Biomedical subjects

N Toda

Publications and source records attributed to N Toda.

At least 145 records · Page 8Linked to original sources

PubMed1993

Monkey cerebral arterial relaxation caused by hypercapnic acidosis and hypertonic bicarbonate.

In helical strips of Japanese monkey cerebral arteries contracted with vasoconstrictors, applications of high CO2 (15% compared with 5% CO2 in control media) and hypertonic NaHCO3 (50 mM) produced relaxations. Similar relaxations were also obtained in human cerebral arterial strips. Hypercapnia increased PCO2 and resulted in acidosis in the bathing media, and the addition of NaHCO3 restored the pH to normal with high PCO2 and increased the osmotic pressure. The relaxant responses were not influenced by endothelium denudation and treatment with indomethacin. The hypercapnia-induced relaxation was suppressed by ouabain but was unaffected by amiloride. On the other hand, hypertonic bicarbonate-induced relaxations were inhibited by ouabain as well as by amiloride. Removal of Na+ from the bathing media abolished the hypercapnia-induced relaxation but did not alter the hyperosmolar relaxation. In contrast to hypertonic NaHCO3, isotonic bicarbonate solutions contracted the arterial strips by neutralizing the pH under hypercapnia. It may be concluded that relaxations elicited by hypercapnic acidosis are associated with a fall of extracellular pH and an activation of the electrogenic Na+ pump, and those caused by hyperosmolarity are due to stimulation of the Na(+)-H+ exchange and the Na+ pump. Endothelium-derived vasoactive substances and cyclooxygenase products do not appear to be involved in these relaxations of monkey cerebral arteries under the experimental conditions used.

Acidosis↗

PubMed1993

Neural mechanism of hypertension by nitric oxide synthase inhibitor in dogs.

This study aimed to determine the mechanism of hypertension associated with nitric oxide synthase inhibition. Intravenous injections of NG-nitro-L-arginine, a nitric oxide synthase inhibitor, produced a sustained increase in systemic blood pressure and a decrease in heart rate in anesthetized dogs, whereas NG-nitro-D-arginine had no effect. L-Arginine reversed the pressor response. NG-Nitro-L-arginine-induced hypertension was markedly attenuated or abolished by treatment with hexamethonium; this inhibition was still observed when the blood pressure fall caused by the ganglionic blocking agent was compensated by continuous infusion of angiotensin II. In dogs treated with phentolamine in a dose sufficient to lower blood pressure to the level similar to that elicited by hexamethonium and to suppress the pressor response to norepinephrine, the hypertensive effect of NG-nitro-L-arginine was not attenuated. We conclude that hypertension caused by the nitric oxide synthase inhibitor is associated with an elimination of nitroxidergic neural function rather than an impairment of the basal release of nitric oxide from the endothelium.

Amino Acid Oxidoreductases↗

PubMed1993

Impairment by damage of the pterygopalatine ganglion of nitroxidergic vasodilator nerve function in canine cerebral and retinal arteries.

Histochemical study revealed that transcutaneous injection of ethanol into the vicinity of the pterygopalatine ganglion greatly decreased the positive staining for NADPH diaphorase activity after 1 week in the ipsilateral ganglion of a dog and abolished the staining of perivascular nerves in the middle and posterior cerebral arteries. Transmural electrical stimulation or nicotine produced a relaxation in middle and posterior cerebral arteries isolated from the side with the nontreated ganglion (control side), whereas the relaxation was abolished or reversed to a contraction in the arteries from the side with the ethanol-treated ganglion. Nitric oxide-induced relaxations did not differ in the arteries from both sides. The response to nerve stimulation of the control arteries was suppressed by treatment with NG-nitro-L-arginine (L-NA), an inhibitor of nitric oxide synthase, and the inhibition was reversed by L-arginine. Nicotine produced a contraction followed by a relaxation in central retinal arterial strips obtained from the control side; the relaxation was abolished and the contraction was potentiated in the arteries from the treated side. The nicotine-induced relaxation was abolished by L-NA, and the contraction was suppressed by phentolamine. On the other hand, the nicotine-induced relaxation in superficial temporal arteries, susceptible to L-NA, was not attenuated by treatment with ethanol. The findings obtained so far support our hypothesis that nitric oxide released from the vasodilator nerve acts as a transmitter to produce arterial smooth muscle relaxation and suggest that the nerve fibers to the cerebral and retinal arteries arise from the pterygopalatine ganglion.

