Disease relevance of losartan

• DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension [1].
• In coarctation plus DuP 753-treated animals heart weight-body weight ratios were not different from sham or sham plus DuP 753 animals (3.9 +/- 0.4 versus 3.6 +/- 0.4 or 3.3 +/- 0.08, respectively) [2].
• Type 1 receptor blockade was accomplished with DuP 753 given in the drinking water and type 2 blockade with PD 123319 delivered by osmotic minipumps beginning with the day of surgery until 72 hours after aortic coarctation [2].
• Accupril- and Cozaar-induced angioedema in the same patient [3].
• 1. In previous experiments in conscious, water-replete Long Evans and Brattleboro rats the non-peptide angiotensin II-receptor antagonist, DuP 753, caused only slight hypotension and peripheral (particularly renal) vasodilatations [4].

Psychiatry related information on losartan

• Responses to DuP 753 were assessed in water-replete animals and in animals following 14h water deprivation to render cardiovascular status dependent on the renin angiotensin system (RAS) [5].

High impact information on losartan

• This increase in DNA synthesis was abolished by the in vivo administration of an Ang II receptor-specific antagonist (DuP 753) [6].
• We examined the effects of the AT1-receptor antagonist Losartan (DuP 753, 0.2-3.2 mg/kg) on coronary arteries in vivo in 11 dogs, using a combination of intravascular two-dimensional and Doppler ultrasound [7].
• In addition, radioligand binding at multiple sites of transient expression of AII receptors in 2-week-old rats, including several thalamic nuclei, the nuclei of the 3rd and 12th cranial nerves, geniculate bodies, cerebellum, and cingulate cortex, was displaced by the AT2 antagonists but not by DuP 753 [8].
• Oral administration of DuP 753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II [9].
• Six hours after 40 mg DuP 753, the systolic blood pressure response to the test-dose of angiotensin II was reduced to 37 +/- 7%, 40 +/- 4%, and 38 +/- 6% of baseline values (mean +/- SEM, n = 6) on days 1, 4, and 8, respectively [9].

Chemical compound and disease context of losartan

• This PD 121981-evoked low concentration effect of AII was selectively inhibited by DuP 753 (0.01-1 nM), dithiothreitol (10 and 100 microM), pertussis toxin (50 and 300 ng/ml, for 2 hr), nifedipine (1 and 10 microM) and 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (1 and 3 microM), which suggests the receptors were the AT1 subtype [10].
• Thus, direct blockade of AII with DuP 753 or with converting enzyme inhibition with captopril produces similar hemodynamic changes in rats with heart failure after myocardial infarction [11].
• I.c.v. injection of [Asn1,Val5]AII totally blocked the bradycardia induced by arginine-vasotocin and this effect was prevented by central administration of DuP 753 [12].
• Pretreatment with the angiotensin II (AngII) receptor subtype 1 (AT1) antagonist, DuP 753 (losartan) significantly attenuated this hypotensive effect, in a dose-dependent manner, while pretreatment with the AngII receptor subtype 2 (AT2) antagonist, PD123177, did not influence AmM-induced hypotension [13].
• In this study, the ANG II subtype AT1 receptor antagonist losartan (DuP 753) was administered perorally (15 mg.kg-1.day-1) for 28 days to rats subjected to partial urethral obstruction or sham surgery [14].

Biological context of losartan

• In marked contrast to undifferentiated cells, CGP 42112A became a potent competitor (IC50, 1 nM) for the majority (90-95%) of Ang II binding, whereas DuP 753 competed for only 5-10% of the binding sites [15].
• Moreover, the reduction of the maximum contractile force by EXP3174 (10 nM) was concentration-dependently restored in the presence of increasing concentrations of DuP 753 (10 nM to 1 microM), indicating interaction with the same binding site [16].
• ICV infusion of DuP 753 produced a significant increase (60 percent) in baroreflex control of heart rate in both Wistar rats and SHR [17].
• Glomerular filtration rate was not altered by DuP 753 or captopril; however, it fell from 1.6 +/- 0.1 to 1.2 +/- 0.1 ml/min/g kidney wt during infusion of the kinin antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)[18]
• Using this method, we demonstrated that transfection of ACE cDNA resulted in increased DNA synthesis, which was inhibited by the specific angiotensin II receptor antagonist DuP 753 (10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)[19]

