Biomedical subjects

N Toda

Publications and source records attributed to N Toda.

At least 199 records · Page 11Linked to original sources

PubMed1990

Mechanisms of contracting action of oxyhemoglobin in isolated monkey and dog cerebral arteries.

Oxyhemoglobin (HbO2) produced a concentration-dependent contraction of monkey and dog cerebral artery strips, which was significantly attenuated by endothelium denudation. The contractile response was suppressed by treatment with indomethacin, aspirin, and diphloretin phosphate, a prostaglandin (PG) receptor antagonist. OKY 046, a thromboxane synthase inhibitor, attenuated both the contractions caused by HbO2 and PGF2 alpha. Contractions by arachidonic acid (AA) of the monkey arteries were markedly inhibited by indomethacin and moderately attenuated by endothelium denudation. Treatment with superoxide dismutase and catalase failed to reduce the response to HbO2 and AA. The median effective concentration of HbO2 in producing dog cerebral artery contraction was approximately 1,000 times as high as the median inhibitory concentration in inhibiting the effect of endothelium-derived relaxing factor (EDRF) released from dog femoral arteries in response to acetylcholine. It is concluded that contractions caused by HbO2 are not associated with suppression of EDRF released spontaneously from monkey and dog cerebral arteries, but with vasoconstrictor PGs released mainly from endothelium. Thromboxane A2, superoxide anions, and hydrogen peroxide do not appear to be involved.

Animals↗

PubMed1990

Mechanism underlying responses to histamine of isolated monkey and human cerebral arteries.

Cerebral artery strips obtained from Japanese monkeys partially contracted with prostaglandin F2 alpha responded to histamine with a relaxation that was attenuated by treatment with cimetidine or chlorpheniramine and was abolished by their combined treatment. Endothelium denudation suppressed the relaxation; the remaining relaxation was not influenced by the H1 antagonism but was abolished by the H2 antagonism. Treatment with methylene blue slowed the development of relaxation and, in the presence of cimetidine, depressed the magnitude of relaxation. Indomethacin did not alter the response. In the main trunk of human middle cerebral arteries obtained during autopsy, histamine predominantly caused contractions, whereas third and fifth branches responded exclusively with a dose-dependent relaxation. The contraction was abolished by chlorpheniramine, and the relaxation was attenuated by either chlorpheniramine or cimetidine. Removal of endothelium suppressed or reversed the relaxation to a contraction. It appears that the histamine-induced relaxation is mediated by endothelial H1 receptors responsible for the release of endothelium-derived relaxing factor and also by H2 receptors in smooth muscle, whereas the contraction is associated with activation of smooth muscle H1 receptors. Involvement of the receptor subtypes in the observed response of monkey and human cerebral arteries quantitatively differs. Physiological and pathophysiological roles of endogenous histamine acting on the large cerebral arteries may be postulated.

Animals↗

PubMed1990

Cholinergic prejunctional inhibition of vasodilator nerve function in bovine basilar arteries.

Helical strips of bovine basilar arteries responded to transmural electrical stimulation with moderate relaxations that were abolished by treatment with tetrodotoxin and oxyhemoglobin and were significantly attenuated by quinidine, as were the relaxations previously seen in dog and monkey cerebral arteries. The relaxant response of the bovine arteries was attenuated by treatment with acetylcholine and physostigmine and was significantly potentiated by atropine. In contrast, relaxations of dog coronary arteries to transmural stimulation, mediated via beta-adrenoceptors, were not influenced by physostigmine and atropine but were attenuated by acetylcholine. Abundant fibers containing cholinesterase were histologically demonstrated in bovine basilar arteries, suggesting the presence of cholinergic innervation. Acetylcholine liberated from the cholinergic nerve appears to act on muscarinic receptors located in vasodilator nerve terminals in bovine cerebral arteries and to interfere with the release of vasodilator transmitters.

Animals↗

PubMed1990

Mechanism underlying the response to vasodilator nerve stimulation in isolated dog and monkey cerebral arteries.

