Characterization of angiotensin II antagonism displayed by SK-1080, a novel nonpeptide AT1-receptor antagonist

The pharmacologic profile of SK-1080, a nonpeptide AT1-selective angiotensin-receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in pithed rats. SK-1080 inhibited the specific binding of [125I]-[Sar1, Ile8]-angiotensin II to human recombinant AT1 receptor with a 12-fold greater potency than losartan [median inhibitory concentration (IC50): 1.01 and 12.3 nM, respectively], but it did not inhibit the binding of [125I]-CGP 42112A to human recombinant AT2 receptor (IC50: >10 microM for both). The Hill coefficient for the competition curve of SK-1080 against AT1 receptor was not significantly different from unity (0.96). Scatchard analysis showed that SK-1080 interacted with human recombinant AT1 receptor in a competitive manner, as with losartan. In functional studies with rat and rabbit aorta, SK-1080 competitively inhibited the contractile response to angiotensin II (pKB values: 9.97 and 9.51, respectively) with 15-25% decrease in the maximal contractile responses, unlike losartan, which showed competitive antagonism without any change in the maximal contractile responses to angiotensin II (pA2 values, 8.02 and 7.59, respectively). In pithed rats, SK-1080 (i.v.) induced a nonparallel right shift in the dose-pressor response curve to angiotensin II (ID50, 0.07 mg/kg) with a dose-dependent reduction in the maximal responses; this antagonistic effect was approximately 25 times more potent than losartan (ID50, 1.74 mg/kg), which showed competitive antagonism. SK-1080 did not alter the responses induced by other agonists such as norepinephrine, KCI, and vasopressin in isolated rabbit aorta and pithed rats. These results suggest that SK-1080 is a highly potent AT1-selective angiotensin II-receptor antagonist with a mode of insurmountable antagonism.     

In vivo pharmacologic profile of SK-1080, an orally active nonpeptide AT1-receptor antagonist

The pharmacologic profile of SK-1080, a newly synthesized AT1-receptor antagonist, was evaluated in conscious normotensive rats, conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated beagle dogs. In angiotensin II-challenged normotensive rats, orally administered SK-1080 had no agonistic effect and dose-dependently inhibited the pressor response to angiotensin II with a slightly weaker potency (ID50: 1.12 and 0.47 mg/kg, respectively), but with a more rapid onset of action than losartan (time to Emax, 30 min and 6 h, respectively). In RHRs, orally given SK-1080 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a potency similar to that of losartan (ED20, 5.06 and 3.36 mg/kg, respectively). Intravenously administered SK-1080 exerted a very highly potent antihypertensive effect (ED20, 0.06 mg/kg), thus indicating a poor oral bioavailability in rats. On repeated dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance throughout the dosing period. On repeated dosing, the antihypertensive effect gradually increased from days 1 to 7 (Emax on day 7, 15.0 and 19.7% at 10 and 30 mg/kg, respectively) and remained at a significant level on days 14 and 21. In furosemide-treated dogs, orally given SK-1080 produced a dose-dependent and long-lasting (>8 h) antihypertensive effect with a rapid onset of action (time to Emax, 1-1.5 h) and 10-fold greater potency than losartan (ED20, 0.72 and 8.13 mg/kg, respectively). In furosemide-treated dogs, SK-1080 showed a good oral bioavailability, unlike that in RHRs. These results suggest that SK-1080 is a potent, orally active AT1-receptor antagonist useful for the treatment of hypertension.     

