Kazuyoshi Kurahashi

The supersensitivity of isolated rabbit atria and aortic strips produced by 6-hydroxydopamine

Abstract The effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) on the sensitivity of isolated rabbit atria and aortic strips to several catecholamines and other nonspecific stimuli has been examined. After 6-OHDA treatment, the inotropic and chronotropic responses of the isolated atria to noradrenaline and adrenaline were potentiated, the potentiation for noradrenaline being greater than that for adrenaline. 6-OHDA failed to potentiate the phenylephrine and isoprenaline responses of atria. In aortic strips, 6-OHDA treatment potentiated the response not only to a specific vascular stimulant (noradrenaline), but also to nonspecific stimuli (phenylephrine, potassium and barium). The supersensitivity for noradrenaline was several times greater than that for nonspecific stimuli. The potentiation of noradrenaline responses in aortic strips from old rabbits (4 kg, 1 year) was much less than that of strips from young rabbits (1.3 kg, 5–6 weeks). This difference was not observed in the potentiation of potassium response. These results indicated that chemical sympathectomy by pretreatment with 6-OHDA produced the presynaptic type of supersensitivity for isolated atria and seemed to induce not only presynaptic but also postsynaptic supersensitivity for aortic strips.

Novel indoline-based acyl-CoA:cholesterol acyltransferase inhibitor with antiperoxidative activity: improvement of physicochemical properties and biological activities by introduction of carboxylic acid.

A series of novel indoline derivatives with an ionizable moiety were synthesized to find a bioavailable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor with antiperoxidative activity. [7-(2,2-Dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate (2, pactimibe sulfate) with low lipophilicity and high water solubility showed good oral absorption and inhibitory activity against foam cell formation in THP-1 cells exposed to acetyl-LDL after differentiation (IC50: 0.3 microM) and an antiperoxidative effect in LDL of hypercholesterolemic rabbits (IC50: 1.0 microM). 2 inhibited macrophage, hepatic, and intestinal ACAT activity (IC50: 1.9, 0.7, and 0.7 microM, respectively). Maximal plasma concentration after oral administration of 2 at 10 mg/kg was 0.9 microg/mL in rats, 3.0 microg/mL in rabbits, and 11.2 microg/mL in dogs. Repeated administration of 2 lowered plasma LDL/VLDL cholesterol in hypercholesterolemic rabbits at 1 mg/kg/day, rats and dogs at 3 mg/kg/day, and in normocholesterolemic hamsters at 3 mg/kg/day. 2 is a promising candidate for antihyperlipidemic and antiatherosclerotic drugs.

The inhibitory action of okadaic acid on mechanical responses in guinea-pig vas deferens

Okadaic acid and nifedipine inhibited contractions induced by noradrenaline (NA), KCl and ATP in guinea-pig vas deferens. NA, KCl and ATP induced initial spike-like changes followed by a sustained increase in cytosolic Ca2+ levels ([Ca2+]cyt) and tension. Okadaic acid inhibited the sustained increments in [Ca2+]cyt and muscle tension due to NA and ATP more than the initial spike-like changes, whereas nifedipine more strongly inhibited the initial spike changes. Okadaic acid also inhibited the KCl-induced contraction with only a small inhibition of the stimulated [Ca2+]cyt. By contrast, nifedipine (10(-7) M) inhibited the increments in both [Ca2+]cyt and muscle tension due to KCl. Okadaic acid markedly inhibited the maximal contractile response to Bay K 8644 but nifedipine only shifted the response curve to the right without affecting the maximum responses. In a Ca2(+)-free medium containing EGTA and nifedipine, okadaic acid did not inhibit the residual phasic contractile response to NA (10(-4) M) but the contractile response to a subsequent addition of Ca2+ (1.2 mM) was suppressed. These results suggest that, in guinea-pig vas deferens, okadaic acid has an inhibitory effect on smooth muscle contraction but not on the intracellular Ca2+ mobilization. The inhibitory effect may be due to the inhibition of Ca2+ influx and the possible interference of contractile elements.

Endothelium-dependent contraction produced by acetylcholine and relaxation produced by histamine in monkey basilar arteries.

The present experiments were carried out to investigate the endothelium dependence of the responses to acetylcholine (ACh), arachidonic acid, and histamine in monkey basilar arteries. ACh and arachidonic acid caused endothelium-dependent contraction (EC) in both monkey and canine basilar arteries. The endothelium-derived contracting factor (EDCF) was probably thromboxane A2 (TxA2), as the EDC was attenuated by a cyclooxygenase inhibitor, TxA2 synthetase inhibitors, and TxA2 antagonists. On the other hand, histamine caused endothelium-dependent relaxation (EDR) in monkey and EDC in canine basilar arteries. The EDR in monkey basilar arteries was attenuated by a nitric oxide synthase inhibitor. The EDR and EDC were antagonized by tripelennamine but not by cimetidine, indicating that they are mediated by H1-receptors. From these results, we suggest that in the monkey basilar artery, either there are two types of endothelium (an EDCF type for ACh and arachidonic acid and an EDRF type for histamine) or there is a single type of endothelium with two types of signalling processes (one for EDC and one for EDR).

Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites.

Summary: Nicotine caused a contraction of the rat coronary artery in the presence of N&ohgr;‐nitro‐L‐arginine methyl ester (L‐NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine‐induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase‐1 (COX‐1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine‐induced contraction in a concentration‐dependent manner, and cyclooxygenase‐2 (COX‐2) inhibitors at high concentrations (nimesulide and NS‐389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY‐046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S‐1452) attenuated the contraction in a concentration‐dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an &agr;‐adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L‐NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX‐1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine.

