angiotensin-i and eprosartan

Studies in animals and humans indicate a role for kinins in the actions of angiotensin type 1 (AT1) receptor blockers. However, the effect of these compounds on kinin levels in humans is unknown.. We measured angiotensin (Ang), bradykinin (BK), and kallidin peptides in subjects with essential hypertension administered placebo, losartan (50 mg OD), and eprosartan (600 mg OD) in randomized order in a double-blind, 3-period, 3-treatment, crossover trial. Peptides were measured in arterial blood using high-performance liquid chromatography-based radioimmunoassays. Losartan increased blood levels of BK-(1-9) and hydroxylated BK-(1-9) by approximately 2-fold and reduced the BK-(1-7)/BK-(1-9) ratio by 55%. There was a trend for eprosartan to produce similar changes in bradykinin levels. There were no changes in blood kallidin levels. Both losartan and eprosartan increased plasma levels of Ang I, Ang II, and Ang-(2-8), and eprosartan increased Ang-(3-8) levels. Ang-(1-7) and Ang-(1-9) levels were unchanged. There was an associated 30% to 35% reduction in Ang II/Ang I ratio and 63% to 69% reduction in Ang-(1-7)/Ang I ratio. Plasma ACE activity was unchanged.. Losartan increases bradykinin levels. The reductions in BK-(1-7)/BK-(1-9), Ang II/Ang I, and Ang-(1-7)/Ang I ratios suggest that the increased bradykinin levels were the result of reduced metabolism by ACE and neutral endopeptidase. Increased bradykinin levels may represent a class effect of AT1 receptor blockers that contributes to their therapeutic actions and may also contribute to the angioedema that may accompany this therapy.

Topics: Acrylates; Adolescent; Adult; Aged; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Bradykinin; Chromatography, High Pressure Liquid; Cross-Over Studies; Double-Blind Method; Female; Humans; Hydroxylation; Hypertension; Imidazoles; Kallidin; Losartan; Male; Middle Aged; Peptide Fragments; Radioimmunoassay; Thiophenes

Circulating angiotensin (Ang) II accumulates in adrenal tissue via binding to Ang II type 1 (AT1) receptors, reaching levels that are 15 to 20 times higher than in blood. Adrenal tissue contains a second renin transcript that gives rise to a truncated prorenin representing a cytosolic form of renin. Here we investigated what percentage of adrenal Ang II originates at adrenal tissue sites, and whether intracellular renin contributes to adrenal angiotensin production.. Concentrations of endogenous and iodine-125 (125I)-labeled Ang I and II were measured in adrenal tissue and blood from pigs after 125I-Ang I infusion.. In the adrenal tissue in all animals, 125I-Ang I was undetectable. In untreated pigs, adrenal 125I-Ang II was 17 +/- 1 times arterial 125I-Ang II, and tissue Ang I and II were 5 +/- 1 and 388 +/- 40 times higher than plasma Ang I and II. The AT1 receptor antagonist eprosartan reduced adrenal 125I-Ang II accumulation by 80%, and increased plasma Ang II to a greater degree than tissue Ang II. As a consequence, eprosartan equally reduced the tissue/plasma concentration ratios of both Ang II and 125I-Ang II. Captopril did not alter 125I-Ang II accumulation, and acutely, but not chronically, reduced the adrenal Ang II/I ratio.. More than 90% of adrenal Ang II originates at adrenal tissue sites. Local adrenal Ang II generation occurs extracellularly and is followed by internalization via AT1 receptor-mediated endocytosis. Enhanced angiotensin generation, combined with incomplete AT1 receptor blockade and the large adrenal AT1 receptor reserve, explains why eprosartan increased rather than decreased adrenal Ang II. Our data do not support angiotensin generation by truncated prorenin.