Animals↗

PubMed1993

Endothelial modulation of contractions caused by oxyhemoglobin and NG-nitro-L-arginine in isolated dog and monkey cerebral arteries.

BACKGROUND AND PURPOSE: Oxyhemoglobin is a key substance in provoking cerebral vasospasm and a scavenger of nitric oxide. The present study was designed to determine whether suppression of the action of endothelium-derived nitric oxide is involved in oxyhemoglobin-induced cerebroarterial contraction. METHODS: Dog and monkey cerebral artery strips with and without endothelium were immersed for isometric tension recording in modified Ringer-Locke solution aerated with 95% oxygen and 5% carbon dioxide. RESULTS: NG-nitro-L-arginine, a nitric oxide synthase inhibitor, produced concentration-related contraction that was greater in the strips with intact endothelium than in those denuded of endothelium. The D-enantiomer caused no or only a slight contraction. In the presence of NG-nitro-L-arginine, oxyhemoglobin elicited additional contraction that is comparable to or even greater than that obtained in the absence of the inhibitor. The oxyhemoglobin-induced contraction was attenuated by endothelium denudation. CONCLUSIONS: Inhibition of the basal release of nitric oxide from endothelium results in dog and monkey cerebral arterial contraction. However, the inhibition of nitric oxide action is not a major mechanism involved in oxyhemoglobin-induced contraction; other mechanisms, such as the release of prostanoids, appear to be important.

Animals↗

PubMed1993

Potentiation by hypoxia of contractions caused by angiotensin II in dog and monkey cerebral arteries.

BACKGROUND AND PURPOSE: Hypoxia alters the responsiveness to endogenous substances of cerebral arteries, possibly resulting in the modulation of blood supply to ischemic brain regions. The present study was undertaken to analyze the mechanism of potentiation by hypoxia of angiotensin II-induced cerebroarterial contractions. METHODS: Monkey and dog cerebral arterial strips with endothelium were suspended for isometric tension recording in Ringer-Locke solution aerated with 95% O2-5% CO2 (partial pressure, 570-600 mm Hg) or 95% N2-5% CO2 (approximately 10 mm Hg). RESULTS: Contractions induced by angiotensin II and substance P were potentiated by exposure to hypoxia, whereas contractile responses to prostaglandin F2 alpha were not influenced. Treatment with cyclooxygenase inhibitors abolished the peptide-induced contraction but did not alter the prostaglandin F2 alpha-induced contraction. Relaxations induced by arachidonic acid were suppressed by indomethacin and hypoxia, whereas those caused by a prostaglandin I2 analogue were unaffected. CONCLUSIONS: The potentiation by hypoxia of cerebroarterial contractions caused by angiotensin II and substance P appears to be due to an interference with the synthesis of prostaglandin I2 from arachidonic acid and a resultant increase in the production of vasoconstrictor prostaglandins.

Angiotensin II↗

PubMed1993

Responsiveness to dopamine of isolated epicardial coronary arteries from humans, monkeys, and dogs.

Dopamine is widely used for the treatment of cardiogenic and hypovolemic shock. This study was undertaken to compare the response to dopamine in epicardial conduit coronary arteries of humans, Japanese monkeys, and dogs, and to determine the mechanism of vasoconstriction and vasodilation. In helical strips of coronary arteries from humans and monkeys partially contracted with prostaglandin F2 alpha, dopamine produced a concentration-related contraction; the human artery contraction was greater. The contractions were reversed to a relaxation by treatment with phentolamine. Relaxation of monkey arteries treated with the alpha adrenoceptor antagonist was not influenced by metoprolol, a beta 1 antagonist, or endothelium denudation, but was reversed to contraction by SCH23390, a dopamine1 receptor antagonist. On the other hand, dog coronary arteries responded to dopamine with a relaxation that was abolished by metoprolol, but not influenced by SCH23390 or butoxamine, a beta 2 antagonist. We conclude that dopamine in clinical doses elicits significant contractions, mediated possibly by alpha adrenoceptors, in human and monkey coronary arteries; thus, care has to be taken when the amine is used in patients with variant angina pectoris. Relaxation of monkey coronary arteries appears to be associated with activation of dopamine1 receptors, whereas those of the dog arteries are mediated mainly by beta 1 receptors.

