Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist.

The aim of this study was to investigate the relationships between plasma concentrations of losartan, an orally active angiotensin II inhibitor, its active metabolite EXP3174, and angiotensin II blockade. Six healthy subjects received single oral doses of 40, 80, or 120 mg losartan and placebo at 1-week intervals in a crossover study. Angiotensin II blockade was assessed by the blood pressure response to exogenous angiotensin II before and after losartan administration. EXP3174 reached higher plasma concentrations and was eliminated more slowly than its parent compound; its levels paralleled the profile of angiotensin II blockade closer than losartan. Inhibition of the pressure response was dose dependent. The Hill-shaped relationship between response and EXP3174 concentration (or time-integrated variables) approached a plateau with 80 mg. The dose-dependent increase in plasma renin and angiotensin II exhibited a considerable individual scatter. We conclude that losartan produces a dose-dependent, effective angiotensin II blockade that is largely determined by the active metabolite EXP3174.     

Different types of antagonism by losartan and irbesartan on the effects of angiotensin II and its degradation products in rabbit arteries

A previous study by our group has demonstrated that the selective AT1-receptor antagonist losartan behaves as a noncompetitive antagonist in rabbit isolated renal artery (RA). In the present investigation, the influence of losartan and irbesartan on the contractile effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) was determined in the rabbit isolated RA and femoral artery (FA). The arteries were set up in organ chambers and changes in isometric force were recorded. In both rabbit isolated RA and FA preparations, AII, AIII and AIV elicited significant contractile responses with a similar efficacy. These effects were impaired by the presence of functional endothelium in RA preparations but not in FA preparations. In both preparations studied, the effects of AII, AIII and AIV were influenced neither by the aminopeptidase-A and -M inhibitor amastatin (10 microM), nor by the aminopeptidase-B and -M inhibitor bestatin (10 microM). In endothelium-denuded FA preparations, preincubation with losartan (3-300 nM) antagonized AII-, AIII- and AIV-induced contractions in a competitive manner. However, in endothelium-denuded RA preparations, losartan depressed the maximal contractile responses induced by AII but not those induced by AIII and AIV. In the same preparations, preincubation of another selective AT1-receptor antagonist irbesartan (3-30 nM) concentration-dependently shifted AII and AIII curves to the right in an insurmountable manner. The reduction of the maximal response of AII is more potent when compared to that of AIII (47.7 +/- 1.51% vs. 66.7 +/- 1.88%, percentage of the initial maximal response; P < 0.05; n=5). The selective AT2-receptor antagonist PD123177 (1 microM) did not influence the responses to all three peptides in both RA and FA preparations. These heterogeneous antagonistic effects of the two AT1-receptor antagonists studied with respect to the contractile actions of AII, AIII and AIV suggest the possible existence of multiple, functionally relevant AT1-receptor subtypes in rabbit RA preparations.     

Differential inhibition of the prejunctional actions of angiotensin II in rat atria by valsartan, irbesartan, eprosartan, and losartan

The effects of valsartan and other nonpeptide angiotensin II type 1 (AT(1)) receptor blockers on the prejunctional actions of angiotensin II were investigated in the isolated left atria of rat. Norepinephrine stores in rat atria were loaded with [(3)H]norepinephrine, and neuronal norepinephrine release was deduced from the radioactivity efflux. Angiotensin II (10(-9) to 10(-6) M) produced concentration-dependent enhancement of the electrical stimulation-induced efflux of [(3)H]norepinephrine from the preparation. Pretreatment of tissues with valsartan, irbesartan, eprosartan, or losartan (10(-8) to 10(-6) M) produced concentration-dependent inhibitions of the stimulation-induced efflux of radioactivity observed in the presence of angiotensin II (10(-7) M). The AT(1) receptor blockers did not decrease the "basal stimulation-induced overflow of radioactivity but rather selectively inhibited the angiotensin II-mediated augmentation of the response. Regression analyses of the inhibition of the angiotensin II-mediated response by valsartan, irbesartan, eprosartan, and losartan revealed corresponding log IC(50) values (log M, with 95% confidence intervals) of -7.78 (-8.19, -7.51), -7.65 (-8.02, -7.40), -7.12 (-7. 37, -6.86), and -6.75 (-7.00, -6.40), indicating that the IC(50) values for valsartan and irbesartan are significantly lower than those for eprosartan and losartan. Thus, valsartan is a potent inhibitor of the prejunctional facilitatory effect of angiotensin II on the release of norepinephrine from peripheral sympathetic nerves. This implies that the therapeutic domain of valsartan may be extended to include pathophysiological conditions such as congestive heart failure wherein prejunctional angiotensin II receptors apparently play a significant role. Whether the high potency of valsartan translates into a significant clinical advantage relative to the other agents tested remains to be ascertained.     

