Resistance artery mechanics, structure, and extracellular components in spontaneously hypertensive rats : effects of angiotensin receptor antagonism and converting enzyme inhibition.
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BACKGROUND: Altered vascular mechanics resulting from changes in collagen and integrins may influence resistance artery structure and function and, therefore, peripheral resistance and blood pressure in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Effects of age, angiotensin-converting enzyme inhibition (fosinopril, 10 to 30 mg/kg per day), and AT(1)-receptor antagonism (irbesartan, 50 mg/kg per day) on vascular structure, mechanics, and composition were assessed in SHR. Systolic blood pressure was elevated in young SHR (130+/-2 mm Hg) compared with Wistar-Kyoto (WKY) rats (106+/-2 mm Hg). In adult SHR, the rise in systolic blood pressure (44+/-3 mm Hg) was blunted by fosinopril (18+/-1 mm Hg) and irbesartan (9+/-3 mm Hg). Lumen diameter of mesenteric resistance arteries was smaller and media/lumen ratio was greater in young and adult SHR versus WKY rats. Growth index was 24% in untreated adult SHR versus WKY rats; these values were -35% for fosinopril-treated and -29% for irbesartan-treated SHR versus untreated SHR. Isobaric wall stiffness was normal despite increased stiffness of wall components in adult SHR vessels. Irbesartan partially prevented stiffening of wall components in SHR. The collagen/elastin ratio was greater in adult SHR vessels (6.5+/-1.3) than in WKY (3.2+/-0.4) vessels. Expression of alpha(v)beta(3) and alpha(5)beta(1) integrins was increased in SHR aged 20 versus 6 weeks. Expression of alpha(5)beta(1) integrins was lower in young SHR, and alpha(v)beta(3) integrins were overexpressed in adult SHR versus WKY rats. Irbesartan and fosinopril attenuated differences in the collagen/elastin ratio and integrin expression. CONCLUSIONS: Wall components of mesenteric resistance arteries stiffen with age in SHR. Interrupting the renin-angiotensin system has normalizing effects on integrin expression and composition, stiffness, and growth of the arterial wall. (+info)
Comparative study of TA-606, a novel angiotensin II receptor antagonist, with losartan in terms of species difference and orthostatic hypotension.
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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. (+info)
Valsartan. Just a second-line antihypertensive drug.
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Valsartan (Diovan) is an antihypertensive drug belonging to the family of angiotensin II receptor antagonists. At a dose of 40 mg/d, its antihypertensive effect is inconsistent. At 80 mg/d its effect on blood pressure, its adverse effects, and its contraindications (mainly pregnancy and renal artery stenosis) are similar to those of angiotensin-converting enzyme (ACE) inhibitors, except that coughing is rarer with valsartan than with ACE inhibitors. Valsartan has no demonstrated advantage over losartan, another angiotensin II antagonist. Valsartan has not been shown to prevent complications of arterial hypertension, and its use is, therefore, less well validated than that of diuretics and beta-blockers. (+info)
Increased leukotriene A(4) hydrolase expression in the heart of angiotensin II-induced hypertensive rat.
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Leukotriene A(4) (LTA(4)) hydrolase is essential for the conversion of LTA(4) to LTB(4), an inflammatory lipid mediator. We investigated whether LTA(4) hydrolase was regulated in the heart by angiotensin II (ang II) infusion. Continuous ang II infusion via an osmotic minipump for up to 7 days upregulated mRNA and protein levels of LTA(4) hydrolase ( approximately 3.5-fold of control) in the heart in a pressor-dependent manner. Immunohistochemistry demonstrated intense LTA(4) hydrolase staining in the myofibroblast as well as migrated monocytes/macrophages. These data suggest that the cardiac LTA(4) hydrolase-LTB(4) system plays a positive role in the promotion of cardiac inflammation in hypertension. (+info)
Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation.
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This study was conducted to investigate whether the novel orally active nonpeptide angiotensin II (Ang II) AT(1) receptor antagonist irbesartan interacts with the thromboxane A(2)/prostaglandin endoperoxide H(2) (TxA(2)/PGH(2)) receptor in canine coronary arteries and human platelets. Coronary artery rings were isolated from male dog hearts (n = 18) and isometric tension of vascular rings was measured continuously at optimal basal tension in organ chambers. Autoradiographic binding of [(3)H]SQ29,548, a TxA(2) receptor antagonist, in canine coronary sections was determined. Blood for platelet aggregation studies was collected by venous puncture from healthy human volunteers (n = 6) who were free of aspirin-like agents for at least 2 weeks. Vascular reactivity and platelet aggregation in response to the TxA(2) analogs U46619 and autoradioagraphic receptor binding to the TxA(2) receptor antagonist [(3)H]SQ29,548 were studied with and without irbesartan. The TxA(2) analog U46619 produced dose-dependent vasoconstriction in coronary rings (EC(50) = 11.6 +/- 1.5 nM). Pretreatment with irbesartan inhibited U46619-induced vasoconstriction, and the dose-response curve was shifted to the right in a dose-dependent manner. The EC(50) of U46619 was increased 6- and 35-fold in the presence of 1 and 10 microM of irbesartan without a change of maximal contraction. At 1 microM, irbesartan is 2-fold more potent than the AT(1) receptor antagonist losartan in the inhibition of U46619-induced vasoconstriction in canine coronary arteries. In contrast, neither AT(1) receptor antagonists (CV11974 and valsartan), the AT(2) receptor antagonist PD123319, nor the angiotensin converting enzyme inhibitor lisinopril had any effect on U46619-induced coronary vasoconstriction. Irbesartan did not change potassium chloride-induced vasoconstriction; however, irbesartan did inhibit the vasoconstriction mediated by another TxA(2)/PGH(2) receptor agonist prostaglandin F(2alpha) (PGF(2alpha)). Neither the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester nor the cyclooxygenase inhibitor indomethacin had any effect on irbesartan's attenuation of U46619-induced vasoconstriction. Irbesartan specifically reversed U46619-preconstricted coronary artery rings with and without endothelium in a dose-dependent manner. Irbesartan at high concentrations significantly competed for [(3)H]SQ29,548 binding in canine coronary sections. U46619 stimulated dose-dependent human platelet aggregation of platelet-rich plasma. Preincubation with irbesartan significantly inhibited platelet aggregation in a concentration-dependent manner. In conclusion, the dual antagonistic actions of irbesartan by acting at both the AT(1) and TxA(2) receptors in blood vessels and platelets may overall enhance its therapeutic profile in the treatment of hypertension, atherosclerosis, and arterial thrombosis. (+info)
Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics.
