Biomedical subjects

N Toda

Publications and source records attributed to N Toda.

At least 235 records · Page 13Linked to original sources

PubMed1988

Mechanism underlying relaxations caused by prostaglandins and thromboxane A2 analog in isolated dog arteries.

In helical strips of dog cerebral, coronary, mesenteric, and renal arteries treated with ONO3708, an inhibitor of vasoconstricting prostaglandin (PG) receptors, and previously contracted with serotonin, PGF2 alpha, PGD2 and epithio-methano thromboxane A2 (sTxA2), a TxA2 analog, caused a relaxation. The cerebral arterial relaxation was suppressed by treatment with indomethacin and abolished by diphloretin phosphate (DPP), a PG antagonist. On the other hand, the relaxation of mesenteric arteries was not influenced by indomethacin but was markedly attenuated by DPP. Removal of endothelium did not alter the relaxation. Relaxations of coronary and renal arteries by PGF2 alpha were suppressed by indomethacin and DPP, whereas the PGD2-induced relaxation was not affected by indomethacin but was abolished by DPP. Concentration--relaxation curves for PGI2 were shifted to the right by treatment with DPP. It is concluded that after ablation of the constrictor response, dog cerebral arteries relax in response to PGs and TxA2, probably due mainly to the release of PGI2-like substance from the arterial wall and to the action of PGI2 receptive sites, whereas the mesenteric arterial relaxation appears to be associated with their action on PGI2 receptors in smooth muscle cells. PGF2 alpha-induced relaxations in coronary and renal arteries may result from the release of PGI2, and relaxations by PGD2 from the action on PGI2 receptors.

Animals↗

PubMed1988

Neuroeffector actions of thromboxane B2 in dog isolated mesenteric arteries.

1. Thromboxane (TX) B2 and epithiomethano (sTXA2), in concentrations that were insufficient to alter the basal tone, potentiated contractile responses of helical strips of dog mesenteric arteries to transmural electrical stimulation. The potentiating effect of TXB2 (up to 10(-6) M) was not abolished by diphloretin phosphate (DPP), a prostaglandin antagonist, whereas the potentiation by sTXA2 was abolished by the antagonist. 2. sTXA2 and TXB2 (3 x 10(-6) M or higher) potentiated the responses to noradrenaline, the potentiation being antagonized by DPP. 3. 3H-overflow evoked by transmural stimulation in superfused arterial strips previously soaked in medium containing [3H]-noradrenaline was increased by TXB2, but not altered by sTXA2. 4. TXB2 in low concentrations potentiated the contractile response to adrenergic nerve stimulation, possibly by increasing the release of noradrenaline, while the potentiation by the TXA2 analogue appears to be due to increased sensitivity of the arteries to noradrenaline. Prejunctional effects of TXB2 may be mediated by receptor sites functionally different from those located postjunctionally.

Animals↗

PubMed1988

Prostaglandins involved in contractions by angiotensin II and bradykinin of isolated dog sphincter pupillae.

1. The dog isolated sphincter pupillae contracted in response to acetylcholine, angiotensin II (AII), bradykinin, prostaglandins F2 alpha, D2, E2 and I2, and thionate thromboxane A2 (sTXA2) in a concentration-dependent manner. 2. AII-induced contractions were suppressed by treatment with saralasin, indomethacin, aspirin and diphloretin phosphate (DPP), a prostaglandin receptor antagonist. Contractions induced by bradykinin were also attenuated by indomethacin, aspirin and DPP. The amount of prostaglandin F2 alpha (PGF2 alpha) in the bathing media was increased approximately 41% following stimulation of the preparations by bradykinin. 3. The potency of contractile responses was in the order of PGF2 alpha greater than PGD2 = sTXA2 greater than PGE2 greater than arachidonic acid greater than PGI2. Contractions induced by PGF2 alpha were not significantly affected by treatment with indomethacin and ONO3708, an antagonist of the vasoconstrictor effect of prostaglandins, but appreciably attenuated by DPP. Arachidonic acid-induced contractions were inhibited by indomethacin. 4. Contractions of dog iris sphincter muscle in response to AII and bradykinin may be mediated via substances synthesized by cyclo-oxygenase from arachidonic acid. The distribution and nature of the prostaglandin receptors appear to differ markedly in iris sphincter and vascular smooth muscles.

Angiotensin II↗

PubMed1988

Endothelium-dependent and -independent responses to vasodilators of isolated dog cerebral arteries.

