Akira Tomiyama

Pharmacological properties of KT3-671, a novel nonpeptide angiotensin II receptor antagonist.

We examined pharmacological profiles of KT3–671, 2-propyl-8-oxo-l-[(2‘-(lH-tetrazole-5-yl) biphe-nyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole, a newly synthesized nonpeptide angiotensin II (AII) receptor antagonist in various in vitro and in vivo studies. KT3–671 displaced specific binding of [125I]Sar1 Ile8-AII to AT1 receptor with a Ki value of 0.71 ± 0.14 x 10-9M in rat liver membranes, but had no affinity for AT2 receptor in bovine cerebellar membranes (Ki > 10-5M). In isolated rabbit aorta, KT3–671 produced a parallel right-ward shift in the concentration-response curve for AH with a pA2 value of 10.04 ± 0.12, but had no effect on K.CI-, norepinephrine (NE)-, and serotonin (5-HT)-induced contractions. In conscious normotensive rats, KT3–671 (0.3–10 mg/kg, p.o.) inhibited the All-induced pressor response dose dependently. In renal arteryligated hypertensive rats, KT3–671 (0.1–3 mg/kg, p.o.) decreased arterial blood pressure (BP) dose dependently. The hypotensive action of 3 mg/kg KT3–671 was maintained for at least 24 h. These results suggest that KT3–671 is a potent AT1 subtype-selective and competitive nonpeptide AII receptor antagonist and has an orally active antihypertensive effect without agonistic activity.

Relaxation of intestinal smooth muscle and calcium movements

The effects of papaverine, isoprenaline and N6,2′‐O‐dibutyryl 3′,5′‐cyclic adenosine monophosphate (DiBu.C‐AMP) on calcium movements in the taenia from the guinea‐pig caecum have been investigated and compared with the effects of phenylephrine. Papaverine and DiBu.C‐AMP antagonized the contraction of KCl‐depolarized muscle induced by CaCl2 and increased 45Ca‐efflux from the taenia. Papaverine also significantly depressed 45Ca‐uptake by this preparation. These findings suggest that papaverine impairs the availability of calcium to the contractile system and that there may be a correlation between relaxation and increase of 45Ca‐efflux. The action of DiBu.C‐AMP resembles that of papaverine but its potency is less.

Relationships between Ca2+ uptake by a microsomal fraction of guinea-pig taenia caecum and its relaxation

Abstract A microsomal fraction isolated from guinea-pig taenia caecum can accumulate calcium ions in the presence of ATP and MgCl 2 . This calcium-accumulating ability depends on the ATP concentration in the reaction mixture, and its pH optimum is near 7·8. Procaine and quinidine inhibit Ca 2+ accumulation by fraction and suppress the relaxation of this tissue induced by papaverine, isoprenaline and phenylephrine. These results suggest that Ca 2+ accumulation by the microsomal fraction isolated from guinea-pig taenia caecum plays an important role during the relaxation of this smooth muscle. Cyclic adenosine 3′,5′-monophosphate (cAMP) does not accelerate Ca 2+ accumulation by the microsomal fraction. The failure of cAMP to accelerate Ca 2+ uptake by this fraction implies that some unknown steps or factors may exist between the intracellular increment of cAMP and the following relaxation of taenia caecum .

Effect of repeated administration of KT3-671, a nonpeptide AT1 receptor antagonist, on diurnal variation in blood pressure, heart rate, and locomotor activity in stroke-prone spontaneously hypertensive rats as determined by radiotelemetry.

KT3-671, a nonpeptide AT1 receptor antagonist, was administered to 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) daily for 3 weeks. Its effects on systolic, mean, and diastolic arterial blood pressure (SAP, MAP, DAP), heart rate and locomotor activity were investigated with radiotelemetry. A clear diurnal variation in blood pressure, heart rate, and locomotor activity was observed in synchrony with the light cycle. KT3-671 at a daily dose of 10 mg/kg orally (p.o), produced a significant and consistent reduction in blood pressure, preventing the development of hypertension. KT3-671 reduced SAP more than DAP, suggesting that it may affect both vascular tone and cardiac output. Although KT3-671 did not affect diurnal rhythms in heart rate and locomotor activity, it did cause a slight but significant reduction in heart rate. The MAP determined 23 h after the administration of KT3-671 showed a significant reduction from the day 2 of therapy to the day 3 after discontinuation of therapy, suggesting a long duration of antihypertensive action. There was no rebound increase in blood pressure after discontinuation of KT3-671 therapy. These results suggest that KT3-671 may be potentially useful in the therapy of hypertension.

Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p- chlorobenzenesulfonylamino)-butyl]-azulene-1-sulfonic acid sodium salt); a new TXA2/prostaglandin endoperoxide receptor antagonist.

