Biochemical effects of losartan, a nonpeptide angiotensin II receptor antagonist, on the renin-angiotensin-aldosterone system in hypertensive patients

We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n = 51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.     

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis

Administration of angiotensin II causes an increase in portal pressure, and plasma concentration of angiotensin II is elevated in patients with cirrhosis, suggesting that angiotensin II may be involved in the pathogenesis of portal hypertension in cirrhosis. We evaluated the effect of the orally active angiotensin II receptor antagonist, losartan, on portal pressure in patients with cirrhosis and portal hypertension. Thirty patients with severe (hepatic venous pressure gradient [HVPG] >/= 20 mm Hg) and 15 patients with moderate (HVPG < 20 mm Hg) portal hypertension at baseline measurement were treated with an oral dose of 25 mg losartan once daily for 1 week and compared with 15 (HVPG >/= 20 mm Hg) and 10 (HVPG < 20 mm Hg), respectively, cirrhotic controls. On the seventh day, HVPG was determined again, and blood pressure, heart rate, body weight, and parameters of liver and kidney function were recorded. Losartan induced a significant (P <.001) decrease of HVPG in the patients with severe (-46.8% +/- 15.5%) and moderate (-44.1% +/- 14.7%) portal hypertension, while no significant change was seen in the controls. Losartan caused a slight but significant (P <.01) fall in mean arterial blood pressure (-3.1 +/- 5.0 and -3.5 +/- 4.3 mm Hg, respectively). One patient treated with losartan had a short symptomatic hypotensive reaction after the first dose of losartan that did not recur despite continued treatment. No deterioration of liver or kidney function was observed. The present study indicates that angiotensin II blockade with orally administered losartan is safe and highly effective in the treatment of portal hypertension.     

Design and synthesis of nonpeptide angiotensin II receptor antagonists featuring acyclic imidazole-mimicking structural units

Extensive molecular modelling studies, including conformational analysis and the comparison of molecular electrostatic potential distributions, wee used to evaluate structural parameters of new antagonists containing acyclic replacements of the N = C-N imidazole region. The synthesis and the biological screening of a series of acyl biphenyltetrazole derivatives were planned and realized to gain an insight into the structure-activity relationships of this unusual class of Angiotensin II antagonists.     

GR144053, a fibrinogen receptor antagonist, enhances the suppression of neointima formation by losartan, an angiotensin II receptor antagonist, in the injured carotid artery of hamster

1. The present study investigated the inhibitory effect of losartan, a type 1 angiotensin II (AT1) antagonist, and of combined treatment with losartan and GR144053, a fibrinogen receptor (GPIIb/IIIa) antagonist, on neointima formation subsequent to vascular injury in the hamster carotid artery. Vascular injury was achieved by a roughened-tip 2F catheter and the neointimal area was measured up to 2 weeks inducing the injury. 2. Compared to non-treated hamsters (intimal area (IA/internal elastic laminal area (IELA) ratio = 60.3 +/- 5.9%, n = 12), losartan dissolved in drinking water (1, 3 and 10 mg kg-1 per day, n = 8 each) reduced neointimal area dose-dependently, a significant decrease (IA/IELA = 39.7 +/- 5.6%) being attained with the highest dose when it was administered from 1 day before injury. However, neointima formation was not prevented even with the highest dose of losartan when the administration was started after injury. 3. When the administration of GR144053 (1.0 mg kg-1 per hour) via an implanted osmotic pump was started 30 min before the injury and continued for the next 2 weeks, no suppression of neointima formation was observed, although platelet aggregation evoked ex vivo by adenosine diphosphate (ADP) at the end of treatment period was efficiently inhibited. 4. In separate experiments in which 5-bromo-2-deoxy-Uridine (BrdU) was used to test smooth muscle cell (SMC) proliferation 1 and 7 days after injury, the ratio of SMC proliferation in the injured area was only slightly decreased by losartan when its administration was started after the injury, despite the marked reduction of SMC proliferation when treatment was started before the injury. Treatment with GR144053 as indicated above also significantly decreased the SMC proliferating index 1 day after the injury. 5. To examine the potential benefit of the coadministration of the GPIIb/IIIa antagonist with the AT1 receptor antagonist, GR144053 (1.0 mg kg-1 per hour) was combined with post-injury treatment with losartan (10 mg kg-1 per day). This markedly reduced the proliferation of SMCs and significantly decreased the neointimal area (IA/IELA = 31.2 +/- 4.6%) measured 2 weeks following the catheterization. 6. According to the results of a time-dependent study in which GR144053 was given in combination with post injury treatment with losartan for 1, 3, 7 or 14 days, neointima formation could be reduced by treatment with GR144053 for just 7 days. 7. In conclusion, GR144053, a fibrinogen receptor antagonist, enhanced the inhibitory effect of losartan, an AT1 receptor antagonist, on neointima formation in the damaged carotid artery of hamsters.     