Effects of subchronic treatment with AT1 receptor antagonists on endothelium-dependent and-independent relaxation

To investigate whether AT₁ receptor antagonists are acting by increasing endothelium-dependent and-independent relaxation of aortas in normotensive rats, AT₁ receptor antagonists, losartan and KR-30988, and angiotensin converting enzyme inhibitor, captopril, were orally administered for two weeks (50 mg/kg, b.i.d.). The blood pressure, heart rate and body weight were not significantly changed by losartan, KR-30988 and captopril compared to the control group. In aortic preparations, the pD₂ of KR-30988 for ACh-induced relaxation was 8.33±0.16, significantly (p<0.05) lower than that of control group (7.71±0.15). ACh-induced relaxation was significantly increased in losartan-treated group (p<0.01) at 10^?6 M of ACh, and in captopril-treated group (p<0.05) at the range of 10^?7–10^?5 M of ACh. The pD₂ values for histamine-induced relaxation of losartan, KR-30988 and captopril were 5.57±0.10, 5.85±0.21 and 5.60±0.01, respectively, with significant differences in all groups (p<0.01) compared to that of control group (5.13±0.09). ACh-induced relaxations of aortic preparations were not changed by pretreatment of indomethacin (10^?5 M), and completely blocked by pretreatment of L-NAME (10^?5 M) in all groups. Sodium nitroprusside-induced relaxations were not significantly changed by all drugs tested in this experiments. These results suggest that AT₁ receptor antagonists, losartan and KR-30988, enhance the endothelium-dependent relaxation on aortic preparations through the release of, or increase sensitivity, to nitric oxide in normotensive rats.     

In vivo pharmacological evaluation of newly synthesized nonpeptidic AT1 receptor antagonists in rats

This study was conducted to characterize thein vivo pharmacology of KR-30988, KR-30992 and losartan, new AT₁ antagonists, given as i.v. cumulative doses, in two animal models of high renin, conscious renal artery-ligated hypertensinve rats (RHRs) and normotensive rats anesthetized with urethane (900 mg/kg, i.p.) and α-chloralose (90 mg/kg, i.p.), with a special emphasis on the pharmacological characterization of the latter model. In conscious RHRs, KR-30988, KR-30992, losartan and captopril caused a dose-dependent decrease in blood pressure, their relative potencies (ED₂₀) being 0.057, 0.208, 0.164 and 0.018 mg/kg i.v., repectively. In anesthetized rats, 2 hours after anesthesia, plasma renin activity was increased from 7.31 to 34.07 ng/ml/h, the level approximately 1.5 times greater than the highest level in RHRs. In anesthtized rats, the ED₂₀S for all four compounds were 0.011, 0.046, 0.035 and 0.004 mg/kg i.v., repectively. By comparison, ED₂₀s from anesthetized rats were 4 to 5 times smaller than those from conscious RHRs, with a good correlation (r=0.999) noted between ED₂₀s from two groups of rats. The data on ED₂₀ may indicate the higher sensitivity of anesthetized rats to the hypotensive activity of the compounds and the same order of potencies in two models. These results suggest that, in addition to RHRs, the nomotensive rats anesthetized as above can serve as a suitable model for the rapid pharmacological evaluation of AT₁ receptor antagonists.     

Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats

Angiotensin AT1 receptor antagonists represent a novel class of cardiovascular drugs. In conscious, normotensive rats, irbesartan ((2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non) and losartan ((2 n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl -4-yl) methyl] imidazol), two specific, high- affinity angiotensin AT1 receptor antagonists administered intravenously (i.v.) at doses of 0.3, 1, 3 and 10 mg/kg body weight, or orally (p.o.) at doses of 1, 3, 10 and 30 mg/kg body weight, antagonized the pressor responses to i.v. angiotensin II (50 ng/kg body weight) in a dose-related manner and with similar potency. In the following sets of experiments, we tested the hypothesis that these angiotensin AT1 receptor antagonists, when applied systemically, can inhibit the effects of angiotensin AT1 receptor stimulation in the brain. Irbesartan and losartan were administered i.v. or p.o. at doses of 3, 10, 30 and 100 mg/kg body weight. The responses to 100 ng angiotensin II injected into the lateral brain ventricle (i.c.v.), namely blood pressure increase, vasopressin release into the circulation and drinking, were recorded for up to 3 h. While both angiotensin AT1 receptor antagonists dose-dependently attenuated the pressor responses to central angiotensin AT1 receptor stimulation to a similar degree (maximal inhibition, irbesartan: 62% i.v., 39% p.o.; losartan: 62% i.v., 46% p.o.; respectively), irbesartan was more effective with respect to the inhibition of vasopressin release (76% i.v., 65% p.o.) and drinking (63% i.v., 79% p.o.) than losartan (58% i.v., 33% p.o and 22% i.v., 56% p.o., respectively). We conclude that systemically administered angiotensin AT1 receptor antagonists have access to central angiotensin receptors. The degree of central angiotensin AT1 receptor blockade following peripheral application may vary between different representatives of this class of drugs.     