Drug-interactions and adverse effects of losartan potassium, an angiotensin II receptor antagonist]

Losartan potassium is mainly metabolized by P450 chiefly in the liver. A P450 inducer, phenobarbital, has no significant effects on the pharmacokinetics of losartan. Cimetidine, known to inhibit P450 activity, has no remarkable effects on the metabolism of losartan. Side effects of losartan has been very few in the clinical trials of this drug on several thousands of patients so far. The rate was as low as that of placebo. Losartan may cause hyperkalemia when used with potassium-sparing diuretics, such as spironolactone or triamterene. Angioedema and acute hepatitis had been reported in 3 patients among thousands of millions of hypertensives under losartan treatment. The etiology was unclear, simple coincidence may not be ruled out. Losartan should not be administered to pregnant women and breast-feeding mothers, because it may disturb the fetal growth or may be harmful to the newborn. It should be cautiously used in patients with renal failure or liver disfunction.     

Time course and extent of angiotensin II antagonism after irbesartan, losartan, and valsartan in humans assessed by angiotensin II dose response and radioligand receptor assay.

OBJECTIVES: To compare the angiotensin II antagonistic properties of the usual recommended oral starting doses of various angiotensin II receptor antagonists-150 mg irbesartan, 80 mg valsartan, and 50 mg losartan-in humans. SUBJECTS AND METHODS: Eighteen healthy men were enrolled in a double-blind, randomized crossover study. Angiotensin II dose-effect curves of diastolic blood pressure and radioreceptor assay were performed before and up to 47 hours after single and multiple doses of the antagonists. The rightward shift of the angiotensin II dose-effect curves (dose ratio-1) assessed the antagonistic effects in vivo. The degree of receptor occupancy in plasma was detected by a rat lung radioreceptor assay ex vivo in vitro. RESULTS: All of the drugs clearly showed antagonistic effects to angiotensin II in vivo (dose ratio-1) and in vitro (radioreceptor assay). Within the given doses the dose ratio-1 for irbesartan was greater than for valsartan and losartan after single and repetitive dosing, reaching statistical significance at various time points up to 36 hours versus valsartan and up to 47 hours versus losartan. The apparent half-lives of the decay of the effects were approximately 8 hours for valsartan and losartan, whereas 15 to 18 hours were obtained with irbesartan. These findings were supported by the radioreceptor assay data: the percentage of receptor occupancy for irbesartan was significantly greater than for valsartan and losartan up to 47 hours. CONCLUSION: Angiotensin II antagonistic effects of irbesartan, valsartan, and losartan were compared. Irbesartan showed the slowest decay and longest duration of its antagonistic effects. With the recommended initial doses used in this study, the following rank order of antagonistic intensity was obtained: irbesartan > valsartan > losartan. The findings of this study, specifically the longer-lasting effects of irbesartan, may have clinical implications.     