Pharmacological nature of TP receptor mediated contraction in human intrapulmonary artery

The present experiments were undertaken to elucidate the pharmacological nature of thromboxane A2/prostaglandin H2 receptor (TP)-mediated contraction in human intrapulmonary arteries. 9,11-epithio-11, 12-methano-thromboxane A2 (STA2) and (15S)-hydroxy-9 alpha, 11 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid (U46619) (TXA2 agonists) caused contractions in a concentration-dependent manner with EC50 values of 1.4 x 10(-9) M and 3.1 x 10(-9) M, respectively. S-1452 and ONO-3708 (TP receptor antagonists) concentration-dependently attenuated the STA2 (10(-8) M)-induced contraction with IC50 values of 5.8 x 10(-9) M and 4.2 x 10(-8) M, respectively. U-73122 (3 x 10(-6) M) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (3 x 10(-5) M) (phospholipase C inhibitors) significantly attenuated the STA2-induced contraction. Ca(+2)-induced contraction in the presence of STA2 (10(-8) M) in Ca(+2)-free medium was attenuated by nifedipine (10(-6) M) by 40%. The remaining nifedipine-resistant Ca(+2)-induced contraction was not attenuated by nitroglycerin (10(-5) M), but forskolin (10(-5) M) (adenylate cyclase stimulant) significantly decreased it by 75%. The results clearly indicate that in human intrapulmonary artery, there are TP receptors coupled with phospholipase C activation and that TP receptor-mediated Ca(+2)-mobilization is in part nifedipine- and nitroglycerin-resistant, but forskolin-sensitive.

The vasoinhibitory action of FR 46171, a new pyridine alcohol antianginal agent, on isolated rabbit vascular smooth muscles

The vasoinhibitory effect of FR 46171, a new pyridine alcohol derivative, on contractile responses to alpha-adrenoceptor agonists was examined in isolated rabbit aorta. FR 46171 (10(-8)-10(-5) M) inhibited the maximum contractile response to clonidine (CL) in a concentration-dependent manner, but it only inhibited the responses to low concentrations of norepinephrine (NE) and methoxamine (MO). In the aorta pretreated with phenoxybenzamine, however, FR 46171 at 10(-5) M inhibited the residual maximum response to NE and MO. FR 46171 at 10(-5) M only inhibited the response to KCl (20 mM). FR 46171 at 10(-6) and 10(-5) M also moderately inhibited the response to added Ca2+ in a Ca2+-free medium in K+-depolarized preparations. Nifedipine at 10(-6) M, by contrast, nearly abolished the responses to potassium or added Ca2+. In a Ca2+-free medium with EGTA, an addition of NE (10(-5) M), MO (10(-5) M), or CL (10(-5) M) induced a phasic contraction. The inhibitory effect of FR 46171 (10(-8)-10(-5) M) was much greater on the response to CL than that to NE or MO. In a Ca2+-free medium with low EGTA and nifedipine (10(-6) M) in the presence of an alpha-adrenoceptor agonist (NE, MO, or CL), an addition of Ca2+ (2 mM) induced a tonic contraction. FR 46171 (10(-9)-10(-5) M) inhibited the Ca2+ response, which is activated by the agonists, in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibitory action of potassium on the mechanical and membranal activities of taenia from guinea pig caecum

Abstract After a prolonged cold storage treatment of the quinea pig taenia caecum, a low concentration of potassium caused muscle relaxation and membrane hyperpolarization. This inhibitory action of potassium was prevented if the taenia was pretreated with oua-bain or incubated in a Li + medium. Reserpine, 6-hydroxydopamine and adrenoceptor blocking agents had no effect on the inhibitory action of potassium. It is suggested that the activation of the electrogenic sodium pump by potassium elicits the membrane hyper-polarization and the accompanied relaxation of the cold stored taenia caecum.

Noradrenaline-induced contraction mediated by endothelial COX-1 metabolites in the rat coronary artery.

Summary: Noradrenaline‐induced contraction of the rat coronary arteries was significantly augmented by the presence of NG‐nitro‐ L‐arginine methyl ester (L‐NAME) and arachidonic acid. The experiments in the study presented here were undertaken to characterize pharmacologically the augmented noradrenaline‐induced contraction in ring preparations of rat coronary arteries. The contraction was stopped by a chemical remover of endothelium (saponin). Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase‐1 inhibitors (flurbiprofen, 10‐7 M) attenuated the noradrenaline‐induced contraction and cyclooxygenase‐2 (nimesulide, 10‐7 M) slightly attenuated the contraction. A thromboxane A2 (TXA2) synthetase inhibitor (OKY‐046) and a TXA2 receptor antagonist (S‐1452) did not affect the contraction. Based on these results, it was suggested that the contraction induced by noradrenaline in the rat coronary artery in the presence of L‐NAME and arachidonic acid is endotheliumdependent, and that it involves reactive oxygen species and endothelial cyclooxygenase‐1 metabolites of arachidonic acid.

Endothelium-Dependent Contraction of Cerebral Arteries

Vascular tone is regulated by neuronal and humoral factors to maintain appropriate blood flow. SinceFurchgott and Zawadzki (1980) found the obligatory role of endothelial cells in the vasodilating action of acetylcholine (ACh) (endothelium-depen-dent relaxation, EDR), extensive studies on physiological activities of the endothelium in various vascular preparations have been investigated. Palmer et al. (1987) have identified chemically that the endothelium-derived relaxing factor (EDRF) is nitric oxide(NO). In peripheral arteries, EDRF has been considered to play an important role in regulation of vascular tone.