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Biomedical subjects

Y Kasuya

Publications and source records attributed to Y Kasuya.

At least 235 records · Page 13Linked to original sources
PubMed1990

Influence of ouabain on the tracheal musculature of the dog.

The effects of ouabain on the smooth muscles of the airway were investigated in anesthetized, paralyzed and artificially ventilated mongrel dogs. Ouabain (30 micrograms/kg, i.v.) caused a constriction of the tracheal smooth muscle which was followed by bradycardia. When ouabain was infused at a rate of 2 micrograms/kg/min (i.v.), the tracheal constriction was induced by a total dose of 45.0 +/- 5.5 micrograms/kg, while the bradycardia appeared with a total dose of 54.4 +/- 6.1 micrograms/kg. The ouabain-induced tracheal constriction was inhibited by bilateral vagotomy. The tracheal constriction induced by i.a. infusion of 10 microM ouabain into the bilateral cranial thyroid arteries was inhibited by bilateral vagotomy, but it was not completely blocked. With bilateral vagotomy, the tracheal constriction induced by i.a. infusion of ouabain was unaffected by 3 microM hexamethonium, but it was significantly inhibited by 1 microM atropine. These results suggest that ouabain may induce tracheal constriction by a neurogenic action in addition to its action via the augmentation of the vagal reflex, and the neurogenic action of ouabain may be related, in large part, to the release of acetylcholine from the presynapses of vagus nerves in dogs.

Animals↗
PubMed1990

Influence of ouabain on the cholinergic neurotransmission in the canine trachea.

The effect of ouabain on the cholinergic neurotransmission of the trachea was investigated using isolated tracheal strips in dogs. Tracheal strips without epithelium were suspended in organ chambers filled with modified Krebs-Henseleit solution. Ouabain (3 X 10(-7)-10(-5) M) concentration-dependently caused a slow sustained tracheal contraction. The contractile response was significantly inhibited by 10(-6) M atropine and was enhanced by 10(-8) M physostigmine. The ouabain-induced tracheal contraction was unaffected by 10(-7) M tetrodotoxin, but was significantly reduced by 10(-3) M hemicholinium-3. In superfusion experiments, ouabain (10(-5) M) produced an increase in the ACh release. Superfusion with Ca(++)-free solution almost eradicated the ACh release and abolished the tracheal contraction induced by ouabain. omega-Conotoxin (5 X 10(-8) M), but not nicardipine (10(-6) M), inhibited significantly the increase in ACh release induced by ouabain. These results suggest that the ouabain-induced tracheal contraction may be mainly due to acceleration of presynaptic ACh release by enhancing the influx of Ca++, and the Ca(+)+ entry may occur through the N-type Ca(+)+ channels in the canine airway presynaptic site.

Acetylcholine↗
PubMed1990

Decrease in endothelium-dependent relaxation and levels of cyclic nucleotides in aorta from rabbits with alloxan-induced diabetes.

To investigate the influence of diabetes mellitus on vascular relaxation response, acetylcholine (ACh)-induced relaxation and production of cyclic GMP and cyclic AMP in aortic rings with endothelium were compared between alloxan-induced diabetic and control rabbits. ACh-induced relaxation was significantly attenuated in the aortic rings of diabetic rabbits. Concentration-response curve for ACh-induced relaxation in the aortic rings of control rabbits was shifted to the right by the pretreatment with hemoglobin, and this concentration-response curve was almost identical to that in the aorta from diabetic rabbits. Sodium nitroprusside (SNP)-induced relaxation in the aortic rings without endothelium from diabetic rabbits was similar to that in the aortic rings without endothelium from control rabbits. Basal levels of cyclic GMP and ACh-induced production of cyclic GMP were markedly lower in diabetic rabbits than those in control rabbits. On the other hand, there were no differences in basal and ACh-induced production of cyclic AMP between diabetic and control aorta. These results suggest that impairment of endothelium but not guanylate cyclase activity may be occurred in the aorta of diabetic rabbits. This impairment leads to the decrease in production of cyclic GMP through the attenuation of endothelium-derived relaxing factor (EDRF) release, and this may be responsible for the decreased endothelium-dependent relaxation of ACh.