Captopril and angiotensin II receptor antagonist therapy in a pacing model of heart failure

Twenty-four splenectomized dogs were subjected to rapid right ventricular pacing (RRVP) at 250 beats/min for five weeks. During the final three weeks, four groups six dogs were untreated or treated with captopril alone, with the angiotensin II type 1 (AT1) receptor antagonist L158,809 alone or with the two drugs combined by constant intravenous infusion. Hemodynamic studies were carried out during light anesthesia at baseline, and after two and five weeks of pacing. Total vascular capacitance and stressed blood volume were calculated from the mean circulatory filling pressure during transient circulatory arrest after acetylcholine administration at three different circulating volumes. Central blood volume and cardiac output were measured by thermodilution. Severe heart failure was present in the untreated group after five weeks of RRVP, characterized by low cardiac output and total vascular capacitance, high right atrial and pulmonary capillary wedge and mean circulatory filling pressure, plus increased stressed and central blood volumes. While L158,809 had not effect, captopril alone or combined with L158,809 ameliorated the reduction in total vascular capacitance, and reduced right atrial and mean circulatory pressure and stressed blood volumes. Combined therapy reduced pulmonary capillary wedge pressure. Thus, angiotensin-converting enzyme inhibition with captopril was effective in this model of chronic low output heart failure, whereas AT1 receptor antagonism was not.     

Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients

BACKGROUND: The angiotensin II receptor antagonist losartan is an effective antihypertensive agent with unique uricosuric properties. This study evaluates the uricosuric effects of losartan in 10 hypertensive heart transplant patients with hyperuricemia. METHODS: The patients were randomized to receive losartan 50 mg once daily and enalapril 20 mg once daily for 4 weeks according to a double-blind crossover design. Office blood pressure, plasma uric acid levels, and urinary uric acid excretion were monitored throughout the study. RESULTS: Plasma uric acid levels decreased significantly after 4 weeks of treatment with losartan (P<0.05) but not with enalapril. On day 1 and after 1 month of treatment, a significant increase in uric acid excretion was observed only with losartan. Significant decreases in office systolic and diastolic blood pressures were obtained with enalapril but not with losartan. CONCLUSIONS: Losartan effectively lowers plasma uric acid levels in hyperuricemic heart transplant patients.     

In vitro pharmacological properties of KRH-594, a novel angiotensin II type 1 receptor antagonist

