neuropeptides in mollusks.

Contrasting effects of angiotensin converting inhibitor and alpha‐1‐antagonist on albuminuria in insulin‐dependent diabetes mellitus patients with nephropathy

The main aim of this study was to examine the effects of an angiotensin converting inhibitor, enalapril, and an alpha-1 (alpha-1) antagonist, doxazosin, on albumin excretion, renal haemodynamics and tubular function in insulin-dependent diabetes mellitus patients with nephropathy. The study consisted of a four-week run-in period, a four-week active treatment period, a four-week wash-out period and a second four-week active treatment period. The study was performed in the out-patient clinic at a university hospital. Ten patients with insulin dependent diabetes mellitus with macroalbuminuria (> 200 micrograms min-1), mild to moderate hypertension (diastolic blood pressure 85-115 mmHg) and serum creatinine level below 200 mumol L-1 were included in the study. The effect of the drugs on albumin and total protein excretion, beta-2-microglobulin, proximal tubular enzyme markers and renal haemodynamics. Systolic and diastolic blood pressure were equally reduced by both drugs. Enalapril reduced albumin excretion from 1090 +/- 281 micrograms min-1 to 742 +/- 246 micrograms min-1 (P < 0.01) and total protein excretion from 2.0 +/- 0.4 g per 24 h to 1.3 +/- 0.4 per 24 h whereas doxazosin was without effect. Glomerular filtration rate and effective renal plasma flow were unchanged by either drug. Doxazosin increased filtration fraction from 0.21 +/- 0.02 to 0.23 +/- 0.01 (P < 0.05). The urinary excretion of the proximal enzyme markers N-acetyl-beta-glucosaminidase and alkaline phosphatase were elevated as well as urinary excretion of beta-2-microglobulin. However, neither the excretion of beta-2-microglobulin nor the enzyme markers were affected by either drug. Enalapril, but not doxazosin, reduces albuminuria in insulin dependent diabetes mellitus patients with nephropathy. The drugs exert differential effects on renal haemodynamics.

Highlights of the Consensus Conference on Prevention of Progression in Chronic Renal Disease: Implications for Dietetic Practice

■ Objective: To determine implications for dietetic practice based on current recommendations from consensus conferences and scientific literature regarding prevention of progression in chronic renal disease. ■ Data sources: National Institutes of Health Consensus Conference, April 1994, and MEDLINE search of published literature 1970 through 1994. ■ Conclusions: Evidence supports the use of protein-modified diets, blood pressure control, renal protective effects of angiotensin-converting inhibitors, and tight glycemic control for insulin-dependent diabetics to delay the progression of renal failure.

Cardiac rehabilitation 1992.

The goal of cardiac rehabilitation is to optimize function through attention to the patient's medical needs, risk factors for recurrent events, physical reconditioning, and psycho-social needs. Medical needs include beta-adrenergic blocking agents and aspirin unless contraindicated, angiotensin converting inhibitors for left ventricular dysfunction, and relief of residual ischemia. Smoking, lipid abnormalities, physical inactivity, and hypertension remain important predictors of reinfarction and death and must be controlled. Obesity must be addressed because it exacerbates these problems. Therefore, the principles of behavior change should be applied to help patients control their risk factors and adopt healthy lifestyles. Smoking cessation and appropriate dietary behaviors can be adopted by the patient while in the hospital. Physical reconditioning can also begin with twice-daily exercises. After discharge from hospital and after an initial submaximal exercise evaluation, the patient will benefit from three sessions per week of outpatient cardiac rehabilitation for six to eight weeks. These sessions should last about an hour and raise the patient's heart rate as much as 30 beats per minute. Along with physical reconditioning, the cardiac rehabilitation program provides an opportunity to address risk factor modification, return to work, return to sexual activity, management of depression and anxiety, and the presence of risk factors in the patient's family. The patient should attend reinforcing sessions every three months for the first year and as necessary after that to control risk factors and reinforce the necessity for physical fitness.

Are the renal haemodynamic and natriuretic effects of calcium antagonists and angiotensin converting inhibitors additive?

Are the renal haemodynamic and natriuretic effects of calcium antagonists and angiotensin converting inhibitors additive?

Severe Hypertension with Segmental Renal Infarction Following Surgical Removal of a Retroperitoneal Malignant Hemangiopericytoma: A Case Report

Severe hypertension developed in a fifty-five year-old woman after surgical removal of a retroperitoneal tumor, when the renal artery was injured. Renal arteriography after the surgery demonstrated a segmental infarction of the right kidney. A close relationship between activation of the renin-angiotensin system and the development of severe hypertension was observed. Satisfactory control of blood pressure concomitant with reduction of plasma renin activity was achieved by a combination of an angiotensin-converting anzyme inhibitor, beta-blocking agent, and calcium-entry blocker. The mechanism of activation of the renin-angiotensin system in renal infarction is discussed.

Are the renal haemodynamic and natriuretic effects of calcium antagonists and angiotensin converting inhibitors additive?