Acetylcholine↗
PubMed1989

Capillary gas chromatographic-mass spectrometric determination of stable isotopically labelled and unlabelled theophylline in serum and urine and of 1,3-dimethyluric acid in urine.

A capillary gas chromatographic-mass spectrometric method for the determination of [13C,15N2]theophylline and unlabelled theophylline (TP) and of 1,3-dimethyluric acid (1,3-DMU), a major metabolite of TP, is described. TP and the metabolite were extracted separately from serum or urine, purified by high-performance liquid chromatography and converted into alkyl derivatives (monoethyl-TP and dibutyl-1,3-DMU). The internal standards used for the respective determinations were [2H6]TP and [2H6]1,3-DMU. Detection was performed by monitoring the molecular ions of the alkyl derivatives. The method needed no complex corrections for contributions and provides good accuracy and precision.

Alkylation↗
PubMed1989

Effects of N-methyl-D-aspartate antagonists on the cough reflex.

The effects of antagonists of N-methyl-D-aspartate (NMDA) on the capsaicin-induced cough reflex in rats were studied. Intracisternal (i. cist.) injection of MK-801, a non-competitive antagonist of NMDA, significantly decreased the number of coughs in a dose-dependent manner. The competitive antagonists of NMDA, 2-DL-amino-5-phosphonovalerate and 2-DL-amino-7-phosphonoheptanoate, also decreased the number of coughs after i. cist. injection. The antitussive potencies of both the competitive and non-competitive antagonists were similar to that of dextromethorphan. Intraperitoneal injection of MK-801 also decreased the number of coughs in a dose-dependent manner. These data suggest that excitatory amino acid neurotransmitters and NMDA receptors may be involved in the regulation of the cough reflex.

Animals↗
PubMed1989

Functional changes in potassium channels in aortas from rats with streptozotocin-induced diabetes.

The effects of K+ activators on aortas from control and diabetic rats were examined. The concentration-response curves for the relaxant effects of cromakalim were shifted to the right in diabetic rats. The relaxation responses of diabetic aortas to nicorandil did not differ from those of the controls. Treatment with oxyhemoglobin significantly reduced the relaxation responses to nicorandil in aortas from diabetic rats. It appears that the activity of aortic potassium channels is reduced in diabetic rats.

Animals↗
PubMed1989

Endothelin-1 induces vasoconstriction through two functionally distinct pathways in porcine coronary artery: contribution of phosphoinositide turnover.

Endothelin-1 (ET1)-induced contraction of isolated porcine coronary artery strips was previously reported to be mainly dependent on extracellular Ca2+. However, even in a Ca2+-free, EGTA-containing solution relatively high concentrations of ET1 induced a weak vasoconstriction, which was markedly but not completely inhibited by pretreatment with caffeine. Over similar dose ranges, ET1 stimulated the production of inositol phosphates in a dose-dependent manner in intact arterial tissues, which was independent of extracellular Ca2+ and was not affected by receptor blockers such as atropine, methysergide and diphenhydramine. Moreover, ET1 was shown to induce an increase in 1,2-diacylglycerol. These results indicate that the activation of ET1 receptors on porcine coronary artery smooth muscle causes phosphoinositide breakdown, leading to intracellular Ca2+ mobilization and protein kinase C activation. It is suggested that phospholipase C-mediated phosphoinositide breakdown as well as previously reported activation of voltage-dependent Ca2+ channels are involved in the mechanism of ET1-induced vasoconstriction.

Animals↗
PubMed1989

Pharmacological action of the phospholipase A2 from the venom of Trimeresurus flavoviridis on the smooth muscle of the rat stomach.

