angiotensin-i and trandolapril

Angiotensin II (ANG II) is an important factor for the progression of renal diseases. ANG II has many pleiotropic effects on the kidney such as pro-inflammatory and profibrotic actions besides the well-known blood pressure-increasing effect.. Organs have local ANG II-generating systems that work independently from their classic systemic counterpart. Renal proximal tubular cells could generate and secrete ANG II into the urine in concentrations that are 10,000 times higher than those found in serum. These local systems are only incompletely blocked by currently used doses of ACE inhibitors or AT(1) antagonists. There are other enzyme systems besides ACE that contribute to the formation of ANG II. Alternative pathways generate peptides such as angiotensin 1-7 that have antagonistic effect compared with ANG II. Degradation products of ANG II such as angiotensin IV bind at separate receptors and could mediate fibrosis. The discovery of AT(1) receptor dimers and agonistic antibodies against AT(1) receptors contributes to the complexity of the system.. The complexity of the renin-angiotensin-aldosterone system (RAAS) implies that dual blockade with ACE inhibitors and AT(1) receptor antagonists makes sense for pathophysiological reasons. First clinical studies have shown that such as dual therapy reduces progression of chronic renal disease more efficiently that the respective monotherapies in certain risk populations. This shows that novel pathophysiological data could lead to innovative clinical treatment strategies.

Topics: Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chronic Disease; Chymases; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Drug Therapy, Combination; Humans; Indoles; Kidney Diseases; Kidney Tubules, Proximal; Losartan; Prospective Studies; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Serine Endopeptidases

The new ACE inhibitor trandolapril was administered to normal volunteers at daily doses of 0.5, 2, and 8 mg for 10 days. Twenty-one volunteers, aged 21-30 years, were included in the study. To randomly selected groups of seven subjects, each dose was administered in a single-blind fashion. None of the doses induced a consistent fall in blood pressure. Angiotensin-converting enzyme activity (ACE) was measured in vitro using three different synthetic substrates (i.e., Hip-Gly-Gly, Z-Phe-His-Leu, or angiotensin I). Although the degree of ACE inhibition assessed with the three methods varied widely, all methods clearly indicated dose-dependent ACE inhibition. These in vitro results were confirmed by measuring ACE inhibition in vivo using the ratio of plasma angiotensin II (ANG II) to blood angiotensin I (ANG I). The dose-dependent ACE inhibition was paralleled by a dose-dependent rise in active renin and blood angiotensin I levels, most evident on day 10. In contrast, plasma ANG II levels on day 10 were not different whether the volunteers received 0.5 or 8 mg trandolapril. Thus, whereas increasing doses of this new ACE inhibitor progressively enhanced the blockade of ACE activity, this was not reflected by additional reductions of plasma ANG II levels. The progressive enhancement of ACE inhibition seemed to be offset by the accentuation of the compensatory rise in renin and ANG I, which was still partially converted to ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Dose-Response Relationship, Drug; Heart Rate; Humans; Indoles; Iodine Radioisotopes; Renin; Renin-Angiotensin System

The brain renin-angiotensin system contributes significantly to progressive left ventricular (LV) dysfunction in rats after myocardial infarction (MI). The present study evaluated the effects of central versus peripheral plus central angiotensin-converting enzyme (ACE) blockade on sympathetic activity, and LV anatomy and function after MI.. Wistar rats were treated for 4 weeks after MI with the lipophilic ACE inhibitor trandolapril at 5 mg/kg/day or the hydrophilic blocker lisinopril at 50 mg/kg/day by once daily subcutaneous injection, or with a central infusion of lisinopril at 0.1 mg/kg/day.. At 24 hours after the last dose, subcutaneous trandolapril caused 70% to 80% ACE inhibition in both brain and kidneys; lisinopril caused 10% to 20% less. Central infusion of lisinopril caused 70% inhibition of brain ACE and minimal (6%) inhibition in the kidneys. All three treatments similarly improved sympathetic reactivity and arterial baroreflex function. All three treatments lowered cardiac Ang I and II, and similarly attenuated the increases in LV end diastolic pressure, circumference, and fibrosis. Both subcutaneous treatments further decreased LV peak systolic pressure and dP/dt max, whereas icv lisinopril caused no change.. Despite marked differences in the extent of peripheral blockade, all three treatments similarly affected sympathetic activity and decreased cardiac Ang II, preload and remodeling after MI. One may speculate that central and peripheral ACE-mediated mechanisms are sequential and therefore only minor additional effects of peripheral ACE blockade are noted.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Brain; Fibrosis; Hemodynamics; Indoles; Infusions, Intravenous; Injections, Subcutaneous; Kidney; Lisinopril; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Renin-Angiotensin System; Sympathetic Nervous System; Ventricular Dysfunction, Left