Although most people are thought to receive their highest acute exposures to gasoline while refueling, relatively little is actually known about personal, nonoccupational exposures to gasoline during refueling activities. This study was designed to measure exposures associated with the use of an oxygenated fuel under cold conditions in Fairbanks, Alaska. We compared concentrations of gasoline components in the blood and in the personal breathing zone (PBZ) of people who pumped regular unleaded gasoline (referred to as regular gasoline) with concentrations in the blood of those who pumped an oxygenated fuel that was 10% ethanol (E-10). A subset of participants in a wintertime engine performance study provided blood samples before and after pumping gasoline (30 using regular gasoline and 30 using E-10). The biological and environmental samples were analyzed for selected aromatic volatile organic compounds (VOCs) found in gasoline (benzene, ethylbenzene, toluene, m-/p-xylene, and o-xylene); the biological samples were also analyzed for three chemicals not found in gasoline (1,4-dichlorobenzene, chloroform, and styrene). People in our study had significantly higher levels of gasoline components in their blood after pumping gasoline than they had before pumping gasoline. The changes in VOC levels in blood were similar whether the individuals pumped regular gasoline or the E-10 blend. The analysis of PBZ samples indicated that there were also measurable levels of gasoline components in the air during refueling. The VOC levels in PBZ air were similar for the two groups. In this study, we demonstrate that people are briefly exposed to low (ppm and sub-ppm) levels of known carcinogens and other potentially toxic compounds while pumping gasoline, regardless of the type of gasoline used.     

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.     

Human pharmacokinetic/pharmacodynamic profile of irbesartan: a new potent angiotensin II receptor antagonist

BACKGROUND: Inhibition of the renin-angiotensin system has been the focus of considerable research as the enzymatic pathway resulting in the production of angiotensin II is implicated in the development of hypertension and cardiovascular disease. ANGIOTENSIN CONVERTING ENZYME INHIBITORS: Blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors is an effective blood pressure control measure, but is less than ideal due to incomplete blockade and the effects of concomitant blockade of kinase II. ANGIOTENSIN II RECEPTOR ANTAGONISTS: Angiotensin II receptor antagonists block the renin-angiotensin system at the receptor level, and thus impede the system regardless of the pathway responsible for the formation of ACE. Irbesartan is a new, unique angiotensin II receptor antagonist with favorable pharmacokinetic/pharmacodynamic properties that are close to ideal for an antihypertensive agent. Irbesartan is a specific AT1 receptor antagonist with rapid oral bioavailability (peak plasma concentrations occurring at 1.5-2 h after administration) and a long half-life (11-15 h) that provides 24-h blood pressure control with a single daily dose. The maximal blood pressure fall occurs between 3 and 6 h after the dose. Unlike other angiotensin II receptor antagonists, irbesartan is relatively unaffected by food or drugs. CONCLUSIONS: The pharmacokinetic/pharmacodynamic properties of irbesartan have been demonstrated to provide superior blood pressure control and tolerability in all classes of hypertension and patient populations.     

A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists

Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.     

Antinociceptive effects of angiotensin-converting enzyme inhibitors and an angiotensin II receptor antagonist in mice

Potential involvement of brain endogenous angiotensin II in the nociception was investigated in mice by using ACE inhibitors and an angiotensin II antagonist. The mice were allocated to the groups which were orally treated with spirapril (5 mg/kg), trandolapril (5 mg/kg), enalapril (30 mg/kg), losartan (10 mg/kg), or vehicle for 1 day (single dose groups) and 7 days (repeated doses groups). Significantly longer jump latencies were obtained for the groups repeatedly treated with spirapril, trandolapril and losartan, while the group with enalapril gained no effect. In contrast, the single dosing of all agents failed to show antinociceptive effect. The brain ACE activity was determined ex vivo immediately after the hot-plate test, and showed to be suppressed for the groups repeatedly treated with spirapril or trandolapril. In the group repeatedly treated with losartan, ex vivo autoradiography depicted the marked decrease in angiotensin II-binding capacity to the sites containing exclusively AT1 receptors within the blood-brain barrier. The antinociceptive effects of repeated doses of spirapril and losartan were reversed by naloxone. These results suggest that brain endogenous angiotensin II is likely to be involved in central nociceptive mechanisms by its antagonistic interaction with endogenous opioid system.     