Aged↗

PubMed1993

Comparison of endothelium-dependent responses of canine internal thoracic and coronary arteries.

The endothelium-dependency of vasodilator responses was compared in helical strips of canine internal thoracic (ITA) and coronary arteries partially contracted with serotonin. The addition of acetylcholine produced a concentration-related relaxation in ITA and coronary arterial strips with an intact endothelium. The relaxations were not influenced by indomethacin, but were markedly inhibited or abolished by methylene blue, NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor, and endothelial denudation. The responses to low concentrations of acetylcholine were significantly greater in ITA than in coronary arteries, whereas relaxations induced by substance P, Ca2+ ionophore (A23187) or NO in ITA were significantly less. The substance P-induced relaxation in ITA and coronary arteries was endothelium-dependent, and it was almost abolished by L-NA. Relaxations induced by ATP in ITA were abolished by endothelium denudation and treatment with L-NA. In the coronary arteries, relaxing responses were inhibited only partially by removal of endothelium and L-NA. Acetylcholine, ATP and substance P relax canine ITA possibly by a mediation of endothelium-derived NO, but not prostaglandin I2. Coronary arterial relaxations induced by ATP appear to be mediated by an indirect action via NO released from the endothelium, in addition to a direct action on the smooth muscle.

Acetylcholine↗

PubMed1993

KRI-1314: an orally effective inhibitor of human renin.

Biochemical and pharmacological properties of KRI-1314, a newly synthesized, low molecular weight (M.W.: 690) renin inhibitor, were investigated in vitro and in vivo. The novel amino acid norstatine, which is shorter in chain length than the well-known statine, was incorporated into KRI-1314 as a tetrahedral transition-state analogue for the Leu10-Val11 scissile peptide in the renin substrate. KRI-1314 more strongly inhibited plasma renins from primates than those from dogs, rabbits, guinea pigs and rats. KRI-1314 competitively inhibited highly-purified human renin with a Ki value of 9.9 x 10(-10) M. KRI-1314 strongly inhibited the tissue renin-like activities of various organs from Japanese monkeys, with IC50 values on the order of 10(-8) M. KRI-1314 was also very stable in various tissue homogenates from Japanese monkeys. Both intravenous (from 0.25 to 3 mg/kg) and oral (10 and 30 mg/kg) administration of KRI-1314 to anesthetized and conscious sodium-depleted Japanese monkeys, respectively, significantly lowered the blood pressure and plasma renin activity without affecting the heart rate. In Japanese monkeys, KRI-1314 was continuously detected in the plasma up to at least 7 hr after oral administration of 10 and 30 mg/kg. These results demonstrate that KRI-1314 is a highly potent, primate-selective and long-lasting oral renin inhibitor with a blood pressure lowering effect.

Administration, Oral↗

PubMed1993

Nitric oxide-mediated retinal arteriolar and arterial dilatation induced by substance P.

PURPOSE: The present study was undertaken to compare vasodilatations caused by substance P in retinal arterioles in vivo and in the extraocular retinal central arteries in vitro, and to analyze the mechanisms of its action. METHODS: In the in vivo study, changes of the retinal arteriolar diameter were continuously measured using a retinal fundus camera. In the in vitro study, changes in the isometric tension were recorded in helical strips of extraocular retinal arteries with and without the endothelium, exposed to aerated bathing media. RESULTS: In anesthetized dogs, infusions of substance P into the carotid artery produced a dose-dependent dilatation of the intraocular retinal arteriole; the maximal response was obtained about 15 seconds later. The vasodilator response was significantly attenuated by treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthase inhibitor, and the inhibition was reversed by L-arginine. On the other hand, vasodilatations caused by nitroglycerin were not influenced by L-NA and L-arginine. In the isolated retinal artery just before entering into the eyeball, the addition of substance P produced a concentration-dependent relaxation only when the endothelium of the strips was intact. Removal of the endothelium abolished the response. The peptide-induced relaxation was abolished by L-NA, whereas relaxations caused by NO and nitroglycerin were unaffected. The inhibitory effect of L-NA was reversed by L-arginine but not by D-arginine. Treatment with methylene blue or oxyhemoglobin abolished the relaxation induced by substance P, NO, and nitroglycerin. CONCLUSIONS: Substance P-induced retinal arteriolar dilatation in vivo appears to be mediated by NO synthesized from L-arginine possibly in the endothelium. The endothelium-dependency would be supported by the findings obtained from isolated retinal arteries.