Are the renal haemodynamic and natriuretic effects of calcium antagonists and angiotensin converting inhibitors additive?

The effects of lowering of blood pressure on pain sensitivity in spontaneously hypertensive rats

It has been reported that elevation of blood pressure produces a reduction in pain sensitivity. This study was designed to clarify the correlation in spontaneously hypertensive rats (SHR) between fall in blood pressure and pain sensitivity. In seven-weeks-old male SHR, the angiotensin converting inhibitor delapril (10 mg/kg/day) or calcium antagonist nifedipine (3 mg/kg/day) was administered orally every day for 8 weeks. Systolic blood pressure (SBP) pretreatment was significantly higher in the SHR than in normotensive Wistar-Kyoto (WKY) rats and pain sensitivity measured with the hot plate method was significantly lower in the SHR than in the WKY rats. Administration of both drugs produced a significant suppression of elevation of SBP, and produced a significant elevation of pain sensitivity. Furthermore, at 8 weeks after drug administration, urinary norepinephrine (UNE) significantly decreased and plasma beta-endorphin (beta-end) significantly increased. A significant correlation was noted between pain sensitivity and SBP and also between pain sensitivity and UNE. Of these, pain sensitivity was the more closely correlated to degree of change in UNE than to degree of change in SBP. It appears that elevation of pain sensitivity is due to suppression of the sympathetic nervous system by antihypertensive drugs, but not to elevation of beta-end levels. These data suggest that a fall in blood pressure through administration of delapril or nifedipine reverses decrease in pain sensitivity in SHR and that decrease in sympathetic tone plays an important role in the restoration of levels of sensitivity to pain.

Clinical Pharmacokinetics of the Newer ACE Inhibitors

The orally active angiotensin-converting inhibitors (ACE inhibitors) such as captopril and enalapril represent a significant therapeutic advance in the treatment of hypertension and congestive heart failure. Enalapril differs from captopril in several respects. It is a prodrug converted by hepatic esterolysis to the active (but more poorly absorbed) diacid, enalaprilat. Enalaprilat is more potent than captopril, more slowly eliminated and does not possess a sulfhydryl (SH) group. Enalapril was rapidly followed by a number of newer ACE inhibitors, the majority of which are similar to enalapril in that they are prodrugs, converted by hepatic esterolysis to a major active but poorly absorbed diacid metabolite. In one case (delapril) there are 2 active metabolites; in another (alacepril) the prodrug is converted in vivo to captopril. Lisinopril is an exception in that it is an enalaprilat-like diacid but with acceptable oral bioavailability, so that the prodrug route is not employed. The newer ACE inhibitors are at widely different stages of development, and it is not yet clear how many will reach regular clinical use. Of these newer drugs, lisinopril is the longest established and is the subject of the widest published literature. For a number there is as yet little published pharmacokinetic information. A variety of assay methods have been employed to characterise the pharmacokinetics of the ACE inhibitors, including enzymatic techniques, radioimmunoassay and chromatography. The peak plasma concentrations of the prodrugs are generally observed at around 1 hour and those of the diacid metabolites at about 2 to 4 hours. However, there is considerable variation within and between drugs, with benazepril and benazeprilat reaching peak concentrations early and enalapril and enalaprilat typical of later times to peak. Absorption of the active diacids is generally poor, and moderate (typically 30 to 70%) for the prodrugs. The bioavailability of lisinopril is about 25%. It is difficult to talk meaningfully about half-lives of the active drugs. The declines in their plasma concentrations are polyphasic and, if analytical sensitivity allows, active drug may be found at 48 hours or more following administration. This may reflect binding to ACE in plasma. Half-lives of accumulation are of the order of 12 hours; protein binding varies from little (lisinopril) to 90% (benazeprilat). Elimination is mostly renal but there may be biliary elimination for some, such as benazeprilat and fosinopril. The half-lives of the prodrugs are short. Impaired renal function decreases the elimination rate of the diacids.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin-converting enzymeI inhibitors: Are there significant clinical differences?

Editorial sur l'ensemble de la classe des inhibiteurs de l'angiotensin converting enzyme: efficacite dans le traitement de l'insuffisance cardiaque, mecanisme action (systeme renin-angiotensin), etude comparative

Cardiac and renovascular effects in the anaesthetized dog of BW A575C: a novel angiotensin converting enzyme inhibitor with beta-adrenoceptor blocking properties.