Biological profile of L-745,870, a selective antagonist with high affinity for the dopamine D4 receptor

L-745,870,(3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H- pyrollo[2,3-b] pyridine, was identified as a selective dopamine D4 receptor antagonist with excellent oral bioavailability and brain penetration. L-745,870 displaced specific binding of 0.2 nM [3H] spiperone to cloned human dopamine D4 receptors with a binding affinity (Ki) of 0. 43 nM which was 5- and 20-fold higher than that of the standard antipsychotics haloperidol and clozapine, respectively. L-745,870 exhibited high selectivity for the dopamine D4 receptor (>2000 fold) compared to other dopamine receptor subtypes and had moderate affinity for 5HT2, sigma and alpha adrenergic receptors(IC50 < 300 nM). In vitro, L-745,870 (0.1-1 microM) exhibited D4 receptor antagonist activity, reversing dopamine (1 microM) mediated 1) inhibition of adenylate cyclase in hD4HEK and hD4CHO cells; 2) stimulation of [35S] GTPgammaS binding and 3) stimulation of extracellular acidification rate, but did not exhibit any significant intrinsic activity in these assays. Although standard antipsychotics increase dopamine metabolism or plasma prolactin levels in rodents, L-745,870 (相似文献   

Nonpeptide endothelin receptor antagonists. XI. Pharmacological characterization of SB 234551, a high-affinity and selective nonpeptide ETA receptor antagonist

The present study describes the pharmacological profile of ((E)-alpha-[[1-butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxy-phenyl ]-1H-pyrazol-4-yl]methlene]-6-methoxy-1,3-benzodioxole-5-propanoic acid) (SB 234551), a high-affinity, nonpeptide endothelin type A (ETA)-selective receptor antagonist. In human cloned ETA and endothelin type B (ETB) receptors, SB 234551 produced a concentration-dependent displacement of [125I]-endothelin-1 with Ki values of 0.13 and 500 nM, respectively. SB 234551 elicited concentration-dependent, rightward competitive shifts in the endothelin-1 concentration-response curves in isolated rat aorta and isolated human pulmonary artery (ETA receptor-mediated vascular contraction) with Kb values of 1.9 and 1.0 nM, respectively. SB 234551 antagonized ETB receptor-mediated vasoconstriction in the isolated rabbit pulmonary artery, as demonstrated by concentration-dependent, rightward shifts in the sarafotoxin S6c concentration-response curves (Kb = 555 nM). SB 234551 produced weak functional inhibition of sarafotoxin S6c-mediated endothelium-dependent relaxation (IC50 = 7 microM). SB 234551 (10 microM) had no significant effect against contraction produced by several other vasoactive agents and did not significantly influence radioligand binding to a number of diverse receptors. SB 234551 (0. 1-1.0 mg/kg i.v.) dose-dependently inhibited the pressor response to exogenous endothelin-1 in conscious rats. In vivo pharmacokinetic analysis in the rat demonstrated that SB 234551 was rapidly absorbed from the GI tract with a bioavailability of 30%. SB 234551 had a plasma half-life of 125 min and a systemic clearance of 25.0 ml/min/kg. The present study demonstrates that SB 234551 is an antagonist with high affinity for the ETA receptor, while sparing the ETB receptor. SB 234551 is a new pharmacological tool that should assist in the elucidation of the role of endothelin in pathophysiology.     

Antihypertensive effect of chronic KT3-671, a structurally new nonpeptide angiotensin AT1-receptor antagonist, in stroke-prone spontaneously hypertensive rats

