ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy.
(9/1416)
Protein trafficking across the glomerular capillary has a pathogenic role in subsequent renal damage. Despite evidence that angiotensin-converting enzyme (ACE) inhibitors improve glomerular size-selectivity, whether this effect is solely due to ANG II blocking or if other mediators also play a contributory role is not clear yet. We studied 20 proteinuric patients with IgA nephropathy, who received either enalapril (20 mg/day) or the ANG II receptor blocker irbesartan (100 mg/day) for 28 days in a randomized double-blind study. Measurements of blood pressure, renal hemodynamics, and fractional clearance of neutral dextran of graded sizes were performed before and after 28 days of treatment. Both enalapril and irbesartan significantly reduced blood pressure over baseline. This reduction reached the maximum effect 4-6 h after drug administration but did not last for the entire 24-h period. Despite transient antihypertensive effect, proteinuria was effectively reduced by both treatments to comparable extents. Neither enalapril nor irbesartan modified the sieving coefficients of small dextran molecules, but both effectively reduced transglomerular passage of large test macromolecules. Theoretical analysis of sieving coefficients showed that neither drug affected significantly the mean pore radius or the spread of the pore-size distribution, but both importantly and comparably reduced the importance of a nonselective shunt pathway. These data suggest that antagonism of ANG II is the key mechanism by which ACE inhibitors exert their beneficial effect on glomerular size-selective function and consequently on glomerular filtration and urinary output of plasma proteins. (+info)
Inhibition of beta-myosin heavy chain gene expression in pressure overload rat heart by losartan and captopril.
(10/1416)
AIM: To study the effects of losartan and captopril on beta-myosin heavy chain (MHC), and alpha-MHC gene expression. METHODS: Pressure overload was produced by abdominal aortic coarctation (AAC) in rats. alpha- and beta-MHC mRNA were measured by Northern blot. RESULTS: In left ventricular myocardium of sham-operated rats, the alpha-MHC mRNA predominated, while the beta-MHC mRNA was only detectable. In response AAC, there was a 70-fold increase in the beta-MHC mRNA (P < 0.01), while alpha-MHC mRNA reduced to 26% (P < 0.01). Losartan (3 mg.kg-1.d-1, i.g. for 11 d) to AAC rats caused inhibitions of beta-MHC by 96% and alpha-MHC by 86% gene expression without lowering blood pressure. A reduction in beta-MHC mRNA was also seen in captopril-treated rats (30 mg.kg-1.d-1, i.g. for 11 d), but the inhibitory effect of captopril on alpha-MHC mRNA was less than that of losartan (44% vs 86%, P < 0.05). CONCLUSIONS: The shift of MHC isoform induced by pressure overload is due to up-regulation of beta-MHC and down-regulation of alpha-MHC gene expression. Inhibition of beta-MHC gene expression by losartan is achieved primarily by direct blockade of angiotensin II type I receptors in the myocardium, independent on hemodynamics. (+info)
Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists.
(11/1416)
Use of angiotensin (Ang) II AT1 receptor antagonists for treatment of hypertension is rapidly increasing, yet direct comparisons of the relative efficacy of antagonists to block the renin-angiotensin system in humans are lacking. In this study, the Ang II receptor blockade induced by the recommended starting dose of 3 antagonists was evaluated in normotensive subjects in a double-blind, placebo-controlled, randomized, 4-way crossover study. At 1-week intervals, 12 subjects received a single dose of losartan (50 mg), valsartan (80 mg), irbesartan (150 mg), or placebo. Blockade of the renin-angiotensin system was assessed before and 4, 24, and 30 hours after drug intake by 3 independent methods: inhibition of the blood pressure response to exogenous Ang II, in vitro Ang II receptor assay, and reactive changes in plasma Ang II levels. At 4 hours, losartan blocked 43% of the Ang II-induced systolic blood pressure increase; valsartan, 51%; and irbesartan, 88% (P<0.01 between drugs). The effect of each drug declined with time. At 24 hours, a residual effect was found with all 3 drugs, but at 30 hours, only irbesartan induced a marked, significant blockade versus placebo. Similar results were obtained when Ang II receptor blockade was assessed with an in vitro receptor assay and by the reactive rise in plasma Ang II levels. This study thus demonstrates that the first administration of the recommended starting dose of irbesartan induces a greater and longer lasting Ang II receptor blockade than that of valsartan and losartan in normotensive subjects. (+info)
Effects of BAY 10-6734 (Embusartan), a new angiotensin II type I receptor antagonist, on vascular smooth muscle cell growth.