Phospholipase A2 (PLA2) from the venom of the snake Trimeresurus flavoviridis produced an increase in resting tension of isolated strips of rat stomach fundus. The contractions of the fundus strips induced by the PLA2 were significantly inhibited by treatment with 10(-6) M indomethacin and in Ca2+-free medium, while treatment of the fundus strips with nordihydroguaiaretic acid caused a marked potentiation of the PLA2-induced contraction. Atropine (10(-6) M), chlorpheniramine (10(-6) M) and methysergide (10(-6) M) had no effects on the contractions induced by PLA2, while tetrodotoxin (10(-6) M) significantly potentiated the contraction. From these results, it appears that exogenously applied PLA2 may cause contraction of the rat stomach fundus through the liberation of endogenous arachidonic acid which may then be transformed into prostaglandins.

Animals↗
PubMed1989

Effects of GABA antagonists on the pentobarbital-induced depression of respiration and cough in rats.

In order to determine the possible involvement of GABA-ergic mechanisms in the modulation of the cough reflex, the effects of GABA antagonists on the pentobarbital-induced depression of respiration and cough were examined in a comparative study in rats. The cough reflex was induced by application of electrical stimulation to the tracheal mucosa by the puncture electrode-induced cough method. The 50% antitussive dose (AtD50) of pentobarbital was calculated by the "up and down" method. Pentobarbital (10 mg/kg, IP) caused a reduction of tidal volume, which was counteracted by pretreatment with picrotoxin (3 mg/kg, IP) or bicuculline (3 mg/kg, IP). However, neither picrotoxin nor bicuculline were able to counteract the reduction in frequency of respiration. The AtD50 of pentobarbital was 1.95 mg/kg when administered IP. The AtD50 of pentobarbital was not altered after pretreatment of rats with picrotoxin (1.85 mg/kg, IP) or with bicuculline (1.55 mg/kg). These results suggest that GABA-ergic mechanisms may not be involved in the cough-depressant effect of pentobarbital.

Animals↗
PubMed1989

Subsensitivity to the cough-depressant effects of opioid and nonopioid antitussives in morphine-dependent rats: relationship to central serotonin function.

The present study was designed to determine whether morphine-dependent rats have a decreased sensitivity to the cough-depressant effects of both opioid and nonopioid antitussives. Morphine dependence was induced by treatment with morphine-admixed food (0.5 mg/g of food) for 7 days. The cough reflex was induced by application of electrical stimulation to the tracheal mucosa by the puncture electrode-induced cough method. The cough-depressant effect was evaluated as the antitussive ED50 calculated by the method of Litchfield and Wilcoxon. The effects of both opioid (morphine and dihydrocodeine) and nonopioid (dextromethorphan and noscapine) antitussive drugs were diminished in morphine-dependent rats. The values of ED50 of these antitussive drugs in morphine-dependent rats were about 3-fold higher than those in control rats. A significantly lower number of serotonin receptors was found in the brainstem of morphine-dependent rats (Bmax: 2.88 +/- 0.32 pmoles/mg protein) than in controls (Bmax: 4.93 +/- 0.50 pmoles/mg protein). It is possible that the decreased sensitivity to both opioid and nonopioid antitussive drugs, in terms of the depression of the cough reflex, in morphine-dependent rats may be due to changes in the number of serotonin receptors.

Animals↗
PubMed1989

Endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca2+ channel in vascular smooth muscle.

Endothelin is a potent endothelium-derived vasoconstrictor peptide recently characterized from porcine and human vascular endothelial cells. Here we provide evidence that endothelin activates the dihydropyridine-sensitive, voltage-dependent Ca2+ channel in porcine coronary artery smooth muscle. The vasoconstrictor action of endothelin is efficiently antagonized by low doses of the dihydropyridine Ca2+-channel blocker nicardipine. Endothelin augments the Ca2+-induced contraction in a high-K+ depolarizing solution, markedly enhances high-threshold Ca2+-channel current on the whole-cell patch clamp recording, and causes a sustained increase in the intracellular Ca2+ that is largely dependent on extracellular Ca2+. These findings suggest that endothelin exerts its vasoconstrictor effect by either directly or indirectly activating the voltage-dependent Ca2+ channel.