Relaxant responses to transmural electrical stimulation and nicotine of cerebral artery strips obtained from dogs and Japanese monkeys were abolished by tetrodotoxin and hexamethonium, respectively, and suppressed by treatment with NG-monomethyl-L-arginine (L-NMMA), a nitric oxide (NO) synthesis inhibitor. The inhibitory effect was prevented and reversed by L-arginine but not by D-arginine. The relaxations suppressed by L-NMMA were not increased by exogenously applied NO. Endothelium denudation did not alter the response to transmural stimulation and nicotine or the inhibitory effect of L-NMMA. D-NMMA did not inhibit the response to vasodilator nerve stimulation. Dog coronary artery relaxations caused by transmural stimulation were not inhibited by L-NMMA but reversed to contractions by propranolol. Relaxations caused by substance P of dog cerebral arteries treated with indomethacin were dependent on endothelium and inhibited by L-NMMA, whereas those by NO and nitroglycerin, endothelium-independent relaxations, were unaffected. It is concluded that chemical and electrical stimulation of vasodilator nerves relaxes dog and monkey cerebral arteries, possibly by a mediation of NO rather than a stimulating action of NO on the release of vasodilator transmitter. Endothelium-dependent relaxations by substance P of dog cerebral arteries appear to be mediated by NO.

Animals↗

PubMed1990

[Endothelium-derived relaxing factor (EDRF)].

The great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of "EDRF = NO" is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K(+)-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.

Animals↗

PubMed1990

Modification by L-NG-monomethyl arginine (L-NMMA) of the response to nerve stimulation in isolated dog mesenteric and cerebral arteries.

Treatment with L-NG-monomethyl arginine (L-NMMA) increased the vasoconstriction induced by adrenergic nerve stimulation in perfused dog mesenteric artery segments and suppressed the relaxant response to transmural nerve stimulation in dog cerebral artery strips, the effects of L-NMMA being reversed by L-arginine. The observed changes in nerve function may be associated with the inhibition of synthesis of nitric oxide.

Animals↗

PubMed1990

Role of nitric oxide in non-adrenergic, non-cholinergic nerve-mediated relaxation in dog duodenal longitudinal muscle strips.

Transmural electrical stimulation caused a relaxation in the dog duodenal longitudinal muscle strips treated with atropine, phentolamine and propranolol, which was abolished by tetrodotoxin. The relaxation was suppressed by oxyhemoglobin and L-NG-nitro-arginine (L-NA), but not influenced by D-NA. Inhibition by L-NA was reversed by L-arginine, but not by D-arginine. The response to transmural electrical stimulation was similar to that caused by nitric oxide or nitroglycerin. Nitric oxide appears to participate importantly in non-adrenergic, non-cholinergic nerve-mediated relaxation.

Animals↗

PubMed1990

Suppression by methylene blue of prostaglandin I2 synthesis in isolated dog renal arteries.

In dog renal artery strips with intact and damaged endothelium, relaxations induced by angiotensin II possibly mediated via the release of prostaglandin (PG) I2 were abolished or reversed to contractions by treatment with methylene blue and indomethacin. Relaxations elicited by arachidonic acid were also inhibited markedly. PGH2-induced contractions in the arteries with endothelium were potentiated, and relaxations caused by PGH2 in the endothelium-denuded arteries were suppressed by methylene blue, whereas these responses were not influenced by indomethacin. Relaxant responses to PGI2 and beraprost, a stable analog of PGI2, were not reduced by methylene blue. The amount of 6-keto PGF1 alpha in the bathing media released from the renal artery was decreased by treatment with methylene blue and indomethacin, whereas amounts of PGE2 and thromboxane B2 were not influenced by methylene blue but were reduced by indomethacin. It may be concluded that methylene blue interferes with the synthesis and release of PGI2 in the dog renal arteries; therefore, the relaxation mediated by endogenous PGI2 is suppressed. However, methylene blue does not appear to inhibit the synthesis of other cyclooxygenase products.

Angiotensin II↗

PubMed1990

Modifications by endogenous prostaglandins of angiotensin II-induced contractions in dog and monkey cerebral and mesenteric arteries.