Biphasic effects of losartan potassium on immobility in mice

The effects of losartan potassium, an angiotensin AT(1) receptor blocker on immobility in forced swim test have been studied. Effect of losartan potassium, nortriptyline HCl, fluoxetine HCl and reserpine per se and in combination on forced swimming-induced immobility in mice have also been studied. In mice, losartan potassium elicits biphasic responses i.e. positive responses at lower doses (0.1, 1.0 and 5 mg/kg, i.p.) in the forced swim test, a test of potential antidepressant activity and vice versa at higher dose (20 and 100 mg/kg, i.p.). In chronic studies, enhancement in immobility was observed for losartan potassium (3 and 30 mg/kg, p.o., 21 days). In acute combination studies, losartan potassium (1 and 5 mg/kg) significantly reversed the reserpine-induced immobility, but vice versa at 100 mg/kg. Losartan potassium (0.1 and 5 mg/kg) potentiate antidepressant activity of nortriptyline (30 mg/kg, i.p.) in mice, but vice versa at 100 mg/kg. Likewise, Losartan potassium (100 mg/kg), significantly reversed antidepressant activity of fluoxetine HCl, but at 0.1 and 5 mg/kg, failed to modify fluoxetine HCl induced immobility. The obtained biphasic effect of losartan potassium on immobility in mice might be due to inhibitory effect on AT(1) receptor at lower dose and pronounced effect on AT(2) receptor at higher dose (large concentrations of losartan potassium can displace Angiotensin II (Ang II) from its AT(1) receptor to AT(2) receptor.     

Pharmacology of the angiotensin II receptor antagonist, eprosartan

The non-peptide angiotensin II receptor antagonists represent a new class of drugs with demonstrated efficacy in the treatment of hypertension. Eprosartan is a potent, orally active AT(1) receptor antagonist which is chemically distinct from losartan and other non-peptide angiotensin II receptor antagonists. Eprosartan has a high affinity for the angiotensin II AT(1) receptor, but does not interact with the AT(2) receptor, adrenergic receptors or other receptors involved in cardiovascular regulation. In contrast to most other angiotensin II antagonists, eprosartan is a true competitive antagonist of the AT(1) receptor. Eprosartan is effective in antagonising the cardiovascular and renal effects of exogenous angiotensin II in both experimental animals and humans. Furthermore, it is an effective antihypertensive agent when administered to renin-dependent hypertension animal models, and in patients with mild to severe hypertension. The antihypertensive effect of eprosartan is maintained over a 24-h interval following a single dose with no reported dose-dependent adverse side-effects.     

Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models

The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.     

Dose-dependent blockade of the angiotensin II type 1 receptor with losartan in normal volunteers

Losartan, an angiotensin II type 1 receptor (AT1) antagonist, was developed as a more specific alternative to angiotensin-converting enzyme (ACE) inhibitors. At a daily dose of 50 mg, losartan is currently evaluated in large outcome trials involving patients with hypertension and postmyocardial infarction. The current study evaluated the level and duration of blockade of a pressor response to angiotensin II by 50 and 150 mg of losartan, compared with 32 mg of candesartan. Eight normotensive volunteers were randomly assigned to a single dose of losartan 50 or 150 mg, candesartan 32 mg, or placebo. Subjects were re-randomized after a 2-week washout period to complete all four study arms. Radial artery systolic pressure response to exogenous angiotensin II was measured at 2, 6, 12, and 24 h after administration of drug. Losartan 50 mg reduced the pressure response to exogenous angiotensin II significantly only at 6 h. In contrast, candesartan and losartan 150 mg produced a greater reduction in the pressure response to angiotensin II throughout the 24-h period. This suppression was not paralleled by a reduction in resting systemic arterial pressure. Higher doses than 50 mg of losartan might be evaluated to elicit optimal clinical effects.     