Animals↗

PubMed1993

[Pharmacokinetics of midazolam in patients with liver damage for hepatectomy].

Pharmacokinetics of midazolam in patients with liver damage for hepatectomy was compared to that in patients without liver injury for gastrectomy. Anesthesia was induced with midazolam 0.15 mg.kg-1 and fentanyl. Serum concentration of midazolam was measured at 30 minutes, 1, 2, 3, 4, 6 and 8 hours after midazolam injection. Serum midazolam levels were not significantly different between the two groups at any time. The elimination half-life of midazolam was about 3 times longer in hepatectomy group (24.2 hours) than in the group without liver injury (8.4 hours). Area under the curve of the serum midazolam concentration was larger in the group with liver damage than in the group without it. But distribution volume and clearance of midazolam were not different between the two groups probably because of more blood transfusion and bleeding in hepatectomy group. The recovery time from anesthesia in hepatectomy group was as long as that in the group without liver injury. The results suggest that in patients with liver damage for hepatectomy, the elimination of midazolam is prolonged but its effect is not.

Aged↗

PubMed1993

Neurogenic and non-neurogenic relaxations caused by nicotine in isolated dog superficial temporal artery.

Nicotine produced a transient contraction followed by biphasic (rapid and slow) relaxations in dog superficial temporal arterial strips denuded of the endothelium. The responses to nicotine were abolished by treatment with hexamethonium. The nicotine-induced contraction was abolished by phentolamine and potentiated by NG-nitro-L-arginine (L-NA), a nitric oxide synthase inhibitor. The slowly developing relaxation was markedly suppressed by indomethacin and tranylcypromine, a prostaglandin I2 synthetase inhibitor, whereas the rapid relaxation was abolished by L-NA. The inhibitory effect of L-NA was reversed by L-, but not D-, arginine. NG-nitro-D-arginine had no effect. Transmural electrical stimulation elicited a transient relaxation in phentolamine-treated arteries. The relaxation was not influenced by indomethacin but was abolished by L-NA and tetrodotoxin. Nicotine increased intracellular cyclic AMP and cyclic GMP in the endothelium-denuded arteries. The increment of cyclic AMP was inhibited by indomethacin but not by L-NA, whereas that of cyclic GMP was not influenced by indomethacin but was abolished by L-NA. It may be concluded that nicotine stimulates the adrenergic and nitroxidergic nerves innervating the temporal arterial wall, resulting in a contraction and a rapidly developing relaxation, respectively; the latter is mediated by cyclic GMP. Potentiation by the nitric oxide synthase inhibitor of the contractile response to nicotine is expected to be a suppression of the relaxation mediated by the nerve-derived nitric oxide. Slow relaxations caused by nicotine appear to be associated with the elevation of cyclic AMP produced possibly by prostaglandin I2, which is released from subendothelial, non-neuronal tissues.

Adrenergic Fibers↗

PubMed1993

Mechanisms of histamine-induced relaxation in external and internal ophthalmic arteries.

PURPOSE: Mechanisms that underlie the relaxant response to histamine were examined in dog external (a branch of external carotid artery) and internal (a branch of internal carotid artery) ophthalmic arteries (EOA and IOA). METHODS: Changes in isometric tensions were recorded in helical strips of the arteries with and without the endothelium. RESULTS: Histamine predominantly produced relaxations in EOA and IOA, partially contracted with prostaglandin (PG) F2 alpha. The relaxation of IOA almost was abolished by treatment with cimetidine (10(-5) mol/l), whereas the response of EOA was partially attenuated by treatment with cimetidine or chlorpheniramine (10(-6) mol/l) and was abolished with their combined treatment. Endothelium denudation depressed the relaxation in EOA but did not affect the response of IOA. The response to histamine of EOA was inhibited by treatment with indomethacin (10(-6) mol/l) or tranylcypromine (10(-4) mol/l), a PGI2 synthesis inhibitor, only when the endothelium was present, but additional treatment with chlorpheniramine did not further inhibit relaxation. On the other hand, IOA's response to histamine was not inhibited by indomethacin, despite the presence of endothelium. CONCLUSIONS: The histamine-induced relaxation in EOA may be associated with the release of vasodilator PGI2 through the activation of H1 receptors in the endothelium and with the direct action on H2 receptors in smooth muscle, whereas the relaxation in IOA is mediated exclusively by H2 receptors in smooth muscle.