Maximising antihypertensive effects of angiotensin II receptor blockers with thiazide diuretic combination therapy: focus on irbesartan/hydrochlorothiazide

BACKGROUND: Evidence-based guidelines for the management of hypertension are now well established. Studies have shown that more than 60% of patients with hypertension will require two or more drugs to achieve current treatment targets. DISCUSSION: Combination therapy is recommended as first-line treatment by the JNC-7 guidelines for patients with a blood pressure > 20 mmHg above the systolic goal or 10 mmHg above the diastolic goal, while the International Society of Hypertension in Blacks recommends combination therapy when BP exceeds targets by > 15/10 mmHg. Current European Society of Hypertension-European Society of Cardiology guidelines also recommend the use of low-dose combination therapy in the first-line setting. Furthermore, JNC-7 recommends that a thiazide-type diuretic should be part of initial first-line combination therapy. Thiazide/diuretic combinations are available for a variety of classes of antihypertensive, including ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers and centrally acting agents. This article focuses on clinical data investigating the combination of an ARB, irbesartan, with the diuretic, hydrochlorothiazide. CONCLUSIONS: These data indicate that the ARB/HCTZ combination has greater potency and a similar side effect profile to ARB monotherapy and represents a highly effective approach for attaining goal BP levels using a therapeutic strategy that very effectively lowers BP, is well tolerated and minimises diuretic-induced metabolic effects.     

Reduced pressor effect of angiotensin II and of noradrenaline in normal man following the oral administration of the calcium-antagonist nifedipine

Abstract. The pressor response to both angiotensin II (5, 10 and 20 ng kg^-1min^-1) and to noradrenaline (50, 100 and 200 ng kg^-1 min^-1) was reduced ( P < 0·05 to < 0·005) in six healthy male subjects following the administration of the calcium-antagonist nifedipine (10 mg p.o.). Nifedipine induced a rise in basal plasma noradrenaline concentrations but did not alter the plasma concentrations of adrenaline, dopamine, renin and aldosterone. A slight reduction in the angiotensin II induced rise of plasma aldosterone by nifedipine was observed after the administration of the largest dose of angiotensin II only ( P < 0·05). The reduced responsiveness towards pressor agents following oral nifedipine is in keeping with the known antihypertensive effect of calcium-antagonistic drugs and could provide a concept for the effectiveness of these drugs in hypertensive crisis.     

Comparative effects of angiotensin II and angiotensin III in rabbit adrenal and aortic tissues

The addition of angiotensin II (AII) and angiotensin III (AIII) to isolated tissue baths produced the same maximal contractile response of rabbit aortic strips. AIII was about 10 times less potent, the slope of its concentration-response curve was less steep and its rate of onset slower than that of AII. The responses of both AII and AIII were inhibited with equal potency by the surmountable AII antagonist Phe4, Tyr8-AII and its unsurmountable analog Sar1, Leu8-AII but the kinetic patterns of inhibition by both were less well defined with the agonist AIII than with AII. The addition of AIII to tissues which had exhibited a maximal response to AII did not increase the level of contraction, in contrast to the case when norepinephrine was added to tissues contracted by AII. Both AII and AIII displaced [125I]AII binding from rabbit adrenal membranes; AIII was 6 times less potent than AII but displayed competitive kinetics as an inhibitor of [125I]AII binding. In further studies two binding sites for [125I]AII were identified in adrenal membranes, having KD values of 2.0 +/- 0.2 and 19.6 +/- 2.3 nM, respectively. Each site was inhibited by both AII and AIII and the ratio of the apparent Ki values for the two hormones was not significantly different. The Hill coefficient for the high affinity site was, however, lower for AIII than AII. We interpret our data to suggest that AII and AIII act on the same receptors. AIII apparently binds less efficiently than does AII in both rabbit adrenal membranes and rabbit aortic strips.     

Comparative study of platelet angiotensin II binding and the angiotensin II sensitivity test as predictors of pregnancy-induced hypertension.