Chronic hypotensive effects of losartan are not dependent on the actions of angiotensin II at AT 2 receptors.

We have previously demonstrated the chronic hypotensive effects of the AT1 antagonist, losartan, in normotensive, salt-replete rats. One explanation for this response is a reduction in vascular resistance due to blockade of AT1 receptors. Another explanation is that increases in angiotensin II levels during losartan administration can bind to AT2 receptors. Studies suggest that binding of angiotensin II at AT2 receptors lowers arterial pressure by vasodilation. We hypothesized that the chronic effects of losartan are mediated by activation of angiotensin II effects at AT2 receptors. We tested this hypothesis by infusing the AT2 receptor antagonist, PD123319 (74 mg/kg/day), in conjunction with losartan (10 mg/kg/day) for 10 days in rats and compared the hypotensive response in rats treated with losartan alone. After 6 days of treatment, arterial pressure decreased similarly in losartan (-21 +/- 2 mm Hg) and losartan+PD123319 (-23 +/- 2 mm Hg) treated rats. However, by day 10 of the infusion, arterial pressure had decreased to a greater extent (p < 0.05) in rats treated with losartan and PD123319 (-31 +/- 2 mm Hg) compared with rats treated with losartan alone (-22 +/- 2 mm Hg). We conclude that the hypotensive effects of losartan are not dependent on the actions of angiotensin II at AT 2 receptors in normotensive, salt-replete rats.     

Pharmacologic profile of UR-7247, an orally active angiotensin II AT1 receptor antagonist, in healthy volunteers. p6

This study was conducted to assess the pharmacologic properties of the new orally active angiotensin II subtype I (AT1) antagonist UR-7247, a product with a half-life >100 h in humans. The experiment was designed as an open-label, single-dose administration study with four parallel groups of four healthy men receiving increasing single oral doses (2.5, 5, and 10 mg) of UR-7247 or losartan, 100 mg. Angiotensin II receptor blockade was investigated < or =96 h after drug intake, with three independent methods [i.e., the inhibition of blood pressure (BP) response to exogenous Ang II, an in vitro Ang II-receptor assay (RRA), and the reactive increase in plasma angiotensin II. Plasma drug levels also were measured. The degree of blockade observed in vivo was statistically significant < or = 96 h with all UR-7247 doses for diastolic BP (p < 0.05) and < or =48 h for systolic BP. The maximal inhibition achieved with 10 mg UR-7247 was measured 6-24 h after drug intake and reached 54 +/- 17% and 48 +/- 20% for diastolic and systolic responses, respectively. Losartan, 100 mg, induced a greater short-term AT1-receptor blockade than 2.5- and 5.0-mg doses of UR-7247 (p < 0.001 for diastolic BP), but the UR-7247 effect was longer lasting. In vivo, no significant difference was observed between 10 mg UR-7247 and 100 mg losartan 4 h after drug intake, but in vitro, the blockade achieved with 100 mg losartan was higher than that seen with UR-7247. Finally, the results confirm that UR-7247 has a very long plasma elimination half-life, which may be due to a high but also tight binding to protein binding sites. In conclusion, UR-7247 is a long-lasting, well-tolerated AT1 receptor in healthy subjects.     

