Effects of the experimental subarachnoid hemorrhage on the eicosanoid receptors in nicotine-induced contraction of the rat basilar artery.

Background: Smoking is one of the most important risk factors for subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the influence of experimental SAH and arachidonic acid metabolites on nicotine-induced contraction in the rat basilar artery.

Methods: Rats were killed at 1 hour and 1 week after SAH, and the basilar artery was isolated and cut into a spiral strip.

Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to arachidonic acid metabolites signaling pathway.

Background: Smoking is one of the most important risk factors for cerebral circulatory disorders. The purpose of this study was to investigate the influence of experimental subarachnoid hemorrhage (SAH) on nicotine-induced contraction (arachidonic acid metabolites) in the basilar arteries of rats.

Methods: Rats were killed at 1 hour and 1 week after blood injection, and the basilar artery was isolated and cut into a spiral strip.

Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to nicotinic acetylcholine receptors, calcium, and potassium channels.

Background: Cigarette smoking is associated with symptomatic vasospasm after subarachnoid hemorrhage (SAH).

Methods: Rat basilar arteries of a normal group and SAH groups (1 hour, 2 days, and 1 week) were removed from the brain and cut into spiral preparations.

Results: A central nervous system (CNS) nicotinic acetylcholine receptor (nAChR) and autonomic ganglionic nAChR antagonist (mecamylamine) and skeletal muscle nAChR antagonist (gallamine) concentration-dependently attenuated the nicotine-induced contraction.

NK1 receptor-mediated endothelium-dependent relaxation and contraction with different sensitivity to post-receptor signaling in pulmonary arteries.

In rabbit intrapulmonary arteries, substance P (SP) has been reported to induce endothelium-dependent relaxation (EDR) and endothelium-dependent contraction (EDC) via tachykinin NK(1) receptors, and endothelium-independent contraction (EIC) via tachykinin NK(2) receptors. The present study pharmacologically examined whether these opposite responses (EDR and EDC) are mediated by the same NK(1) receptor. Five tachykinin agonists, including septide, a reportedly atypical NK(1) agonist, caused concentration-dependent EDR in the presence of NK2 antagonist (SR-48968) + TXA2 synthetase inhibitor (ozagrel), which blocked EIC and EDC, in pre-contracted arteries, and concentration-dependent EDC in the presence of NK2 antagonist (SR-48968) + nitric oxide synthase inhibitor (l-N(G)-nitro-arginine methyl ester), which blocked EIC and EDR, in non-contracted arteries.

Relationships between lipophilicity and biological activities in a series of indoline-based anti-oxidative acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors.

A novel series of 1-alkyl-7-amido-indoline-based anti-oxidative acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors have been reported and are expected to lower plasma cholesterol levels due to the inhibition of intestinal and hepatic ACAT, and to inhibit cholesterol accumulation in macrophages due to the inhibition of low density lipoprotein (LDL) oxidation. In the present study, relationships between lipophilicity and biological activities were examined in 13 derivatives. Lipophilicity (logP) increased and water solubility decreased with dependence on the number of carbons in the 1-alkyl chain.

Regional heterogeneity of substance P-induced endothelium-dependent contraction, relaxation, and -independent contraction in rabbit pulmonary arteries.

Aims: The present study examined whether substance P (SP)-induced endothelium-dependent TXA(2)-mediated contraction (EDC), nitric oxide (NO)-mediated relaxation (EDR), and endothelium-independent contraction (EIC) are different between the rabbit proximal and distal intrapulmonary arteries.

Main Methods: The helically cut strips of isolated proximal and distal arteries were fixed vertically between hooks in organ bath, and changes in isometric tension were measured.

Key Findings: SP-induced EDC was greater in the distal than proximal arteries, and EDR was greater in the proximal than distal arteries.

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.

Impairment of endothelium-dependent ACh-induced relaxation in aorta of diabetic db/db mice--possible dysfunction of receptor and/or receptor-G protein coupling.

Diabetes is a risk factor of ischemic heart disease, cerebral ischemia, and atherosclerosis, in which endothelial dysfunction plays a role in the pathogenesis. We examined vascular responses in the aorta of pre-diabetic db/db mice with normoglycemia, hyperlipidemia, and hyperinsulinemia (6 weeks old), and diabetic db/db mice with hyperglycemia, hyperlipidemia, and hyperinsulinemia (11 weeks old) in comparison with age-matched non-diabetic db/+ mice. Prostaglandin F2alpha (PGF2alpha)-induced contraction was significantly enhanced in the aorta of diabetic but not pre-diabetic db/db mice compared to age-matched non-diabetic db/+ mice.

Effects of an anti-oxidative ACAT inhibitor on apoptosis/necrosis and cholesterol accumulation under oxidative stress in THP-1 cell-derived foam cells.