Pharmacologic properties of KT2–962 (6-iso-propyl-3-[4-(p-chlorobenzenesulfonylamino)butyl]-azu-lene-1-sulfonic acid sodium salt, KT) were studied in isolated rat aorta, rat tail artery, rabbit aorta, rabbit renal artery, and pig coronary artery. KT competitively inhibited the contractions induced by thromboxane A2 (TXA2) mimetic, U46619 (pA2 values 9.95, 8.85, 7.87, 8.49, and 9.12, respectively). KT also inhibited the contraction of rabbit aorta induced by prostaglandin2α, (PGF2α, pA2 value 7.85) and the contraction of guinea pig ileum induced by LTD4 (pA2 value 5.48) but did not alter the contractions induced by norepinephrine (NE). Ca2+, serotonin, and histamine. KT did not alter the contractions of guinea pig ileum, which did not contract with U46619, induced by PGE2 and PGF2α, KT inhibited the aggregations of rabbit platelets induced by U46619, arachidonic acid, and collagen (IC50 values 7.9, 140, and 16 μM, respectively) but not those induced by ADP. It also inhibited the specific binding of TXA2/PGH2 receptor antagonist, [3H]SQ29,548, to rabbit gel-filtered platelets with an IC50 value of 1.5 × 10-8 M. In in vivo experiments with mice, oral administration of KT protected the U46619-induced sudden death with the minimum effective dose of 0.3 mg/kg and provided such protection for ≥8 h at 1.0 mg/kg. These results indicate that KT is a new nonpros-tanoid type TXA2/PGH2 receptor antagonist that is orally effective and long acting.

Therapeutic effect of egualen sodium (KT1-32), a new antiulcer agent, on chronic gastritis induced by sodium taurocholate in rats

We investigated the therapeutic effects of egualen sodium (KT1-32), a new antiulcer agent, on chronic erosive and atrophic gastritis induced by 5 months administration of sodium taurocholate (TCA; 5 mM) in rats. The chronic gastritis was manifested by mucosal surface injuries (erosions), reduced mucosal thickness, reduction of the number of parietal cells, infiltration of inflammatory cells, and proliferation of collagenous fiber. Egualen sodium, (10–100 mg/kg, t.i.d) administered orally to the rats for 2 weeks after the withdrawal of TCA, dose-dependently and significantly decreased the total length of erosions. The indicators of atrophic gastritis, i.e., reduced mucosal thickness and reduction in the number of parietal cells, were improved dose-dependently by the administration of this agent. Egualen sodium also reduced the inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa in a dose-dependent manner. The reduced staining of neutral gastric mucus was improved by a high dose (100 mg/kg) of egualen sodium. The therapeutic effects of egualen sodium on experimental gastritis were superior to those of sofalcone and sodium guaiazulene 3-sulfonate. These results suggest that egualen sodium may be a promising agent for the treatment of erosive and atrophic gastritis.

The inhibitory effect of KT3-671, a nonpeptide angiotensin-receptor antagonist, on rabbit and rat isolated vascular smooth muscles : A possible involvement of KATP channels

The vasoinhibitory effect of KT3-671, a recently synthesized nonpeptide angiotensin II (Ang II), AT1-receptor antagonist, and the factors affecting insurmountable antagonism of Ang II were examined in rabbit and rat isolated vascular smooth muscle preparations. In rabbit and rat aortic rings, KT3-671 caused insurmountable antagonism of Ang II. In addition, KT3-671 inhibited contractile responses to angiotensin III (Ang III). In rabbit isolated smooth muscles, KT3-671 was most effective in reducing the maximal contraction induced by Ang II in the renal artery followed by the basilar artery and the aorta. In rat renal arterial rings, KT3-671 (10(-5) M) inhibited the concentration-response curves of prostaglandin F2alpha and STA2. In rabbit and rat aortic rings without endothelium, the insurmountable antagonisms of Ang II by KT3-671 and EXP 3174 were changed to surmountable antagonism by pretreatment with DuP 753 and KT3-671, respectively. In addition, KT3-671 abolished the inhibitory effect of CV- 11974 in the rat aorta but not in the rabbit aorta. Indomethacin (10(-5) M) or the removal of endothelium did not affect the inhibitory effect of Ang II by CV-11974 or EXP 3174 but enhanced the insurmountable antagonism by KT3-671. ODQ (3 x 10(-6) M), N(G)-nitro-L-arginine (3 x 10(-4) M), 4-aminopyridine (3 x 10(-3) M), tetraethylammonium (TEA; 10(-3) M), or iberiotoxin (10(-7) M) did not affect the inhibitory action of KT3-671 or CV-11974. Methylene blue (3 x 10(-6) M), KCl (10(2) M), TEA (10(-2) M), or BaC12 (10(-4) M) changed the insurmountable antagonism by KT3-671 to surmountable antagonism and abolished the inhibitory effect of CV-11974. However, glibenclamide (3 x 10(-6) M) did not affect the inhibitory action of KT3-671 but reduced the insurmountable antagonism by CV- 11974. These results indicate that KT3-671 is an insurmountable antagonist of Ang II in the rabbit and rat aorta. The results in the rat aorta also suggest that K(ATP) channels may be involved in insurmountable antagonism of Ang II by KT3-671 and CV-11974. Key Words: KT3-671-Rabbit-Rat-Vascular smooth muscle-Angiotensin II-Insurmountable antagonist-K(TP)channels.