Anatomical context of losartan

• In the adult rat brain, DuP 753 inhibited radioligand binding to the circumventricular organs and paraventricular nucleus but not to the lateral septum, subthalamic nucleus, and inferior olive [8].
• Type 1 angiotensin II receptors in the anterior hypothalamic area were blocked by local microinjection of DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly selective nonpeptide antagonist [20].
• DuP 753 (1 mg/d, n = 8) infused perivascularly for 14 days in the vicinity of injured carotid artery also markedly suppressed myointimal thickening (-60%, P < .01) [21].
• Neither DuP 753 nor captopril administered acutely (15 minutes) or for 2 days significantly altered the depressed baroreceptor reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)[22]
• DuP 753 (20 or 40 micrograms; in 100 nl artificial cerebrospinal fluid) or vehicle alone was microinjected into the anterior hypothalamic area of conscious NaCl-sensitive spontaneously hypertensive rats and Wistar-Kyoto controls [20].

Associations of losartan with other chemical compounds

• Mean carotid blood pressures and the carotid-femoral artery blood pressure gradients were not different among coarctation, coarctation plus DuP 753, and coarctation plus PD 123319 animals [2].
• In follicular oocytes, the peptide AII receptor antagonists saralasin (IC50 = 25 nM) and CGP 42112A (IC50 = 400 nM) were orders of magnitude more potent than the non-peptide antagonists DuP 753 and PD-123177 (IC50 greater than 10 microM) as inhibitors of AII-induced Ca2+ mobilization [23].
• Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure [24].
• In both normal and furosemide-treated spontaneously hypertensive rats (low Na+ diet plus furosemide), intracerebroventricular DuP 753 alone at 10 or 100 micrograms caused transient but significant pressor responses; however, no significant reduction in pressure (versus controls) was observed over the next 48 hours [25].
• The magnitude and duration of the depressor responses to DuP 753 and EXP 3174 were significantly greater in the 8% salt-fed spontaneously hypertensive rats than in 1% salt-fed rats [26].

Gene context of losartan

• Using the Ang II receptor subtype-selective nonpeptide antagonists, DuP 753 [selective for the type 1 Ang II (AT1) receptor] and PD 123319 [selective for the type 2 Ang II (AT2) receptor], we show that follicular granulosa cells, in vivo and in vitro, exclusively express the AT2 receptor [27].
• By virtue of the more than 1000-fold selectivity of losartan (DuP 753) for the AT1 angiotensin II (AII) receptor subtype compared with the AT2 subtype, [3H]losartan may be a useful radioligand for studies of the AT1 receptor subtype [28].
• Successive administration of ineffective doses of DuP 753 (losartan) and AT2 (angiotensin II) significantly decreased seizure intensity [29].
• LY-53857 inhibited the AVP, OT, and ACTH responses to 5-HT (P<0.01), whereas DuP-753 inhibited only the AVP response (P<0.01) [30].
• Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753 [31].

Analytical, diagnostic and therapeutic context of losartan

• The AT1-receptor antagonist DuP 753 (10 mg/kg per day in drinking water) was administered to 27 of these rats during low-salt diet [32].
• Normal rats and three groups of clipped rats were studied: an untreated group (HYP), a group treated with captopril (CEI), and a group treated with DuP 753 (DuP) 5 days before micropuncture [33].
• In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization [34].
• In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate [1].
• However, although angiotensin II levels increased after SR 47436 or DuP 753 treatment, they decreased after treatment with enalaprilat [35].

References