Captopril given intracerebroventricularly, subcutaneously or by gavage inhibits angiotensin-converting enzyme activity in the rat brain

In rats with permanent brain cannulas intracerebroventricular (i.c.v.) injections of 2 microgram captopril nearly abolished drinking responses elicited by i.c.v. injections of 1 mUnit hog renin, 10 pmol synthetic renin substrate or 10 pmol angiotensin I but did not reduce drinking elicited by 10 pmol angiotensin II. Inhibition of the response to precursors of angiotensin II was long-lasting (at least 2 h) and dose-dependent (20 ng-2 microgram captopril). Captopril was 3-5 times more potent than SQ 20,881 i.c.v. Subcutaneous injections of captopril in doses 0.1 to 1.0 mg/kg reduced pressor responses to intravenous injections of angiotensin I without attenuating drinking elicited by i.c.v. injections of angiotensin precursors. Higher doses of captopril, however, given subcutaneously (5-50 mg/kg) or by gavage (10 mg/kg) did not reduce drinking to i.c.v. injections of renin or angiotensin I (but not angiotensin II). We conclude that captopril inhibits angiotensin-converting enzyme activity in the brain even when given subcutaneously or by gavage in doses commonly used in the rat.     

Evidence that angiotensin II enhances apomorphine-induced jaw movements via AT1 receptors in the ventrolateral striatum: studies by magnet-sensing system in freely moving rats

The role of angiotensin AT(1) receptors in the ventrolateral striatum in modulating apomorphine-induced jaw movements was studied using a magnet-sensing system combined with an intracerebral drug microinjection technique in freely moving rats. Bilateral injections of angiotensin II (1 and 2 micro g/0.2 micro l in each side) into the ventrolateral striatum, which alone did not significantly elicit jaw movements, dose-dependently enhanced apomorphine (1 mg/kg i.v.)-induced repetitive jaw movements. The enhancement of apomorphine-induced jaw movements by angiotensin II (2 micro g) was dose-dependently antagonized by the angiotensin AT(1) receptor antagonist losartan (15 and 30 mg/kg i.p.), given 3 h before, while losartan (30 mg/kg i.p.) alone did not significantly affect the apomorphine (1 mg/kg)-induced jaw movements. These results indicate that angiotensin II enhances apomorphine-induced jaw movements via stimulation of angiotensin AT(1) receptors located in the ventrolateral striatum.     

Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO-K1 cells expressing human angiotensin II AT1 receptors

1. CHO-K1 cells that were stably transfected with the gene for the human AT1 receptor (CHO-AT1 cells) were used for pharmacological studies of non-peptide AT1 receptor antagonists. 2. In the presence of 10 mM LiCl, angiotensin II caused a concentration-dependent and long-lasting increase of inositol phosphates accumulation with an EC50 of 3.4 nM. No angiotensin II responses are seen in wild-type CHO-K1 cells. 3. [3H]-Angiotensin II bound to cell surface AT1 receptors (dissociates under mild acidic conditions) and is subject to rapid internalization. 4. Non-peptide selective AT1 antagonists inhibited the angiotensin II (0.1 microM) induced IP accumulation and the binding of [3H]-angiotensin II (1 nM) with the potency order: candesartan > EXP3174 > irbesartan > losartan. Their potencies are lower in the presence of bovine serum albumin. 5. Preincubation with the insurmountable antagonist candesartan decreased the maximal angiotensin II induced inositol phosphate accumulation up to 94% and, concomitantly, decreased the maximal binding capacity of the cell surface receptors. These inhibitory effects were half-maximal for 0.6 nM candesartan and were attenuated by simultaneous preincubation with 1 microM losartan indicating a syntopic action of both antagonists. 6. Losartan caused a parallel rightward shift of the angiotensin II concentration-response curves and did not affect the maximal binding capacity. EXP3174 (the active metabolite of losartan) and irbesartan showed a mixed-type behavior in both functional and binding studies. 7. Reversal of the inhibitory effect was slower for candesartan as compared with EXP3174 and irbesartan and it was almost instantaneous for losartan, suggesting that the insurmountable nature of selective AT1 receptor antagonists in functional studies was related to their long-lasting inhibition.     