KT3-671 (2-propyl-8-oxo-1-[(2'-(1H-tetrazole-5-yl)biphenyl-4-yl)methyl]-4,5,6, 7-tetrahydrocycloheptimidazole), a structurally new nonpeptide angiotensin AT1-receptor antagonist, was administered orally and repeatedly to 15-week-old stroke-prone spontaneously hypertensive rats for 7 weeks; and its effects on blood pressure, heart rate, renal function, plasma renin concentration (PRC), plasma aldosterone concentration (PAC) and hypertension-related tissue damage in the brain, heart, kidney and mesenteric artery were investigated. KT3-671 at a dose of 3 or 10 mg/kg, p.o. per day prevented development of hypertension and produced a significant and consistent reduction of blood pressure in a dose-dependent manner. Enalapril at a dose of 10 mg/kg per day produced cardiovascular effects similar to those of KT3-671 at 10 mg/kg. Despite marked reduction in blood pressure, neither KT3-671 nor enalapril affected the heart rate. KT3-671 at 10 mg/kg produced a transient and significant reduction of urinary sodium excretion in the second week, but did not affect renal function at any other time during the experimental period. Both KT3-671 at 10 mg/kg and enalapril at 10 mg/kg produced a significant increase in PRC and showed a tendency to decrease PAC. Repeated administration of KT3-671 reduced the severity of the pathological changes in the kidney. These results suggest that KT3-671 is a potentially useful antihypertensive drug.     

Characterization of glucuronic acid conjugates of a novel angiotensin receptor antagonist

Nanogram quantities of glucuronic acid conjugates of GR117289 in rat and dog bile have been analysed by semi-microbore high-performance liquid chromatography (HPLC)/ionspray mass spectrometry with on-line UV diode array detection. The determination of drug metabolites in bile has often proved problematical due to the large number of endogenous components in this biological matrix, in particular the bile acids. Semi-microbore HPLC is useful for concentrating small quantities of material and, in combination with an on-line diode array detector, for distinguishing between drug related and endogenous components. A novel angiotensin II receptor antagonist, GR117289, had proved difficult to analyse by thermospray mass spectrometry because of its thermal lability. The use of the less thermally dependent technique of ionspray mass spectrometry allowed the characterization of nanogram quantities of glucuronic acid metabolites of GR117289 in bile.     

Effect of losartan, an angiotensin II receptor antagonist, on response of cortisol and aldosterone to adrenocorticotrophic hormone

Many imidazole derivatives are shown to inhibit adrenal steroid biosynthesis. The present study was undertaken to examine an effect of another imidazole derivative, losartan (an angiotensin II receptor antagonist), on responses of cortisol and aldosterone to adrenocorticotrophic hormone (ACTH). Nine patients with essential hypertension were given placebo orally for 7 days and 50 mg of losartan for the next 9 days. Response of serum cortisol and plasma aldosterone to intramuscular ACTH injection were determined before and at the end of the treatment with losartan. Serum cortisol and plasma aldosterone significantly increased after ACTH injection in both periods of treatment (placebo and losartan). The increments in these parameters during treatment with losartan were not significantly different from those during treatment with placebo. These results suggest that the inhibitory effect of losartan on adrenal steroid biosynthesis is negligible.     

Pharmacological profiles of a novel non-peptide angiotensin II type I receptor antagonist HR720 in vitro and in vivo

The relationship, in 539 individuals infected with the human immunodeficiency virus (HIV), between two prognostic markers, the CD4 count and beta-2-microglobulin (B2M), and the development of the acquired immunodeficiency syndrome (AIDS) and death was investigated. Cox proportional hazards models were used to determine the risk of AIDS or death. In a multivariate model which adjusted for demographic factors and treatment, the most recent measurements of B2M (relative hazard (RH) 1.37 per g/l higher) and CD4 count (RH 2.17 per log-unit lower) were both significantly associated with the development of AIDS. Similarly, in a multivariate model which additionally adjusted for the development of AIDS as a time dependent covariate, there was a strong relationship with risk of death for the most recent measurements of B2M (RH 1.34 per g/l higher), and CD4 lymphocyte count (RH 1.91 per log-unit lower). A difference in the level of B2M could be used among patients with similar CD4 counts as an indicator of increased risk of progression to AIDS or death. Using the most recent values of these markers provides a better estimate of the risk of AIDS or death, compared to the more common method of analysis, where baseline values of the markers are used.     