1. Platelet angiotensin II binding was measured in 34 primigravid women (between 28 and 32 weeks gestation), in whom the pressor response to infused angiotensin II was also determined. 2. There was a significant correlation between the platelet angiotensin II binding and the slope of the curve relating the diastolic pressor response to infused angiotensin II (P less than 0.01), suggesting that co-linearity between the two techniques exists and supporting the use of platelet angiotensin II binding as a model of vascular smooth muscle pressor responsiveness. 3. Ten of the 34 women subsequently developed pregnancy-induced hypertension. Platelet angiotensin II binding in the patients who subsequently developed pregnancy-induced hypertension was sixfold higher than in the patients who remained normotensive (P less than 0.001). There were, however, no significant differences between the groups in any of the parameters derived from the angiotensin II infusion experiments. 4. The use of platelet angiotensin II binding alone in predicting the outcome of the pregnancies, as assessed using discriminant analysis, was more successful than when any of the infusion parameters were used, with 77% of patients being correctly classified.     

Clinical profiles of new angiotensin II receptor blockers: telmisartan, olmesartan medoxomil, and irbesartan

Clinical use of type 1 angiotensin II receptor blockers(ABRs) is rapidly increasing because of their high safety as well as excellent efficacy. Recent clinical trials have demonstrated that telmisartan at a daily dose of 20-80 mg, olmesartan medoxomil at 10-40 mg, and irbesartan at 150-300 mg are effective and safe for the treatment of essential hypertension, severe hypertension and hypertension associated with renal diseases. These ARBs are similar to ACE inhibitors in terms of antihypertensive efficacy, but lack the adverse effect of cough. Long-term effects should be compared among ARBs, ACE inhibitors, and other antihypertensive drugs.     

The effect of oral protease administration in the rat remnant kidney model

It has been demonstrated that intraperitoneal administration of proteolytic enzymes ameliorates the progression of renal diseases in various animal models. In the present study, we employed the rat remnant kidney model to study the effectiveness of oral administration of proteases. Twenty male Wistar rats underwent sham operation (CTRL), while 25 were subjected to 5/6 nephrectomy (5/6 NX). Rats were randomised into placebo (PL) (2 ml tap water/day by gavage), or Phlogenzym (E; fixed mixture of trypsin 2.42 mg, bromelain 4.54 mg, and rutozid 5.04 mg added as antioxidant, in 2 ml tap water daily by gavage) treated group. Duration of the study was 45 days. Rats were pair-fed. Enzyme treatment exerted salutary effects on various functional and morphological parameters. Proteinuria was higher in both 5/6 NX group rats throughout the study. Administration of proteases ameliorated its rise effectively (data at sacrifice: CTRL-PL 6.27ǃ.25, CTRL-E 9.27ǂ.99, 5/6 NX-PL 74.04ᆩ.33, 5/6 NX-E 39.09lj.93 mg/ 24 h; P<0.01). Increased urinary excretion of the fibrogenic cytokine transforming growth factor (TGF-#₁) was improved, too (CTRL-PL 0.349ǂ.051, CTRL-E 0.693ǂ.230, 5/6 NX-PL 3.044ǂ.540, 5/6 NX-E 1.390ǂ.238 ng/ µmol creatinine; P<0.05). At sacrifice, tubulointerstitial fibrosis was less pronounced in E-treated rats. Correspondingly, the volume fraction of tubulointerstitial tissue in the renal cortex was improved in 5/6 NX-E rats (CTRL-PL 9.9ǂ.2, CTRL-E 10.0ǂ.2, 5/6 NX-PL 17.9ǃ.8, 5/6 NX-E 13.8ǂ.9%; P<0.05). The protein/DNA ratio in isolated glomeruli and tubules, as an estimate of glomerular matrix accumulation and hypertrophy of tubules, was enhanced in 5/6 NX groups and a tendency towards lower values was observed after E treatment. Renal function as evaluated by serum creatinine and urea levels was not influenced by the enzyme therapy. No between-group differences in blood pressure were observed. In summary, oral administration of proteolytic enzymes improved proteinuria and urinary TGF-#₁ excretion, as well as the severity of tubulointerstitial fibrosis without signs of toxicity.     