Topics: Acrylates; Adrenal Glands; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Chromatography, High Pressure Liquid; Female; Imidazoles; Infusions, Intra-Arterial; Iodine Radioisotopes; Male; Models, Biological; Renin-Angiotensin System; Swine; Thiophenes

Topics: Acrylates; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antihypertensive Agents; Benzimidazoles; Benzoates; Biphenyl Compounds; Clinical Trials as Topic; Germany; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Olmesartan Medoxomil; Placebos; Telmisartan; Tetrazoles; Therapeutic Equivalency; Thiophenes; Time Factors; Valine; Valsartan

His256 (HisVI:16) of transmembrane segment (TM)-VI of the rat angiotensin type 1 (AT1) receptor was targeted for mutagenesis to investigate its potential involvement in ligand binding. Substitution of His256 with alanine, phenylalanine, glutamine, or isoleucine did not affect the binding of either angiotensin II or nine different biphenylimidazole AT1 antagonists. In contrast, the binding affinity of the prototype imidazoleacrylic acid antagonist SKF-108,566 was reduced 15-fold by the exchange of His256 with alanine. Substitution of His256 with either isoleucine or phenylalanine yielded similar results, whereas a glutamine residue was able to substitute for His256, suggesting that the epsilon-nitrogen of His256 could be involved in the interaction with the imidazoleacrylic acid. To identify the chemical groups on SKF-108,566 that interact with His256 and with Asn295, a previously identified interaction point for nonpeptide antagonists located in TM-VII, we tested the binding of 15 analogs of SKF-108,566 in which different chemical moieties were systematically exchanged. The results indicated that the carboxyphenyl group of SKF-108,566 interacts with the imidazole side chain of His256. The data did not point to any particular contact group on the antagonist for Asn295. It is concluded that the imidazoleacrylic acid antagonists share some interactions in TM-VII of the AT1 receptor with the biphenylimidazole antagonists, but the binding of the imidazoleacrylic acid compounds is uniquely dependent on His256 in TM-VI, possibly through the carboxyphenyl moiety.

Topics: Acrylates; Amino Acid Sequence; Angiotensin I; Angiotensin Receptor Antagonists; Animals; Binding Sites; Cells, Cultured; Histidine; Humans; Imidazoles; Molecular Sequence Data; Mutagenesis; Rats; Receptors, Angiotensin; Thiophenes

Topics: Acrylates; Acute Kidney Injury; Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Cough; Dogs; Enalapril; Female; Glomerular Filtration Rate; Imidazoles; Male; Renal Circulation; Thiophenes

The antihypertensive activity of the nonpeptide angiotensin II receptor antagonist, SK&F 108566 (E)-alpha-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5- yl]methylene]-2-thiophene propanoic acid), was examined in rats and dogs. SK&F 108566 produced dose-dependent decreases in blood pressure in renin-dependent hypertensive rats. At 10 mg/kg intraduodenally, mean arterial blood pressure fell from between 150-160 mm Hg to approximately 124 mm Hg. A sustained infusion of SK&F 108566 at 25 micrograms/min intraduodenally normalized blood pressure during 3 days of infusion and for 18 h following cessation of the infusion. Evaluation of the systemic hemodynamic effects of SK&F 108566 in chronically instrumented renin-dependent hypertensive rats demonstrated that the antihypertensive effects of SK&F 108566 were accompanied by a significant increase in cardiac output with little change in stroke volume. In dogs made acutely hypertensive by an intravenous infusion of angiotensin I, SK&F 108566 resulted in dose-dependent decreases in blood pressure. The antihypertensive activity of SK&F 108566 at 10 mg/kg p.o. was maintained for between 13-15 h, a similar duration of action as observed with enalapril (1 mg/kg, p.o.). Administration of DuP 753 (losartan) intravenously caused a small and short-lived fall in blood pressure in the angiotensin I-infused hypertensive dog. However, the active metabolite of losartan, EXP 3174, resulted in a response of longer duration. In dogs made hypertensive by placement of an ameroid constrictor on the left renal artery, SK&F 108566 (10 mg/kg, p.o.) or enalapril (1 mg/kg, p.o.) resulted in antihypertensive responses of at least 12 h duration. The data indicate that SK&F 108566 is a long-acting antihypertensive agent in the rat and dog.

Topics: Acrylates; Angiotensin I; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Biphenyl Compounds; Dogs; Hemodynamics; Hypertension; Imidazoles; Losartan; Male; Rats; Rats, Inbred Strains; Tetrazoles; Thiophenes