1. In the anaesthetized open-chest dog, BW A575C (N-(1-(S)-carboxy-5-[4(3- isopropylamino-2-(R,S)-hydroxypropoxy)indole-2- carboxamido]pentyl)-(R,S)-alanyl-(S)-proline) causes a dose-dependent inhibition of the isoprenaline response (increased cardiac rate). In this preparation BW A575C is approximately 50 times less active than propranolol, and 500 times less active than pindolol at the cardiac beta 1-adrenoceptor. 2. At equieffective cardiac beta 1-adrenoceptor blocking doses in the anaesthetized, open-chest dog, BW A575C (5.0 mg kg-1, i.v.) significantly reduces diastolic blood pressure and reduces cardiac contractility and rate. By contrast, propranolol (0.1 mg kg-1, i.v.) and pindolol (0.01 mg kg-1, i.v.) have little effect on diastolic blood pressure, but significantly reduce cardiac contractility and rate. The effects of BW A575C on cardiac rate are not significantly different from those of propranolol and pindolol, but its effects on cardiac contractility are significantly less than those of propranolol. BW A575C also produces some increase in left ventricular internal dimensions at end-diastole. This small cardiac dilatation is not significantly different from that observed with pindolol but is significantly less than that of propranolol. 3. In the anaesthetized closed-chest dog, BW A575C causes a dose-dependent inhibition of the angiotensin I pressor response. In this preparation BW A575C is approximately equiactive with enalapril at preventing the pressor response due to conversion of exogenous angiotensin I to angiotensin II (inhibition of angiotensin converting enzyme (ACE)). 4. At equieffective ACE-inhibition doses in the anaesthetized, closed-chest dog, BW A575C (1.0 mg kg-1 by i.v. infusion) significantly reduces diastolic blood pressure, cardiac contractility and rate, whereas enalapril (1.0 mg kg-1 by i.v. infusion) only significantly reduces diastolic blood pressure. This blood pressure lowering effect of enalapril is not significantly different from that of BW A575C. In this preparation BW A575C and enalapril also significantly increase renal blood flow, and renal excretion of urine and Na+. There is however no significant difference between their renovascular effects. 5. These studies demonstrate that BW A575C produces changes in cardiac and renovascular function which can be ascribed to its being an ACE-inhibitor and a beta-adrenoceptor blocking agent. The combination of these pharmacological properties results in a fall in blood pressure without compromising either cardiac performance or renal function.

The future of angiotensin-converting enzyme inhibitors.

After a brief introduction summarizing their historical development and the classification of angiotensin-converting enzyme inhibitors by chemical structure, the considerations involved in developing new and improved drugs of this pharmacologic class are discussed. These include properties such as the drug's potency, route of absorption and excretion, pharmacokinetics, drug disposition, and toxicity. Although increased potency, a traditional method for improving efficacy, can be achieved with angiotensin-converting inhibitors by introducing additional binding sites or by increasing the strength of binding at existing sites, safety testing has shown that with some compounds this approach may cause nephrotoxicity. Because renal disease is a common cause of hypertension and the two conditions frequently coexist, in some patients agents that are eliminated by both renal and hepatobiliary routes may be more desirable than those eliminated almost exclusively by the kidneys, such as captopril. This and other shortcomings of captopril have led to the development of two new angiotensin-converting enzyme inhibitors, zofenopril and fosfenopril, which are both in the early phase of clinical investigation. The former is an analog of captopril and the latter is classified as a first phosphinic acid angiotensin-converting enzyme inhibitor. Another possibility for the future is the incorporation of two therapeutic objectives into a single compound in the form of an angiotensin-converting enzyme inhibitory diuretic which, although chemically feasible, may be of questionable practical value. Also, the success of blood pressure control through intervention at the level of the renin-angiotensin-aldosterone system has created interest in the development of renin inhibitors. The primary stimulus for this avenue of investigation was the specificity of renin, which has only one substrate while converting enzyme has many.

Central cardiovascular effects of SQ 14,225, an angiotensin-converting enzyme inhibitor in chloralose-anesthetized cats

Experiments were conducted in chloralose-anesthetized cats to investigate the central and peripheral cardiovascular effects of a new orally active angiotensin-converting inhibitor, SQ 14,225 (3-mercapto-2-D-methylpropanoyl-L-proline). I.v. administration of SQ 14,225 (0.31-3100 microgram/kg) antagonized the pressor responses to angiotensin I (AI) (310 ng/kg) i.v. in a dose-related manner but did not alter responses to angiotensin II (AII) (200 ng/kg) i.v. Similarly, intracerebroventricularly (i.c.v.) administered SQ 14,225 (0.31-310 microgram/kg perfused over 10 min) produced dose-related decreases in the centrally mediated pressor responses and heart increases elicited by AI (310 ng/kg) i.c.v. The central responses to AII (200 ng/kg) i.c.v. were not affected by SQ 14,225. Passage of SQ 14,225 out of the ventricular system into the systemic circulation was detected, but only at doses greater than that required to antagonize central AI responses. Doses of SQ 14,225 (310 microgram/kg and 3.1 mg/kg) i.v. which maximally inhibited i.v. AI responses, had no effect upon central AI activity. This finding suggests that passage of SQ 14,225 across the blood brain barrier into the central nervous system is restricted. Peripheral or central administration of SQ 14,225 produced only minimal transient decreases in blood pressure (less than 10 mm Hg). The results of these studies indicate that SQ 14,225 is a potent inhibitor of AI conversion in the brain as well as in the peripheral circulation.