Animals↗

PubMed1992

AE0047, a new dihydropyridine Ca2+ entry blocker, inhibits the responses to adrenergic nerve stimulation and substance P in dog mesenteric arteries.

AE0047, a new dihydropyridine-type Ca2+ entry blocker, significantly inhibited the contractions induced by transmural electrical stimulation and norepinephrine in dog mesenteric artery strips. The inhibition was greater in the case of the response to nerve stimulation. The 3H-overflow ratio evoked by electrical stimulation from strips previously soaked in [3H]norepinephrine was significantly reduced by AE0047 but not by nicardipine in a concentration sufficient to attenuate the response to norepinephrine. In aorta homogenate preparations, [3H]bunazosin binding was not replaced by AE0047 but by phentolamine. In strips treated with indomethacin, the endothelium-dependent relaxation caused by substance P and bradykinin was attenuated by treatment with AE0047 but not with nicardipine. The nitric oxide (NO)-induced relaxation was not influenced by AE0047. Cyclic GMP levels in the artery strips increased in response to substance P; the increase was markedly suppressed by AE0047 but not by nicardipine. In contrast to nicardipine, AE0047 appeared to inhibit the release of norepinephrine from adrenergic nerves and of NO from endothelial cells. The inhibition may be associated with the decreased transmembrane influx of Ca2+ in these tissues.

Adrenergic alpha-Agonists↗

PubMed1992

Selective necrosis in hamster pancreatic tumours using photodynamic therapy with phthalocyanine photosensitization.

Photodynamic therapy (PDT) is often thought to be able to effect selective tumour necrosis. This therapeutic selectivity, based on transient differences in tumour: normal tissue photosensitizer concentration ratios, is rarely useful clinically in extracranial tumours, although PDT itself may be of value by virtue of the nature of the damage produced and healing of normal tissue by regeneration. This report describes the effects of PDT on normal pancreas and chemically induced pancreatic cancers in the hamster, where a different mechanism of selective necrosis may be seen. Photosensitizer distribution in normal and neoplastic pancreas was studied by chemical extraction and fluorescence microscopy. Correlation of distribution studies with necrosis produced by PDT shows that the photodynamic dose (product of tissue concentration of sensitizer and light dose) threshold for damage is seven times as high for normal pancreas as for pancreatic cancer. Tumour necrosis extended to the point where tumour was invading normal areas without damaging the normal tissue. In rat colonic cancer, photodynamic dose thresholds in tumour and normal tissue are similar and so such marked selectivity of necrosis is not possible. The reason for this selectivity in the pancreas is not clear, but recent evidence has suggested a difference in response to PDT between normal and neoplastic pancreatic cell lines and the presence of a singlet oxygen scavenger in normal pancreas is postulated. Furthermore, the present fluorescence microscopy studies suggest that tumour stroma contains the highest level of photosensitizer and thus receives the highest photodynamic dose during PDT. These results suggest a possible role for PDT in treating small pancreatic tumours or as an adjuvant to other techniques, such as surgery, that reduce the main bulk of tumours localized to the pancreas.

Animals↗

PubMed1992

Mechanisms of relaxation induced by prostaglandins in isolated canine uterine arteries.