1. Inhibition of the renin-angiotensin system (RAS) improves symptoms and prognosis in heart failure. The experimental basis for these benefits remains unclear. We examined the effects of inhibition of ACE or blockade of angiotensin II type 1 (AT1) receptor on the haemodynamics, cardiac G-proteins, and collagen synthesis of rats with coronary artery ligation (CAL), a model in which chronic heart failure (CHF) is induced. 2. Rats were orally treated with the ACE inhibitor trandolapril (3 mg kg(-1) day(-1)) or the AT1 receptor blocker L-158809 (1 mg kg(-1) day(-1)) from the 2nd to 8th week after CAL. CAL resulted in decreases in the left ventricular systolic pressure and its positive and negative dP/dt, an increase in the left ventricular end-diastolic pressure, and the rightward shift of the left ventricular pressure-volume curve. Long-term treatment with either drug improved these signs of CHF to a similar degree. 3. Cardiac Gsalpha and Gqalpha protein levels decreased, whereas the level of Gialpha protein increased in the animals with CHF. Long-term treatment with trandolapril or L-158809 attenuated the increase in the level of cardiac Gialpha protein of the animals with CHF without affecting Gsalpha and Gqalpha protein levels. Cardiac collagen content of the failing heart increased, whose increase was blocked by treatment with either drug. 4. Exogenous angiotensin I stimulated collagen synthesis in cultured cardiac fibroblasts, whose stimulation was attenuated by either drug. 5. These results suggest that blockade of the RAS, at either the receptor level or the synthetic enzyme level, may attenuate the cardiac fibrosis that occurs after CAL and thus affect the remodelling of the failing heart.

Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Chronic Disease; Collagen; Dose-Response Relationship, Drug; Fibroblasts; GTP-Binding Proteins; Heart; Heart Failure; Heart Septum; Heart Ventricles; Hemodynamics; Imidazoles; Indoles; Lung; Male; Organ Size; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Tetrazoles

It was possible to assess that ACE inhibitors bound to two different sites on the enzymes which consist in two homologous domains. Accordingly, it was also shown that testis ACE which consists in a single domain exhibits only one site for inhibitors. The common binding site of both enzymes contains Zn2+, bears the enzymatic activity, is less sensitive to added Zn2+ and Cl- and has a lower affinity for inhibitors than the first one, found only in duplicated domain enzymes and highly sensitive to the effect of ions.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Binding Sites; Brain; Captopril; Cell Membrane; Indoles; Lung; Male; Peptidyl-Dipeptidase A; Pyrroles; Ramipril; Rats; Rats, Inbred Strains; Testis

Trandolapril (RU 44570), a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor chemically related to enalapril, and its diacid (RU 44403), were investigated for their ability to inhibit angiotensin-converting enzyme. Trandolapril attenuated angiotensin I (Ang I)-induced pressor responses following i.v. administration to rats and dogs with ID50 values of 13.1 +/- 1.3 and 21.1 +/- 2.3 micrograms/kg. RU 44403 produced corresponding values of 9.9 +/- 0.7 and 7.2 +/- 2.3 micrograms/kg. Trandolapril (3-300 micrograms/kg) produced a dose-related attenuation of Ang I-induced pressor responses (ID50 30 micrograms/kg) following oral administration to rats. Oral administration of trandolapril (30-1000 micrograms/kg) to dogs inhibited Ang I pressor responses for over 6 h. The depressor action of bradykinin in the rat was potentiated by i.v. trandolapril and RU 44403 with ED50 values of 5.5 +/- 0.8 and 4.9 +/- 0.3 micrograms/kg respectively. Trandolapril was 2.3-10-fold more potent than enalapril in all experiments, depending on species or route of administration. RU 44403 and MK 422 were approximately equipotent, implying that trandolapril was more readily hydrolysed than enalapril. Trandolapril (0.3-30 mg/kg) produced dose-related, long-lasting (greater than 24 h) reductions in blood pressure (BP) in spontaneously hypertensive rats (SHR) following oral administration. The anti-hypertensive effect was potentiated significantly in hydrochlorothiazide-pretreated SHR when the plasma renin activity was increased. Enalapril was 10-fold less potent than trandolapril in reducing BP. The anti-hypertensive action of trandolapril (3 mg/kg) was abolished in SHR that were bilaterally nephrectomized 24 h beforehand, but was maintained in SHR pretreated by indomethacin (5 mg/kg p.o.). Trandolapril (1 mg/kg i.v.) produced a modest and transient reduction in BP in anesthetized dogs. Trandolapril produced dose-related (30-1000 micrograms/kg) reductions in BP, total peripheral resistance and heart work in dogs pretreated with hydrochlorothiazide to increase plasma renin activity.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Hemodynamics; Indoles; Male; Rats; Rats, Inbred SHR; Rats, Inbred Strains