Animals↗
PubMed1989

The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.

Three distinct human endothelin-related genes were cloned by screening a genomic DNA library under a low hybridization stringency with a synthetic oligonucleotide probe encoding a portion of the endothelin sequence. Genomic Southern blot analysis with the same oligonucleotide probe showed three corresponding chromosomal loci not only in the human genome but also in porcine and rat genomes. The nucleotide sequences of the three human genes were highly conserved within the regions encoding the 21-residue (mature) endothelins, in spite of the fact that the immediately upstream exon sequences, which encode a part of the propeptides, retained little similarity. Moreover, each of the human genes predicted a putative 21-residue peptide, similar to but distinct from each other: (i) the "classical" endothelin (ET-1), (ii) [Trp6,Leu7]endothelin (ET-2), and (iii) [Thr2,Phe4,Thr5,Tyr6, Lys7,Tyr14]endothelin (ET-3). Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. However, the quantitative profiles of the pharmacological activities were considerably different among the three isopeptides, suggesting the possible existence of endothelin receptor subtypes.

Animals↗
PubMed1989

Conversion of big endothelin-1 to 21-residue endothelin-1 is essential for expression of full vasoconstrictor activity: structure-activity relationships of big endothelin-1.

The vasoconstrictor activities of porcine big endothelin-1 (big ET-1), a 39-residue intermediate predicted from cDNA sequence analysis, and of its shorter derivative, big ET-1 [1-25], were characterized in vitro by measuring the contraction of porcine coronary artery strips. Synthetic big ET-1 [1-39] and big ET-1 [1-25] induced a slow developing, long-lasting, and strong vasoconstriction as in the case of 21-residue ET-1. However, the contractile molar potencies of big ET-1 [1-39] and big ET-1 [1-25] were approximately 140- and 50-fold lower than that of ET-1, respectively. These results indicate that the conversion of big ET-1 to "mature" ET-1 is essential for the expression of the full vasoconstrictor activity, suggesting the physiological importance of the unusual proteolytic processing catalyzed by the putative "ET converting enzyme."

Animals↗
PubMed1989

Impairment of endothelium-dependent relaxation and changes in levels of cyclic GMP in aorta from streptozotocin-induced diabetic rats.

1. Acetylcholine (ACh)-induced relaxation of aortic strips with endothelium and production of cyclic GMP between streptozotocin-induced diabetic and age-matched control rats were compared. 2. The concentration-response curve for ACh-induced relaxation was shifted to the right in diabetic rats. IC50 values for ACh were 4.57 +/- 0.67 x 10(-8) M and 1.00 +/- 0.87 x 10(-7) M in aortic strips from age-matched control and diabetic rats, respectively (n = 6, P less than 0.05). 3. Relaxations produced by atrial natriuretic peptide (ANP) in diabetic aortae were similar to those in age-matched vessels. 4. Relaxations produced by sodium nitroprusside (SNP) in diabetic aortae were similar to those in age-matched vessels. 5. Basal levels of cyclic GMP and ACh-induced production of cyclic GMP were significantly decreased in diabetic rats. 6. These results suggest that functional changes in endothelium but not in guanylate cyclase activity in the aorta may occur in diabetes, and thus, spontaneous and ACh-induced formation of cyclic GMP may be decreased. This decrease in production of cyclic GMP may be responsible for the decreased response of the aorta to the relaxant effect of ACh.

Acetylcholine↗
PubMed1989

Endothelium-dependent vasodilator effects of platelet activating factor on rat resistance vessels.