Role of receptor cycling in the regulation of angiotensin II surface receptor number and angiotensin II uptake in rat vascular smooth muscle cells.

In vivo data on the factors controlling angiotensin II (AII) cell surface binding are conflicting. We studied the specific effects of AII on AII binding in rat mesenteric artery vascular smooth muscle cells in culture. Incubation with unlabeled AII at 21 degrees C resulted in time- and concentration-dependent decreases in AII surface binding at 4 degrees C, with a 30% reduction after exposure to 300 nM AII for 15 min. Reductions in cell surface binding were due to decrements in receptor number rather than changes in binding affinity. Loss of surface receptors was mediated by receptor internalization as maneuvers that blocked ligand internalization (cold temperature and phenylarsine oxide [PAO]) attenuated AII-induced loss of surface receptors. After removal of AII, recovery of surface binding was rapid (t1/2 = 15 min) and was mediated by reinsertion of a preexisting pool of receptors into the surface membrane rather than by new receptor synthesis. To determine the role of receptor cycling on AII-induced surface receptor loss, cells were incubated with the endosomal inhibitor chloroquine during exposure to AII at 21 degrees C. Incubation with AII plus chloroquine resulted in a 70% greater loss of surface binding than after incubation with AII alone. To determine the role of receptor cycling on uptake of ligand, cells were incubated with PAO or endosomal inhibitors during exposure to AII at 4 and 21 degrees C. Compared with buffer these agents did not alter AII uptake at 4 degrees C, but decreased uptake by 12-50% at 21 degrees C. These results indicate that after binding AII receptors cycle and that receptor cycling attenuates AII-induced losses of surface receptors and enhances ligand uptake by providing a continuous source of receptors to the cell surface.     

Effects of direct renin inhibition versus angiotensin II receptor blockade on angiotensin profiles in non-diabetic chronic kidney disease

Background: Direct renin inhibition (DRI) is clinically inferior to other blockers of the renin–angiotensin system (RAS). Thus far, the underlying molecular causes of this finding remain unknown.

Methods: Twenty four patients with non-diabetic chronic kidney disease (CKD) stages III–IV and albuminuria were randomized to DRI or angiotensin receptor blocker (ARB). Employing a novel mass-spectrometry method, the concentrations of renin, aldosterone and plasma angiotensin peptides [Ang I, Ang II, Ang-(1-7), Ang-(1-5), Ang-(2-8), Ang-(3-8)] were quantified before and after an 8-week treatment.

Results: While blood pressure, renal function and albuminuria decreased comparably in both groups, profound RAS component differences were observed: DRI led to a massive renin increase, while suppressing both vasoconstrictive (Ang I and Ang II) and vasodilatory RAS metabolites (Ang-(1-7) and Ang-(1-5)). In contrast, ARB led to a four-fold increase of Ang I and Ang II, while Ang-(1-7) and Ang-(1-5) increased moderately but significantly. With ARB treatment, a decreased aldosterone-to-Ang II ratio suggested efficacy in blocking AT1 receptor.

Conclusions: DRI therapy abolishes all RAS effector peptides. ARB increases both vasoconstrictive and vasodilative angiotensins, while this is accompanied by efficient blockade of vasoconstrictive effects. These differential molecular regulations should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients.

• Key messages

• Direct renin inhibition leads to a complete and lasting abolition of both classical and alternative RAS components.

• Angiotensin receptor blockade leads to effective receptor blockade and up-regulation of alternative RAS components.

• Differential molecular regulations of the RAS should be considered when selecting optimal antihypertensive and disease-modifying therapy in CKD patients.

     

The effects of angiotensin II receptor antagonists on insulin resistance]

Many of hypertensive individuals have glucose intolerance and dyslipidemia, and insulin resistance is common disorder on the basis of these diseases. It is important to take care of these metabolic disease for not only the control of hypertension, blood glucose and hyperlipidemia, but also the prevention of atherosclerosis. We reviewed the effects of angiotensin II receptor antagonists on insulin resistant syndrome.     

Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing

OBJECTIVES: We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT(1)-receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses. METHODS: Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study. All doses were given once daily for 8 days. The angiotensin II receptor blockade was assessed with two techniques, the reactive rise in plasma renin activity and an in vitro radioreceptor binding assay that quantified the displacement of angiotensin II by the blocking agents. Measurements were obtained before and 4 and 24 hours after drug intake on days 1 and 8. RESULTS: At 4 and 24 hours, valsartan induced a dose-dependent "blockade" of AT(1) receptors. Compared with other antagonists, 80 mg valsartan and 50 mg losartan had a comparable profile. The 160-mg and 320-mg doses of valsartan blocked AT(1) receptors at 4 hours by 80%, which was similar to the effect of 150 mg irbesartan. At trough, however, the valsartan-induced blockade was slightly less than that obtained with irbesartan. With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan. CONCLUSIONS: These results show that the differences in angiotensin II receptor blockade observed with the various AT(1) antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan.     

Localization of the angiotensin II and its receptor subtype expression in human endometrium and identification of a novel high-affinity angiotensin II binding site.

Angiotensin (ANG) II is not only a potent vasoconstrictor but may also be involved in the regeneration of new blood vessels. In proliferative endometrium, ANG II-like immunoreactivity was detected in glandular epithelium and stroma with negligible staining around the vascular endothelium. In contrast, in secretory endometrium intense immunostaining was seen in the perivascular stromal cells around the endometrial spiral arterioles with negligible staining of the other cell types. Quantitative receptor autoradiography using the nonselective radioligand [125I]-ANG II and subtype selective competing compounds showed that endometrium contained predominantly AT2 receptors, with relatively low expression of AT1 receptors and a novel non-AT1/non-AT2 angiotensin II recognition site that was insensitive to AT1 or AT2 selective ligands. Levels of specific [125I]-ANG II receptor binding displayed cyclic changes during the menstrual cycle, reaching a maximum in early secretory endometrium and then decreasing in mid to late secretory endometrium to levels seen in early to mid proliferative endometrium. In situ hybridization showed AT1 receptor mRNA expression in the glands and in the endometrial blood vessels. The cyclic changes in ANG II-like immunoreactivity together with expression of both the known and the novel AT receptor subtypes imply that this octopeptide may play a dual role both in the control of the uterine vascular bed and also in the regeneration of the endometrium after endometrial shedding, acting as an angiogenic and mitogenic mediator.     

Ontogeny of type 1 angiotensin II receptor gene expression in the rat.

To determine whether the expression of the type 1 angiotensin II receptor (AT1) gene is developmentally regulated and whether the regulation is tissue specific, AT1 mRNA levels were determined by Northern blot analysis in livers and kidneys from fetal, newborn, and adult rats, using a 1133-bp rat AT1 cDNA. In the liver, AT1 mRNA levels increased fivefold from 15 d gestation to 5 d of age. Liver AT1 mRNA levels at 5 d of age were similar to those of adult rats. In the kidney, AT1 mRNA levels were higher in immature than in adult animals. The intrarenal distribution of AT1 mRNA was assessed by in situ hybridization to a 35S-labeled 24 residues oligonucleotide complementary to rat AT1 mRNA. In the adult, AT1 mRNA was present in glomeruli, arteries, and vasa recta, whereas in the newborn AT1 mRNA was observed also over the nephrogenic area of the cortex. We conclude that: (a) fetal kidney and liver express the AT1 gene; (b) the AT1 gene expression is developmentally regulated in a tissue-specific manner; (c) during maturation, localization of AT1 mRNA in the kidney shifts from a widespread distribution in the nephrogenic cortex to specific sites in glomeruli, arteries, and vasa recta, suggesting a role for the angiotensin receptor in nephron growth and development.