OBJECTIVE: Prostaglandins liberated from the uterus in response to chemical and physical stimuli would be important modulators of uterine arterial tone and blood flow. This study was aimed at analyzing mechanisms of vasodilator action of prostaglandins in uterine arteries. STUDY DESIGN: Canine uterine artery strips were suspended in Ringer-Locke solutions for isometric tension recording. RESULTS: Prostaglandin F2 alpha-induced relaxation was reversed to contraction by cyclooxygenase inhibitors and suppressed by tranylcypromine (prostaglandin I2 synthesis inhibitor) or diphloretin phosphate (an inhibitor of prostaglandin F2 alpha and prostaglandin I2 actions) but was unaffected by endothelium denudation. Prostaglandin E2-induced relaxation was not attenuated by indomethacin but was partially inhibited by a nitric oxide synthase inhibitor and endothelium denudation. Relaxation induced by beraprost (prostaglandin I2 analog) was suppressed by diphloretin phosphate but was not influenced by indomethacin and endothelium denudation. CONCLUSION: It appears that prostaglandin F2 alpha-induced relaxation is mediated by prostaglandin I2 released from subendothelial tissues, whereas prostaglandin E2-induced relaxation is caused by release of endothelium-derived nitric oxide and also by an endothelium-independent mechanism.

Animals↗

PubMed1992

Local generation and action of angiotensin II in dog iris sphincter muscle.

Existence of the renin-angiotensin system was pharmacologically investigated in the dog isolated iris sphincter muscle. The sphincter muscle contracted in response to tetradecapeptide, a synthetic renin substrate, angiotensin (ANG) I and ANG II dose-dependently. The contractions induced by these peptides were suppressed by treatment with saralasin, indomethacin and aspirin. Contractile responses to tetradecapeptide and ANG I were also reduced by KRI-1314, a renin inhibitor, and captopril, respectively. ANG II stimulated the release of prostaglandin (PG) F2 alpha from the sphincter muscle. Angiotensin-converting enzyme activity was measurable in the sphincter muscle. Miosis was observed by intracameral injection of ANG I and ANG II into the anterior chamber. These results strongly suggest that angiotensin generating enzymes function in the sphincter muscle and ANG II produced by these enzymes contracts the sphincter muscle via the formation of PG (s), possibly PG F2 alpha.

Angiotensin I↗

PubMed1992

Regional difference in the response mediated by beta 1-adrenoceptor subtype in bovine cerebral arteries.

Helical strips of bovine rostral cerebral arteries (anterior cerebral, middle cerebral, and internal carotid artery) responded to norepinephrine with contractions, whereas the caudal cerebral arteries (posterior communicating, posterior cerebral, and basilar artery) relaxed in response to the amine. After blockade of alpha-adrenoceptors, norepinephrine-induced rostral artery contractions were reversed to relaxations, which were smaller than those in the caudal arteries. Isoproterenol, dobutamine, and terbutaline produced greater relaxations in caudal than in rostral arteries, but forskolin relaxed these arteries to a similar magnitude. The isoproterenol-induced relaxation was not affected by removal of the endothelium. Maximal relaxations induced by terbutaline in caudal arteries were much inferior to those by isoproterenol, norepinephrine, and dobutamine. Relaxations caused by isoproterenol, norepinephrine, and terbutaline in the caudal arteries were attenuated by metoprolol, but not influenced by butoxamine. Relaxations mediated possibly by beta 1-adrenoceptor subtypes are greater in bovine caudal cerebral arteries than in the rostral arteries. The heterogeneity does not appear to be associated with the different ability of cyclic AMP to relax arterial smooth muscle but with the difference of beta-adrenoceptor populations and/or processes from the receptors to adenylate cyclase.

Adrenergic beta-Agonists↗

PubMed1992

Existence of renin in the endothelium of human artery.

OBJECTIVE: The existence and localization of renin in situ was examined in human arteries under non-pathological conditions. DESIGN: Biochemical and immunohistochemical procedures were adopted to examine the existence of renin in human gastroepiploic arteries using an antibody raised against human recombinant renin or a specific renin inhibitor. METHODS: (1) Renin activity (angiotensin I generating activity sensitive to antihuman recombinant renin antibody or a specific renin inhibitor) in the homogenate of human gastroepiploic arteries with and without endothelium was compared; (2) vascular renin was immunohistochemically stained using a modified avidin-biotin-peroxidase complex method. RESULTS: (1) Renin activity in human gastroepiploic arteries with endothelium was significantly higher than in those without endothelium; (2) immunoreactive staining selectively occurred in the endothelial cells of human gastroepiploic arteries. CONCLUSIONS: Renin is present in endothelial cells of human arteries under non-pathological conditions. Endothelial renin may play a role in the control of vascular tone through local production of angiotensin II.

Aged↗