Comparative study of TA-606, a novel angiotensin II receptor antagonist, with losartan in terms of species difference and orthostatic hypotension

Losartan is a prodrug type Angiotensin II (Ang II) AT1-receptor antagonist whose efficacy depends on the oxidase activity of individuals. In addition, losartan affects the normal blood pressure and can potentially cause orthostatic hypotension. In this report, we examined effects of TA-606 [(3-pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H -tetrazole-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridine-4-carboxylate hydrochloride], a prodrug type AT1-receptor antagonist, on the Ang II-induced pressor response and hypertension in a dog model, which is known to have lower oxidase activity than other species, and orthostatic hypotension in the rat tilting model. The results indicated that TA-606 was immediately converted to its active form, 606A, after oral administration, and it demonstrated potent inhibition of the Ang II-induced pressor response in conscious normotensive dogs (0.3-3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K,1C-renal hypertensive dogs (0.3-10 mg/kg, p.o.). These effects of TA-606 were 32 and 30 times more potent than those of losartan, respectively. In addition, EXP3174 (1, 10 mg/kg, i.v.), an active metabolite of losartan, but not 606A (1-30 mg/kg, i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These results suggest that TA-606 is an effective Ang II receptor antagonist without the drawbacks of losartan.     

Downregulation of cardiac AT1-receptor expression and angiotensin II concentrations after long-term blockade of the renin-angiotensin system in cardiomyopathic hamsters.

We monitored cardiac angiotensin II concentration and AT1-receptor density after long-term blockade of the renin-angiotensin system in inbred control hamsters treated with placebo or losartan (100 mg/kg/day) and cardiomyopathic hamsters treated with placebo, low-(30 mg/kg/day), or high-dose (100 mg/kg/day) losartan or quinapril (100 mg/kg/day). All treatments were started at age 50 days. Angiotensin II-receptor density and affinity were measured by radioligand-binding assays, and ventricular angiotensin II concentration was determined by radioimmunoassay. After 125 and 275 days of treatment, both doses of losartan significantly reduced AT1-receptor density, whereas quinapril had no effect. The administration of both drugs resulted in significant reductions in ventricular angiotensin II concentration. The prolonged administration of losartan was associated with an increase in cardiac hypertrophy, suggesting that angiotensin II signaling is not directly involved or at least does not play a major role in the remodeling process observed in cardiomyopathic hamsters.     

Losartan potassium, a nonpeptide antagonist of angiotensin II, chronically administered p.o. does not readily cross the blood-brain barrier.

Recently several novel nonpeptide antagonists of angiotensin II (Ang II) have been identified. One of these, losartan potassium (formerly DuP 753) was developed as an orally active and highly selective antagonist for Ang II. As it is inhibited by sulfhydryl agents, it is specific for the AT1 receptor subtype. Since Ang II has both central and peripheral effects, we investigated whether losartan, given p.o. chronically, crosses the blood-brain barrier. The effects of chronic administration of losartan orally (p.o.) at 3 mg/kg per day for three days on the dipsogenic and pressor responses to a pre-established dose of Ang II i.v.t. (50 ng) were studied. Three series of experiments were carried out using conscious normotensive Sprague-Dawley rats. The rats were injected with Ang II intraventricularly (i.v.t.) before and after treatment of losartan p.o. and blood pressure and drinking responses measured. The experiments established that 3 mg/kg losartan p.o. for 3 days antagonized pressor effects of Ang II intravenously (i.v.), but did not antagonize the pressor or drinking effects of Ang II i.v.t. Daily water intake significantly increased with chronic losartan p.o.. Since chronic administration of losartan p.o. was able to block the effects of Ang II i.v. but had no effect on Ang II i.v.t. we conclude that losartan potassium does not readily cross the blood-brain barrier using this dose regimen.     