We compared responses to calcium ionophore A23187, vasopressin, and substance P in helical strips of dog middle cerebral, basilar, and posterior communicating arteries to obtain a better understanding of humoral control of cerebrovascular tone in different brain regions and its potential impact on mechanisms of cerebral vasospasm. A23187 relaxed these different arterial strips partially precontracted with prostaglandin F2 alpha to a similar extent. Vasopressin produced concentration-dependent relaxation in basilar and posterior communicating arterial strips, whereas middle cerebral arterial strips either contracted or relaxed slightly. Relaxations induced by A23187 and vasopressin were either abolished or converted to contractions by removal of the endothelium. In contrast, the relaxation of cerebral arterial strips to substance P was markedly attenuated but not abolished by endothelium denudation; the remaining relaxation was suppressed by indomethacin. In some cerebral arterial strips with intact endothelium, substance P caused a transient contraction that was reversed to a relaxation by indomethacin or ONO-3708, a prostaglandin antagonist. In arterial strips denuded of endothelium from the same dogs, substance P always produced relaxations. Relaxations of cerebral arterial strips to A23187 and vasopressin appear to be mediated by endothelium-derived relaxing factor. The function of vasopressin receptors in endothelial cells differs markedly in basilar and posterior communicating arteries versus middle cerebral arteries. Substance P-induced relaxations appear to be primarily associated with endothelium-derived relaxing factor and with prostaglandin I2, whereas contractions appear to be mediated by endothelium-derived prostaglandins.

Animals↗

PubMed1988

Prostaglandin F2 alpha-induced contraction in isolated dog cerebral, coronary and mesenteric arteries soaked in excess potassium.

Concentration-response curve for prostaglandin (PG) F2 alpha in helical strips of dog cerebral, coronary and mesenteric arteries were compared in control media and in those in which all the NaCl was replaced with isomolar KCl. Contractile responses to PGF2 alpha in concentrations up to 2 x 10(-6) M in cerebral arteries, to 10(-5) M in coronary arteries and to 5 x 10(-7) M in mesenteric arteries were not attenuated by excess K+. Contractions caused by PGF2 alpha, at least at these concentrations or lower, may not be associated with membrane depolarization.

Animals↗

PubMed1988

Functional and histological changes in mesenteric arteries and aortas from monkeys fed a high cholesterol diet.

Treatment of Japanese monkeys for 8 months with a high fat, high cholesterol diet produced atherosclerotic lesions in the aorta and mesenteric arteries, such as fatty dots, streaks and plaques, intimal thickening with accumulation of spindle-shaped cells and macrophages and endothelial cell flattening. Contractile responses of mesenteric arteries from control and atherosclerotic monkeys to electrical stimulation of adrenergic nerves, norepinephrine and angiotensin II did not differ, whereas contractions caused by serotonin in the atherosclerotic monkey arteries were significantly greater. Ketanserin and cinanserin suppressed the serotonin-induced contraction. Relaxations caused by adenosine and K+ (5 mM) were moderately attenuated in atherosclerotic monkey mesenteric arteries, and those by acetylcholine were reduced only slightly or not affected in the arteries or aortas. Relaxations of control and atherosclerotic arteries in response to nitroglycerin, isoproterenol and prostaglandin I2 did not differ. The relaxant response to K+ was reversed to a contraction by ouabain. Acetylcholine-induced relaxations were dependent on the endothelium and suppressed by atropine. Diet-induced atherosclerosis appears to potentiate contractions mediated via serotonergic 5-HT2 receptors and to attenuate relaxations possibly caused by activation of the electrogenic Na+ pump in the smooth muscle cell membrane. Endothelium-dependent relaxations via muscarinic receptors would not evidently be affected in mesenteric arteries and aortas from atherosclerotic Japanese monkeys.

Animals↗

PubMed1988

Prejunctional alpha adrenoceptor and angiotensin receptor function in isolated human, monkey and dog arteries.

Transmural electrical stimulation (2-20 Hz) produced a frequency-dependent contraction in dog mesenteric, monkey mesenteric and human gastroepiploic arterial strips, which was abolished by tetrodotoxin and suppressed by phentolamine. Treatment with yohimbine (10(-9) and 10(-8) M) potentiated the response to nerve stimulation dose-dependently in the dog arteries, but rather attenuated the response of the primate arteries. Yohimbine (10(-8) M) attenuated the contraction caused by exogenous norepinephrine in the dog and monkey arteries. Angiotensin (ANG) II (2 X 10(-10) M) and ANG I (10(-9) M) potentiated the response to transmural stimulation in the dog and monkey arteries, whereas the response to norepinephrine was unaffected. The ANG I-induced potentiation was suppressed by treatment with ANG converting enzyme inhibitors. 3H-Overflow evoked by transmural stimulation in tissues prelabeled with [3H] norepinephrine was increased by yohimbine in the superfused dog arteries but was not increased significantly in the monkey arteries. The overflow was increased significantly by ANG II in the dog and monkey arteries. It may be concluded that prejunctional alpha-2 adrenoceptors mediating the inhibition of transmitter release do not function significantly in human gastroepiploic and monkey mesenteric arteries, and postjunctional alpha-2 receptors are involved partly in contractions of the monkey arteries due to adrenergic nerve stimulation. ANG II appears to be synthesized from ANG I via ANG converting enzyme in the primate arteries; the octapeptide potentiates the contraction caused by adrenergic nerve stimulation, possibly due to prejunctional ANG receptor activation and increased norepinephrine release.