Inhibition by angiotensin II type 1 receptor antagonist of cardiac phenotypic modulation after myocardial infarction

The purpose of this study was to examine the cardiac phenotype and remodeling after myocardial infarction and the effect of the angiotensin II type 1 (AT1) receptor antagonist (TCV-116) on the gene expression. Myocardial infarction in rats was produced by ligation of the coronary artery. TCV-116 (10 mg/kg/day) was administered orally to rats from 1 day after myocardial infarction. At 1, 2 and 3 weeks after myocardial infarction, blood pressure and heart rate were measured, and the heart was removed. The left ventricle was measured for infarct size and weight, and then the total RNA from the non-ischemic left ventricle was extracted. mRNAs in the non-ischemic left ventricle were measured by Northern blot analysis. The weight of the non-ischemic left ventricle was significantly increased 3 weeks after infarction. This was completely prevented by TCV-116 treatment. mRNA levels for beta-myosin heavy chain (beta-MHC), atrial natriuretic polypeptide (ANP), collagen types I and III and transforming growth factor-beta 1 (TGF-beta 1) in the non-ischemic left ventricle were increased by a factor of 3.0, 6.7, 7.9, 4.0 and 1.4 (P < 0.01), respectively, 1 week after infarction. There was no increase in alpha-skeletal actin mRNA at 1 and 2 weeks, but it was increased by a factor of 2.9 (P < 0.05) at 3 weeks. On the other hand, there was no change in alpha-MHC mRNA during the 3 weeks. TCV-116 significantly suppressed the increased gene expression of beta-MHC and alpha-skeletal actin in the non-ischemic myocardium at all time points, and also suppressed the expression of ANP at 2 and 3 weeks. However, TCV-116 failed to inhibit the expression of collagen I and III mRNAs at 1 and 3 weeks. These results show that myocardial infarction causes a rapid shift of myocytes to fetal phenotype and a rapid activation of collagen genes in the non-ischemic myocardium. AT1 receptor may be responsible for the phenotypic modulation of myocytes following myocardial infarction.     

A review of mutagenesis studies of angiotensin II type 1 receptor, the three-dimensional receptor model in search of the agonist and antagonist binding site and the hypothesis of a receptor activation mechanism

OBJECTIVE: To seek the mechanism whereby agonists, competitive antagonists and insurmountable antagonists affect the receptor function differently, by reviewing recent mutagenesis studies of angiotensin II type 1 receptor (AT1) in which the binding of the agonist and antagonists and receptor signaling were affected. AT1 RECEPTOR STRUCTURE AND LIGAND BINDING SITES: We built a model of seven transmembrane spanning domains of the AT1 receptors using bacteriorhodopsin as a template. The carboxy terminal of angiotensin II binds to Lys199 in transmembrane domain 5, whereas the guanidinium group of Arg2 binds to Asp281 in transmembrane domain 7. Results of studies using mutagenesis supporting proposed ligand-docking models are discussed. HYPOTHESIS FOR THE LIGAND-INDUCED RECEPTOR SIGNALING MECHANISM: We submit a set of hypotheses for a mechanism whereby the ligand binding induces changes in the receptor conformation by the rotation of transmembrane helices as the initial event for the subsequent activation of a G protein. In this mechanism antagonists are not capable of rotating the helices but agonists are able to do so, which results in the formation of a hydrogen bond between Asp74 in transmembrane domain 2 and Tyr292 in transmembrane domain 7. This mechanism also provides plausible explanation for the activation of monoamine receptors. COMPETITIVE AND INSURMOUNTABLE ANTAGONISTS: Competitive antagonists share the same binding sites with agonists, but insurmountable antagonists do not, and binding of the latter does not preclude agonist binding, for example, to Asp281. CONCLUSION: This hypothesis of the intrareceptor signaling mechanism and the receptor model indicate that some amino acid residues essential for the signaling play their roles in the intrareceptor activation mechanism, whereas others participate directly in ligand binding.