In monkey and dog cerebral artery strips, angiotensin (ANG) II (10(-7) M) produced a transient contraction, which was abolished or suppressed by treatment with indomethacin, aspirin, ONO3708, diphloretin phosphate, antagonists of prostaglandins (PGs) and OKY046, a thromboxane A2 synthesis inhibitor, and by endothelium denudation. On the other hand, PGF2 alpha-induced contractions were not influenced by indomethacin and aspirin, but were suppressed by treatment with ONO3708 and OKY046. Treatment with indomethacin or aspirin potentiated the contractile response of monkey mesenteric arteries, whereas treatment with ONO3708 and removal of endothelium did not alter the response significantly. Saralasin abolished the response to ANG II in these arteries. These findings may indicate that ANG II contracts monkey and dog cerebral arteries by activation of ANG II receptors mainly in endothelium, releasing arachidonic acid and synthesizing vasoconstrictor PGs, such as PGF2 alpha, E2, A2 and D2. Involvement of thromboxane A2 is if any minimal. Vasoconstrictor and dilator PGs released by ANG II appear to modify differently the contraction caused by direct actions of the octapeptide on smooth muscle in monkey cerebral and mesenteric arteries.

Angiotensin II↗

PubMed1990

Beta adrenoceptor subtype in isolated human, monkey and dog epicardial coronary arteries.

Isolated human, Japanese monkey and dog epicardial coronary arteries and dog renal and mesenteric arteries treated with phentolamine responded to isoproterenol with a concentration-related relaxation. The KB values of metoprolol, a beta-1 antagonist, in the coronary arteries from different mammals did not differ, but were appreciably smaller than those in the dog renal and mesenteric arteries. Treatment with butoxamine, a beta-2 antagonist, inhibited the relaxation of dog mesenteric arteries to a greater extent than that of monkey and dog coronary arteries. Terbutaline, a beta-2 agonist, produced a greater relaxation in monkey mesenteric and dog renal and mesenteric arteries than in human, monkey and dog coronary arteries. Norepinephrine relaxed the monkey and dog coronary arteries dose-dependently via mainly beta-1 adrenoceptors, but elicited a contraction or a minute relaxation in dog mesenteric arteries even when treated with high concentrations of phentolamine. Contractile responses to electrical stimulation of adrenergic nerves in monkey coronary arteries were potentiated by treatment with metoprolol and propranolol, whereas the contractions in dog mesenteric arteries were unaffected. It is concluded that the amine-induced relaxation of human and monkey epicardial coronary arteries is mediated mainly by beta-1 adrenoceptor subtype, as is the response of dog coronary arteries. Involvement of beta-1 subtype in coronary artery relaxations would be a mechanism underlying potentiation by beta antagonists of the contraction caused by norepinephrine released from adrenergic nerves in primates.

Animals↗

PubMed1990

Comparison of the response to 5-carboxamidotryptamine and serotonin in isolated human, monkey and dog coronary arteries.

In isolated dog coronary arteries, serotonin (5-HT) produced a contraction, whereas 5-carboxamidotryptamine (5-CT), a serotonergic 5-HT1-like receptor agonist, mainly relaxed the arteries, and the contraction, if any, was slight. Human and Japanese monkey coronary artery strips responded to these amines only with contractions, the magnitude being markedly greater than that of serotonin-induced contractions in the dog arteries. Removal of endothelium slightly potentiated the serotonin-induced contraction and abolished the relaxation by 5-CT or reversed it to a contraction in the dog arteries; however, contractions elicited by serotonin and 5-CT in the human and monkey arteries were not influenced. Treatment with 10(-7) M 5-CT suppressed the contraction by serotonin in the dog arteries but did not alter the response of the monkey arteries. Relaxation of the dog arteries with endothelium caused by 5-CT and contraction of the arteries denuded of endothelium were not inhibited by ketanserin but they were by methysergide. 5-CT-induced contractions of human and monkey coronary arteries were attenuated by ketanserin and methysergide, although the inhibition was less with the 5-HT2 antagonist. Ketanserin inhibited the contraction by serotonin to a greater extent than the 5-CT-induced contraction in the monkey arteries. It may be concluded that 5-CT stimulates 5-HT1-like and 5-HT2 receptor subtypes in smooth muscle of human and monkey epicardial coronary arteries but acts exclusively on 5-HT1-like receptors in endothelium and smooth muscle of dog coronary arteries. Serotonin contracts the primate arteries, possibly by predominant activation of 5-HT2 over 5-HT1-like receptors.

Animals↗

PubMed1989

Different involvement of endothelium-derived relaxing factor and prostacyclin in vasodilator response to bradykinin in isolated dog blood vessels.