1. To elucidate the mechanisms of the powerful and long-lasting hypotension produced by platelet activating factor (PAF), its effects on perfusion pressure in the perfused mesenteric arterial bed of the rat were examined. 2. Infusion of PAF (10(-11) to 3 x 10(-10) M; EC50 = 4.0 x 10(-11) M; 95%CL = 1.6 x 10(-11) - 9.4 x 10(-11) M) and acetylcholine (ACh) (10(-10) to 10(-6) M; EC50 = 3.0 +/- 0.1 x 10(-9) M) produced marked concentration-dependent vasodilatations which were significantly inhibited by treatment with detergents (0.1% Triton X-100 for 30 s or 0.3% CHAPS for 90 s). 3. Pretreatment with CV-6209, a PAF antagonist, inhibited PAF- but not ACh-induced vasodilation. 4. Treatment with indomethacin (10(-6) M) had no effect on PAF- or ACh-induced vasodilatation. 5. These results demonstrate that extremely low concentrations of PAF produce vasodilatation of resistance vessels through the release of endothelium-derived relaxing factor (EDRF). This may account for the strong hypotension produced by PAF in vivo.

Acetylcholine↗
PubMed1989

Platelet-activating factor: lack of direct action on guinea pig myocardium and possible transmitter release from cardiac sympathetic nerve endings at high concentrations.

Microelectrode and mechanical studies were performed with isolated guinea pig myocardium (right ventricular free walls and papillary muscles) to examine the effects of platelet-activating factor (PAF) and lysophosphatidylcholine (LPC). Low concentrations of PAF (10(-8) to 10(-6) M, a range equivalent to the blood concentrations that produce marked hypotension in vivo) had no effects on action potential configuration and contractile force. High concentrations (10(-5) to 10(-4)M) of PAF and LPC per se elicited slow response action potentials with concomitant contraction (restored contraction) in the myocardium depolarized with elevated K+ (25 mM); they also augmented slow responses and restored contractions produced by a low concentration of isoproterenol (10(-8) M). Although these results suggested there was an increase in slow Ca current, the slow responses and restored contractions thus produced were greatly suppressed or abolished by the addition of a beta-adrenoceptor blocking agent, sotalol (10(-5) M), and by pretreatment with reserpine (5 mg/kg i.p., 24 h prior). In accordance with our previous conclusions, the present results suggest that direct cardiac action is not involved in the mechanisms of hypotension produced by PAF. It was also shown that high concentrations of PAF and LPC may act nonspecifically as amphiphilic compounds to induce transmitter release from sympathetic nerve endings, which may in turn augment the Ca current channels in the myocardial cell membrane.

Action Potentials↗
PubMed1989

Mechanism of contraction to endothelin in isolated porcine coronary artery.

To elucidate the mechanisms of action of endothelin (ET) on vascular smooth muscles, the contractile responses of the isolated porcine coronary artery to ET were precisely investigated. ET produced concentration-dependent vasoconstrictions that were not mediated by biogenic amines, arachidonate metabolites, or endothelium-derived contractile factors. The maximum response to ET was identical to the response to K+ depolarization. The vasoconstrictor activity of ET was at least one or two orders of magnitude more potent than other vasoconstrictors (BAY K 8644, histamine, acetylcholine, and prostaglandin F2 alpha) examined. The action of ET was antagonized by a dihydropyridine Ca2+ antagonist, nicardipine, in a competitive fashion. ET-induced vasoconstriction was not mediated by membrane depolarization. A small amount of ET (2 x 10(-10) M) caused a leftward shift of the concentration-response relationship for K+. ET (5 x 10(-10), 5 x 10(-8) M) accelerated 45Ca2+ uptake to the smooth muscle cells, which were inhibited by nicardipine. However, ET did not affect the specific binding of [125I]iodipine to the smooth muscle cell membrane. These results suggest that ET produces vasoconstriction via ultimately accelerating Ca2+ influx through voltage-dependent Ca2+ channels but that the binding site is distinct from that of dihydropyridines.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