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A series of benzamidine isoxazoline derivatives was evaluated for their inhibitory potency against purified human factor Xa (fXa) and in a rabbit model of arteriovenous shunt thrombosis for their antithrombotic activities, expressed as K(I) and IC(50), respectively. A highly significant correlation was found between K(I) and IC(50) (r = 0.93, P <.0001). The antithrombotic effects of SF303 [mol. wt. 536; K(I): fXa, 6.3 nM; thrombin, 3,100 nM; trypsin, 110 nM; tissue plasminogen activator >20,000 nM; plasmin, 2,500 nM] and SK549 [mol. wt. 546; K(I): fXa, 0.52 nM; thrombin, 400 nM; trypsin, 45 nM; tissue plasminogen activator >33,000 nM; plasmin, 890 nM] were compared with recombinant tick anticoagulant peptide [K(I)(fXa) = 0.5 nM], DX-9065a [K(I)(fXa) = 30 nM], and heparin or low molecular weight heparin (dalteparin) in a rabbit model of arteriovenous shunt thrombosis. ID(50) values for preventing arteriovenous shunt-induced thrombosis were 0.6 micromol/kg/h for SF303, 0.035 micromol/kg/h for SK549, 0.01 micromol/kg/h for recombinant tick anticoagulant peptide, 0.4 micromol/kg/h for DX-9065a, 21 U/kg/h for heparin, and 23 U/kg/h for low molecular weight heparin. SK549 produced a concentration-dependent antithrombotic effect with an IC(50) of 0.062 microM. To evaluate its potential oral efficacy, SK549 was given intraduodenally at a dose of 5 mg/kg; it produced a peak antithrombotic effect of 59 +/- 4% with a duration of action greater than 6.7 h. Therefore, our study suggests that SF303, SK549, and their analogs represent a new class of synthetic fXa inhibitors that may be clinically useful as antithrombotic agents. (+info)
Disposition of irbesartan, an angiotensin II AT1-receptor antagonist, in mice, rats, rabbits, and macaques.
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Metabolism and disposition of irbesartan, an angiotensin II AT(1) receptor antagonist, were investigated in mice, rats, rabbits, and macaques. In both rats and macaques, irbesartan was characterized by a rapid oral absorption, a large volume of distribution, a low plasma clearance, and a long terminal half-life. The oral bioavailability in macaques was notably higher than in rats. Irbesartan was highly protein bound in rats and macaques. A lower binding rate was found in mice and rabbits. In distribution studies performed in rats, mice, and rabbits, irbesartan was rapidly distributed into most organs and tissues including brain, intrauterine area, and milk. No retention of radioactivity in tissues other than liver and kidney was noted. Irbesartan was the main circulating compound in rats, rabbits, and macaques representing a maximum of 67, 68, and 80% of plasma radioactivity, respectively. The drug was metabolized mainly by glucuronidation (primarily on the tetrazole ring), hydroxylation, and additional oxidation. The overall pathways within the different species generated 18 metabolites identified from bile, urine, and feces samples. Irbesartan did not significantly induce or inhibit most of the isoenzymes commonly associated with drug metabolism in either rats or macaques after oral administration for 1 month. In most species irbesartan and its metabolites were mainly excreted in feces with more than 80% of a radioactive dose recovered within 24 or 48 h. Enterohepatic circulation was demonstrated in rats and macaques. (+info)
Analysis of three structurally related antiviral compounds in complex with human rhinovirus 16.
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Rhinoviruses are a frequent cause of the common cold. A series of antirhinoviral compounds have been developed that bind into a hydrophobic pocket in the viral capsid, stabilizing the capsid and interfering with cell attachment. The structures of a variety of such compounds, complexed with rhinovirus serotypes 14, 16, 1A, and 3, previously have been examined. Three chemically similar compounds, closely related to a drug that is undergoing phase III clinical trials, were chosen to determine the structural impact of the heteroatoms in one of the three rings. The compounds were found to have binding modes that depend on their electronic distribution. In the compound with the lowest efficacy, the terminal ring is displaced by 1 A and rotated by 180 degrees relative to the structure of the other two. The greater polarity of the terminal ring in one of the three compounds leads to a small displacement of its position relative to the other compounds in the hydrophobic end of the antiviral compound binding pocket to a site where it makes fewer interactions. Its lower efficacy is likely to be the result of the reduced number of interactions. A region of conserved residues has been identified near the entrance to the binding pocket where there is a corresponding conservation of the mode of binding of these compounds to different serotypes. Thus, variations in residues lining the more hydrophobic end of the pocket are primarily responsible for the differences in drug efficacies. (+info)