Angiotensin II receptor subtypes involved in the modulation of purinergic and adrenergic vasoconstrictions to periarterial electrical nerve stimulation in the canine splenic artery.

Article

Author: Yang, Xiao-Ping ; Chiba, Shigetoshi

Previous experiments demonstrated that periarterial electrical nerve stimulation induced a double-peaked vasoconstriction consisting of an initial transient, predominantly P2X-purinoceptor-mediated, constriction followed by a prolonged, mainly alpha1-adrenoceptor-mediated, response in the canine splenic artery. Angiotensin II at a concentration of 0.1 nM did not affect the basal vascular tone and vasoconstrictions to exogenously administered noradrenaline (0.03-3 nmol) and adenosine 5'-triphosphate (0.01-1 micromol), but it markedly potentiated the double-peaked responses to nerve stimulation. The potentiating effect of angiotensin II was inhibited by KRH-594 (10 nM), a selective angiotensin II type 1 receptor antagonist, but was not influenced by PD123319 (0.01-0.1 microM), a selective angiotensin II type 2 receptor antagonist. The results indicate that angiotensin II potentiates sympathetic purinergic and adrenergic vasoconstrictions through the prejunctional angiotensin II type 1 receptor subtype in the canine splenic artery.

01 Feb 1999·The Journal of pharmacology and experimental therapeutics

Angiotensin II type 1 receptor blockade prevents up-regulation of angiotensin II type 1A receptors in rat injured artery.

Article

Author: Tazawa, S ; Chiba, S ; Nakane, T

We investigated the effects of the angiotensin II (Ang II) type 1 receptor (AT1) antagonist KRH-594 on levels of the mRNAs for AT1A, AT1B, platelet-derived growth factor-receptor beta (PDGF-Rbeta), and extracellular matrix (ECM)-related genes using the competitive reverse transcription-polymerase chain reaction (RT-PCR) method and on neointimal formation in the balloon-injured rat carotid artery. The mRNA levels for AT1A and PDGF-Rbeta, but not for AT1B, increased from day 3 after injury to day 14. KRH-594 administered orally at 3 and 10 mg/kg/day significantly suppressed these increases. KRH-594 (10 mg/kg/day) also suppressed the injury-induced gene expressions for transforming growth factor-beta1 and fibronectin and reduced collagen alpha1(I) and alpha1(III) mRNA levels for the first 7 days after injury. KRH-594 (10 and 30 mg/kg/day) significantly and dose-dependently reduced the neointimal area in cross sections of the artery 14 days after injury. Another AT1 antagonist, TCV-116 (candesartan cilexetil; 1 and 3 mg/kg/day p.o.), had similar effects on the morphological change and AT1A mRNA level, whereas a smooth muscle relaxant, hydralazine (10 mg/kg/day p.o.), did not. These results indicate that up-regulation of AT1A, PDGF-Rbeta, and ECM-related genes in the balloon-injured carotid artery is in part an AT1-mediated phenomenon and that prevention of receptor up-regulation may contribute to the attenuating effects of AT1 antagonists on neointimal formation after injury.

01 Nov 1997·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Pharmacologic Profiles of KRH-594, a Novel Nonpeptide Angiotensin II-Receptor Antagonist

Q4 · MEDICINE

Article

Author: Mikoshiba, Imao ; Hirata, Terukage ; Hashimoto, Ken ; Amano, Hirotaka ; Okuhira, Masayasu ; Tamura, Koichi ; Inokuma, Ken-ichi

We studied pharmacologic profiles of KRH-594, dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4 -thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarb oxylate, a novel angiotensin II (AII)-receptor antagonist. KRH-594 potently displaced specific binding of [125I]-AII from AT1 receptor with a Ki of 0.39 nM in rat liver membranes, but not from AT2 receptor in bovine cerebellar membranes (Ki > 10 microM). KRH-594 exhibited no affinity for 21 other receptors and two enzymes [50% inhibitory concentration (IC50) > 10 microM], demonstrating its high specificity toward AT1 receptors. In isolated rabbit aorta, KRH-594 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response with a pK(B) of 10.4. We evaluated the in vivo efficacy and the duration of action in freely moving rats under nonfasting conditions. In normotensive rats, orally administered KRH-594 inhibited AII-induced pressor responses with a 50% inhibitory dose (ID50) of 0.39 mg/kg. In spontaneously hypertensive rats (SHRs), both KRH-594 (1 mg/kg p.o.) and losartan (10 mg/kg p.o.) exerted similar blood pressure-reducing effects, and their effects were still significant at 24 h after drug administration. We concluded that KRH-594 is a specific and efficacious AT1 antagonist that may find its use in the treatment of human hypertension.

100 Deals associated with KRH-594

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetic Nephropathies	Phase 2	JP	-	-
Heart Failure	Phase 2	JP	-	-
Hypertension	Phase 2	JP	-	-
Hypertension	Phase 2	-	Wakunaga Pharmaceutical Co., Ltd.	-
Hypertension	Phase 2	-	Kissei Pharmaceutical Co., Ltd.	-

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