The study presented so far demonstrates that there is a heterogeneity in the mechanisms of vasodilator action of BK in various dog blood vessels (coronary vs mesenteric artery, and mesenteric artery vs vein). The different mechanisms underlying the BK-induced vasodilatation are summarized in Fig. 3. Three mechanisms are at least involved; 1) EDRF-release from endothelial cells which may not be mediated by B1 receptor, but presumably by B2 receptor, 2) PGI2-release from endothelial cells, 3) PGI2-release from smooth muscle (subendothelial) cells. The PGI2-release may be mediated by B1 receptor. Vasodilatation caused by BK is mediated via "1" in coronary arteries, "2" + "3" in mesenteric veins, and "1" + "2" + "3" in mesenteric and renal arteries in the dog. Another reasons for the differences in the BK-induced vasodilatation may be different number or sensitivity of BK receptors located on the endothelial and smooth muscle cells, or the responsiveness of the vascular smooth muscle cells to the intermediate vasodilator substances and BK itself.

Animals↗

PubMed1989

In vivo inhibition of tissue kallikreins by kininogen sequence analogue peptides.

Kininogen sequence analogs containing amino acid residues around the Arg-Ser cleavage site of bovine kininogens were prepared with bulky aliphatic residues in P3 position. KKI-7 (containing a cyclohexylacetyl group) and KKI-8 (containing an adamantaneacetyl group) both inhibited human urinary kallikrein (HUK) with Ki of 4 microM. These inhibitors were 40 times more potent than the corresponding peptide containing the naturally occurring Pro at P3 and were one-seventh as susceptible to hydrolysis by HUK. Rat submaxillary kallikrein (RSK) and porcine pancreatic kallikrein (PPK) were also inhibited by these analogs. Both analogs were poor inhibitors of human plasma kallikrein, while their capacity to inhibit bovine trypsin was 1/3 and 1/17, respectively, that to inhibit HUK. In a rat blood flow study, KKI-7 infusion depressed the response to injected RSK. The response gradually returned toward normal 30 to 60 min after the infusion was terminated. Blood flow increase of dog jejunal artery in response to infused PPK was blunted by the simultaneous local infusion of Trasylol, KKI-7, or KKI-8, whereas these infusions did not alter the response to infused bradykinin. The vehicle infusion did not attenuate the response either to PPK or bradykinin. These analogs appear to have greater specificity and stability than those previously developed and to be appropriate for the in vivo inhibition of glandular kallikreins.

Amino Acid Sequence↗

PubMed1989

Methylreductic acid and hydroxymethylreductic acid: oxygen radical-forming agents in heated starch.

Two compounds forming oxygen radicals were isolated from heated starch by monitoring the potency to form 8-hydroxydeoxyguanosine from deoxyguanosine during purification procedures. These compounds were identified as hydroxymethylreductic acid and methylreductic acid. The former compound was mutagenic to Salmonella strains TA100, TA102 and TA104 and the latter compound induced sister-chromatid exchanges in human NL3 cells. Hydroxymethylreductic acid was found to be a novel compound. Considerable amounts of these compounds were detected in various heat-processed foods.

Animals↗

PubMed1989

The contractile responses of isolated dog cerebral and extracerebral arteries to oxybarbiturates and thiobarbiturates.

In helical strips of dog cerebral, coronary, mesenteric, renal, and femoral arteries, the addition of thiamylal and thiopental, 10(-5) to 10(-3) M, caused a dose-related contraction; the contraction was significantly more intense in cerebral than in extracerebral arteries. Secobarbital caused a slight contraction only in the cerebral artery. In contrast, pentobarbital did not produce a contraction in any artery studied. The thiamylal-induced contraction was not affected by treatment with phentolamine, diphenhydramine, or cinanserin but was attenuated by treatment with Ca entry blockers, such as nifedipine or diltiazem. In the cerebral artery soaked in Ca++-free media for 60 min, the addition of Ca++ produced triphasic responses; a transient contraction followed by a relaxation and a slowly developing, persistent contraction. The persistent contraction was potentiated by 10(-4) M thiamylal but abolished at 10(-3) M. In the mesenteric artery soaked in Ca++-free media, the addition of Ca++ produced only a slight contraction, which was potentiated by thiamylal (10(-4) and 10(-3) M). It is concluded that thiobarbiturates are more potent vasoconstrictors than oxybarbiturates and that the barbiturates produce greater contraction in cerebral arteries than in extracerebral arteries. The thiamylal-induced contraction appears to be associated mainly with influx of Ca++ from extracellular fluids.