THP-1 cell-derived foam cells were exposed to oxidative stress through combined treatment with acetylated LDL (acLDL) and copper ions (Cu2+). The foam cells showed caspase-dependent apoptotic changes on exposure to oxidative stress for 6 h, and necrotic changes with the leakage of LDH after 24 h. KY-455, an anti-oxidative ACAT inhibitor, and ascorbic acid (VC) but not YM-750, an ACAT inhibitor, prevented apoptotic and necrotic changes.

Pharmacological nature of nicotine-induced contraction in the rat basilar artery: involvement of arachidonic acid metabolites.

The pharmacological nature of nicotine-induced contraction in the rat basilar artery is poorly understood. The purpose of this study was to investigate the endothelium dependency and involvement of arachidonic acid metabolites in nicotine-induced contraction in the rat basilar artery. The rat basilar artery was removed from the brain and cut into a spiral preparation.

Hypersensitivity to hydroxyl radicals in rat basilar artery after subarachnoid hemorrhage.

Vasospasm after subarachnoid hemorrhage (SAH) is a serious complication and we have been investigating the relationship between vasoconstrictors and vasospasm after SAH. The present study was designed to investigate the vasocontractile responses to reactive oxygen species in isolated rat basilar arteries from the control and experimental SAH rats. Contractile responses to hydroxyl radicals in basilar arteries from SAH rats were 3-6-fold higher than those in control rats.

Cysteinyl leukotrienes and leukotriene B mediate vasoconstriction to arginine vasopressin in rat basilar artery.

Arginine vasopressin (AVP) has been reported to be involved in the development of cerebral vasospasm after haemorrhage and cerebral oedema following ischaemia. Endogenously produced 5-lipoxygenase metabolites are able to contract isolated endothelium-preserved arterial strips and modulate vascular permeability. The present study addresses the role of 5-lipoxygenase and its products, namely cysteinyl leukotrienes (CysLTs) and leukotriene (LT) B4, in the contraction induced by AVP in rat basilar artery.

Involvement of endothelial cyclo-oxygenase metabolites in noradrenaline-induced contraction of rat coronary artery.

1. Noradrenaline (NA; 0.3 micromol/L) caused a contraction of the rat coronary artery that markedly increased in the presence of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 100 micromol/L) and arachidonic acid (1 micromol/L; P < 0.

Enhanced reactivity to vasopressin in rat basilar arteries during vasospasm after subarachnoid hemorrhage.

Subarachnoid hemorrhage increases the plasma level of vasopressin, a well-known vasoconstrictor. We examined the sensitivity to vasopressin in rat basilar artery after subarachnoid hemorrhage using a rat subarachnoid hemorrhage model. Vasospasm was observed 1-2 days after subarachnoid hemorrhage induction, and the contractile response to vasopressin in rat basilar arteries was assessed.

Participation of vasopressin in the development of cerebral vasospasm in a rat model of subarachnoid haemorrhage.

1. Previous studies have suggested the involvement of arginine vasopressin (AVP) and inflammation in the development of cerebral vasospasm after subarachnoid haemorrhage (SAH). The aim of the present study was to clarify the role of AVP in the arterial narrowing following cerebral haemorrhage by examining the effect of SR 49059 (a V(1) receptor antagonist) on the diameter of rat basilar artery exposed to SAH.

Hypolipidemic and antioxidant activity of the novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor KY-455 in rabbits and hamsters.

The hypolipidemic and antioxidant effects of N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide (CAS 178469-71-1, KY-455), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were examined in hyperlipidemic rabbits and normolipidemic hamsters. KY-455 inhibited rabbit intestinal, hepatic, macrophage and adrenal ACAT with IC50 values of 0.4, 0.

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

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).

Diversity of endothelium-derived vasocontracting factors--arachidonic acid metabolites.

Vascular endothelium releases vasocontracting and/or vasorelaxing substances. Here, we report the diversity of endothelium-derived vasocontracting factors (EDCFs), arachidonic acid metabolites, and discuss the pathophysiological significance. In the canine basilar artery and the rabbit intrapulmonary artery, acetylcholine-induced contractions (ACh-induced EDC) are due to endothelial thromboxane A2 (TXA2) (TXA2-type).

Role of intracellular Ca2+ in endothelium-dependent contraction and relaxation of rabbit intrapulmonary arteries.

We examined whether Ca(2+) mobilizers induce endothelium-dependent contraction and relaxation (EDC and EDR) in isolated rabbit intrapulmonary arteries. Ionomycin (10(-7) M) and A-23187 (10(-7) M), both Ca(2+) ionophores, and thapsigargin (10(-6) M), an endoplasmic reticulum Ca(2+)-ATPase inhibitor, caused a contraction in the non-contracted preparations, and a transient relaxation followed by a transient contraction and sustained relaxation in the precontracted preparations. Endothelium-removal abolished the contraction and transient relaxation (EDC and EDR) but not sustained relaxation (endothelium-independent relaxation, EIR).