(12/1416)
Angiotensin II (AII), an important hypertrophic factor in the cardiovascular system, exerts most of its known effects in vivo through the AII receptor type 1 (AT1) subclass of AII receptors. These receptors are also responsible for the growth-related effects of AII in cultured vascular smooth muscle cells (VSMCs). We presently investigated the effects of BAY 10-6734 (Embusartan), a new orally active AT1 antagonist, on VSMC growth and proliferation of cultured VSMCs isolated from the aortae of Wistar Kyoto rats and spontaneously hypertensive rats. BAY 10-6734 and losartan (considered as AT1 receptor antagonist of reference), as well as their respective active metabolites, were studied for their inhibition of: 1) [125I]AII binding to its receptors, 2) AII-induced DNA and protein synthesis (by measuring the incorporation of 5-bromo-2'-deoxyuridine and [3H]L-leucine, respectively), and 3) AII-induced variations in intracellular Ca2+ concentration, using cells labeled with Fura-2. All of the tested compounds inhibited the aforementioned parameters in a concentration-dependent manner. Half-maximal inhibitory concentration values indicated that BAY 10-6734 was significantly more potent than losartan and that spontaneously hypertensive rat-derived VSMCs were more sensitive than Wistar Kyoto rat-derived ones. Neither BAY 10-6734 nor losartan affected the intracellular Ca2+ concentration of unstimulated VSMCs but both compounds inhibited both AII-induced Ca2+ mobilization from internal stores and Ca2+ influx. Neither compound affected arginine-vasopressin-, basic fibroblast growth factor-, or serum-induced DNA and protein synthesis. BAY 10-6734 appears therefore as a potent and specific new inhibitor of AII-induced growth-related events in VSMCs. (+info)
Serial changes in sarcoplasmic reticulum gene expression in volume-overloaded cardiac hypertrophy in the rat: effect of an angiotensin II receptor antagonist.
(13/1416)
This study was designed to clarify whether gene expression in the cardiac sarcoplasmic reticulum [sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, ryanodine receptor and calsequestrin] changes in accordance with left ventricular functional alterations in the volume-overloaded heart. Further, the effect of the angiotensin II type 1 receptor antagonist, TCV-116, on the expression of these genes was also evaluated. Left ventricular fractional shortening was significantly increased at 7 days, had returned to control levels at 21 days, and had significantly decreased at 35 days after the shunt operation, compared with sham-operated rats. The level of SERCA mRNA was significantly decreased at both 21 days and 35 days after the shunt operation. The levels of ryanodine receptor and phospholamban mRNAs were significantly decreased at 35 days in shunt-operated rats. The decrease in the SERCA mRNA level preceded the development of cardiac dysfunction. The levels of SERCA and ryanodine receptor mRNAs were correlated positively with left ventricular fractional shortening (r=0.73, P<0.0001 and r=0.61, P<0.01 respectively). Attenuation of the decrease in left ventricular fractional shortening occurred on treatment with TCV-116. After the treatment with TCV-116, the levels of SERCA and phospholamban mRNAs were restored to the respective values in sham-operated rats. Ryanodine receptor mRNA levels remained unchanged after treatment with TCV-116. These results indicate that the down-regulation of SERCA and ryanodine receptor mRNA levels may be related to cardiac dysfunction in the volume-overloaded heart. In addition, treatment with an angiotensin II receptor antagonist may restore the altered sarcoplasmic reticulum mRNA levels to control levels, and this may result in attenuation of the functional impairment in the volume-overloaded heart. (+info)
Effect of angiotensin II and telmisartan, an angiotensin1 receptor antagonist, on rat gastric mucosal blood flow.