Animals↗

PubMed1989

Action of atrial natriuretic peptide (ANP) on dog cerebral arteries: evidence that neurogenic relaxation is not mediated by release of ANP.

1. Atrial natriuretic peptide (ANP) (10(-9) to 10(-8) M) produced a concentration-related relaxation in helical strips of dog cerebral arteries partially contracted with prostaglandin F2 alpha. The relaxation was not affected by treatment with ouabain, quinidine, oxyhaemoglobin, methylene blue, or removal of endothelium. 2. Relaxations induced by nicotine or transmural electrical stimulation were not reduced in arteries in which tachyphylaxis to ANP had developed. 3. In arteries exposed to Ca2+-free media under severe hypoxia, contractions due to prostaglandin F2 alpha and Ca2+ were attenuated by treatment with ANP, whereas the reoxygenation-induced contraction was unaffected. 4. The results suggest that ANP does not mediate neurogenic relaxation of dog cerebral arteries. The ANP-induced relaxation is not associated with activation of the sodium pump but is due to an inhibitory action on the release and influx of Ca2+, probably as a result of stimulation of guanylate cyclase.

Animals↗

PubMed1989

Mechanisms underlying response to hypercapnia and bicarbonate of isolated dog cerebral arteries.

In helical strips of dog cerebral arteries contracted with K+ or prostaglandin F2 alpha, the increase in CO2 from 5 to 15% in the gas aerating the bathing media produced a persistent relaxation in association with a rise of PCO2 and a fall of pH and PO2. Elevation of the NaHCO3 concentration from 25 to 75 mM in the bathing media under hypercapnia almost reversed the arterial tone when the osmolarity was balanced; the pH was completely reversed, whereas PCO2 was maintained at the high level. When 50 mM NaHCO3 were applied to the hypercapnic media without having the osmolarity balanced, the arteries relaxed further. Infusions of the HCl solution lowered the pH and relaxed the arterial strips; however, such a relaxation was significantly less than that caused by hypercapnia-induced acidosis. Relaxant responses to hypercapnia were attenuated by treatment with ouabain but were not influenced by amiloride and superoxide dismutase or by removal of endothelium. Relaxations due to hypertonic NaHCO3 were abolished or reversed to contractions by ouabain and were reduced by treatment with amiloride. It may be concluded that the hypercapnia-induced cerebroarterial relaxation is associated mainly with a fall of extracellular pH and is mediated partly by an activation of the electrogenic Na+ pump. Cerebral vasodilatation by increased osmolarity with NaHCO3 appears to result from stimulated Na+-H+ exchange and activated Na+ pump.

Animals↗

PubMed1989

Endothelium-dependent and -independent responses to vasoactive substances of isolated human coronary arteries.

In epicardial conduit coronary artery strips obtained during autopsy within 2.5 h after death, relaxations induced by low concentrations of histamine were reversed to contractions by removal of endothelium, whereas those caused by bradykinin, substance P, and Ca2+ ionophore A23187 were almost abolished. In the artery strips with intact endothelium, which responded to histamine, bradykinin, and substance P with moderate or marked relaxations, acetylcholine elicited contractions. Endothelium denudation failed to potentiate the contractile response to acetylcholine and serotonin. Relaxant responses to histamine, bradykinin, and substance P did not significantly differ in coronary arteries from adults (35-48 yr old) and seniors (63-82 yr old). Two strips from a 2-mo-old male responded to acetylcholine only with contractions, and their responses to the vasodilators were not greater than those seen in the adult and senior arteries. Histamine increased guanosine 3',5'-cyclic monophosphate (cGMP); the increments did not differ in the arteries from adults and seniors. It may be concluded that endothelium is a major site for relaxant actions of histamine, bradykinin, and substance P, whereas muscarinic receptors, if any, in endothelium do not play an important role in the generation of relaxing factor from human coronary arteries. The endothelium-dependent relaxations do not appear to be altered with increasing age or in the arteries with slight atherosclerotic changes.

Acetylcholine↗