Pharmacokinetic evaluation of losartan

INTRODUCTION: Blockade of the renin-angiotensin system is one of the major therapeutic strategies in the management of patients with essential hypertension, congestive heart failure and diabetic as well as non-diabetic renal diseases. As the first angiotensin II receptor blocker (ARB) on the market, losartan belongs to the most frequently prescribed ARB. AREA COVERED : The present review examines the pharmacokinetics of losartan with a special discussion on the dose of losartan that should be used in clinical practice to obtain the maximal benefits of the drug. Readers are provided with arguments suggesting that the dose of 50 mg losartan is probably too low and that losartan should preferably be prescribed at the dose of 100 mg/day or higher. EXPERT OPINION : Losartan is an effective antagonist of angiotensin II AT(1) receptors which has been shown to provide important clinical benefits in patients with hypertension, congestive heart failure and renal diseases. Losartan should be prescribed at the dose of 100 mg/day and the use of higher doses should be reconsidered in future studies to improve its clinical efficacy.     

Cardiovascular reactivity after blockade of angiotensin AT1 receptors in the experimental model of tilting test in conscious rats

BACKGROUND AND PURPOSE: Studies have shown that the angiotensin II AT(1) receptor antagonist, losartan, accentuates the hypotensive response in the orthostatic stress test (tilt) performed in anaesthetized rats. The same effect was not reported with other AT(1) antagonists. The aim of this study was to re-evaluate the effects of AT(1) receptor blockade on the cardiovascular response to tilt in a model developed for conscious rats. EXPERIMENTAL APPROACH: Rats (n=5-7 per group) were instrumented for infusion of drugs and recording of cardiovascular parameters and, after recovery, placed in a plastic tube positioned over the tilt board. The tilt test was conducted by raising the head side of the tilt board from horizontal position to 75 degrees head up position for 15 min. KEY RESULTS: Compared with control group (NaCl 0.9%, 1 ml kg(-1)), oral treatment with 1 mg kg(-1) per day of losartan or telmisartan did not alter the blood pressure response during tilt. With the 10 mg kg(-1) dose, both antagonists altered the blood pressure response during tilt (mean maximum changes -11+/-3 mm Hg; P<0.01). A post-tilt hypotension was observed with both doses in losartan and telmisartan groups (-13+/-1 and -9+/-2 mm Hg, respectively; P<0.01). CONCLUSIONS AND IMPLICATIONS: The present results indicate that the effect of losartan on the cardiovascular reactivity to tilt shares a similar profile to that of other AT(1) antagonists. Evidence discussed addresses the importance of using a conscious model for testing the influence of antihypertensive drugs on the cardiovascular reactivity to orthostatic challenges.     

Unchanged cardiac angiotensin II levels accompany losartan-sensitive cardiac injury due to nitric oxide synthase inhibition

Chronic nitric oxide synthase (NOS) inhibition results in hypertension and myocardial injury. In a rapid and severe model of chronic NOS inhibition, we determined the role of angiotensin II in these effects by using angiotensin II receptor blockade and by measuring cardiac angiotensin II concentrations before and during development of cardiac damage. Rats received either no treatment, the NOS inhibitor Nomega-nitro-L-arginine (L-NNA; 500 mg/l), the angiotensin AT(1) receptor antagonist losartan (400 mg/kg chow), or L-NNA plus losartan for 21 days. In the second protocol, five groups of rats received L-NNA (500 mg/l) for 0, 4, 7, 14 and 21 days, respectively. L-NNA increased systolic blood pressure (SBP) (227+/-8 versus 143+/-6 mm Hg; P<0.01), heart weight index (0.44+/-0.02 versus 0.32+/-0.01; P<0.01) and induced coronary vasculitis and myocardial necrosis. Co-treatment with losartan prevented all changes. L-NNA during 4 days decreased cardiac angiotensin II (23+/-4 versus 61+/-15 fmol/g; P<0.05). Although after 7 days, fresh infarcts and after 14 days organized infarcts were present, cardiac angiotensin II was only slightly increased after 21 days (100+/-10 fmol/g; P<0.05). In conclusion, losartan-sensitive cardiac damage due to chronic NOS inhibition is not associated with primary increase of cardiac angiotensin II, suggesting that chronic NOS inhibition increases cardiac sensitivity for angiotensin II.