(14/1416)
BACKGROUND: Angiotensin II (ATII) has been suggested to contribute to shock-induced dysfunction of the gastric circulation. AIM: To substantiate this conjecture, the effects on gastric mucosal haemodynamics and the hyperaemic response to acid back-diffusion of ATII and the angiotensin AT1 receptor antagonist, telmisartan, were examined in normal rats and in animals subjected to haemorrhage. METHODS: Gastric mucosal blood flow in phenobarbital-anaesthetized rats was recorded with the hydrogen clearance technique, and acid back-diffusion was induced by perfusing the stomach with ethanol (25%) in HCl (0.05 M). RESULTS: Intravenous infusion of ATII (0.3-10 nmol/min/kg) led to dose-dependent hypertension and a reduction of blood flow and vascular conductance in the gastric mucosa. The gastric hyperaemia caused by acid back-diffusion was attenuated by ATII (1 nmol/min/kg). These effects of ATII were antagonized by intravenous injection of telmisartan (1-10 mg/kg) which per se caused hypotension and dilated the gastric mucosal vasculature, but did not modify the gastric mucosal hyperaemia evoked by acid back-diffusion. Hypotension induced by haemorrhage (1.3 mL blood per 100 g body weight) failed to alter the hyperaemia due to acid back-diffusion, but caused gastric mucosal vasoconstriction, an effect that was left unaffected by telmisartan. CONCLUSIONS: ATII constricts the rat gastric microvasculature via an action involving AT1 receptors. The effects of telmisartan indicate that endogenous ATII contributes to the homeostatic regulation of gastric vascular tone but does not compromise the ability of the gastric microvasculature to react to influxing acid. These results negate the concept that ATII contributes to the gastric vascular perturbances in haemorrhagic shock. (+info)
Assessing the economic value of antihypertensive medications.
(15/1416)
OBJECTIVE: To assess the economic value of antihypertensive medications by comparing the likelihood of coronary heart disease and stroke events and subsequent event treatment costs. STUDY DESIGN: Duration of blood pressure reduction was used to profile event risk reduction of three antihypertensive medications. METHODS: We used clinical data to determine the duration of blood pressure reduction achieved with use of two angiotensin converting enzyme inhibitors and one angiotensin II receptor antagonist. We then used trough-to-peak ratios to calculate the reduction in risk of coronary heart disease and stroke events associated with each medication. RESULTS: Across a number of different event treatment cost and population size estimates, the economic value of different medications can be assessed. CONCLUSION: Our method for assessing the economic value of antihypertensive medications can be applied to other drug classes and can be further refined by integrating patient population and other risk-related data. (+info)
Effects of angiotensin II receptor blockade on proximal fluid uptake in the rat kidney.
(16/1416)
Angiotensin II has a well described dose-dependent biphasic action on proximal tubule fluid uptake, although the concentration and effect of endogenous luminal angiotensin II remain controversial. Shrinking split-droplet micropuncture was used to examine the fluid uptake in response to the luminal application of three AT1 antagonists (losartan, EXP3174, candesartan). Addition of losartan at 10(-8) M decreased fluid uptake rate (Jva) by 17.5+/-2.2% (P<0.05). Luminal addition of EXP3174 at concentrations between 10(-9)-10(-5) M caused a dose-dependent decrease in fluid uptake, with a maximum decrease of 41.0+/-9.5% (P<0.01) at 10(-6) M. Candesartan also decreased fluid uptake, by 21.9+/-4.9% (P<0.05) at 10(-8) M and 23.6+/-5.5% (P<0.05) at 10(-5) M. All three antagonists at a low concentration (10(-8) M) decreased fluid uptake. EXP3174 and candesartan at a higher concentration (10(-5) M) also decreased fluid uptake in contrast to the previously reported effect of losartan. We conclude that the endogenous concentration of antiotensin II in the proximal luminal fluid is low and exerts a stimulatory effect on fluid absorption. Losartan at concentrations greater than 10(-6) M may have a non-selective action on fluid uptake. (+info)