Aged↗

PubMed1988

Role of vascular angiotensin converting enzyme in hypertension.

The possible role of vascular angiotensin converting enzyme (ACE) in the maintenance of one-kidney, one clip (1-K,1C) hypertensive rats was studied in comparison with age-matched, one-kidney (1-K) normotensive rats. Mean blood pressure was elevated after partial occlusion of the left renal artery with unilateral nephrectomy, and the high blood pressure persisted for at least 11 weeks, whereas no significant changes in mean blood pressure were observed in 1-K rats. Plasma and vascular renin activities and plasma ACE activity did not differ between the two groups of rats, both 5 and 11 weeks after operation. In contrast, ACE activity in lung and mesenteric arteries in 1-K,1C hypertensive rats was significantly elevated 11 weeks after operation, but not 5 weeks after operation, compared with the matched 1-K normotensive rats. In addition, the decreases in mean blood pressure induced by ACE inhibition were significantly greater in 1-K,1C rats than those in 1-K rats. These results indicate that the elevation of vascular ACE activity may play an important role in the maintenance of high blood pressure and may result in hypotension in response to ACE inhibitors in the chronic stage of 1-K,1C hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Endothelium-dependent and independent responses to prostaglandin H2 and arachidonic acid in isolated dog cerebral arteries.

The addition of prostaglandin (PG) H2 produced a transient contraction followed by a relaxation in helical strips of dog cerebral arteries partially contracted with PGF2 alpha or K+. The contraction was abolished by removal of endothelium, and the relaxation was potentiated. Relaxation induced by PGI2 was not influenced by endothelium denudation. The PGH2-induced contraction in strips with intact endothelium was not influenced by OKY-046, a thromboxane A2 synthesis inhibitor, but was abolished by treatment with ONO3708, an antagonist of vasoconstrictor PGs, whereas the relaxation was inhibited by tranylcypromine or diphloretin phosphate, a nonselective PG antagonist. Contraction induced by arachidonic acid (AA) was reversed to relaxation by removal of endothelium or treatment with ONO3708. Treatment with indomethacin attenuated the AA-induced contraction in the intact strips and also the relaxation in the strips treated with ONO3708 or denuded of endothelium. It may be concluded that vasoconstrictor PGs are synthesized from PGH2 or AA mainly in endothelium, and the production of PGI2 from PGH2 is not dependent on endothelium. Thromboxane A2 in concentrations sufficient to elicit significant contractions does not appear to be liberated from the cerebroarterial wall stimulated by PGH2.

Animals↗

PubMed1987

Different distribution of two types of angiotensin II-generating enzymes in the aortic wall.

Dog, monkey and human aortic tissues contained two distinct types of angiotensin II-generating enzymes; angiotensin converting enzyme (ACE) and chymostatin-sensitive angiotensin II-generating enzyme (CAGE). Endothelium, media and adventitia of canine thoracic aortae were separated using collagenase digestion, and determined for their ACE and CAGE activity. ACE activity was assayed by hippuryl-His-Leu cleavage. CAGE activity was estimated with ANG I as substrate in the presence of inhibitors of ACE and angiotensinases. His-Leu, the common product of both enzyme reactions, was fluorimetrically quantified after o-phthalaldehyde condensation. ACE localized mainly in endothelium, while CAGE distributed predominantly in adventitia. Similar results were obtained with human and monkey aortae. Such a contrasting distribution may indicate the distinct functional role of these two enzymes.

Aorta↗

PubMed1987

Heterogeneity in mechanisms of bradykinin action in canine isolated blood vessels.

The relaxation induced by bradykinin in helical strips of coronary arteries contracted with prostaglandin (PG) F2 alpha was abolished by removal of the endothelium and was markedly suppressed by treatment with methylene blue or AA861, a lipoxygenase inhibitor. Indomethacin did not alter the response. Renal arterial relaxation by bradykinin was partially reduced by removal of the endothelium. Indomethacin moderately attenuated the response in the strips with endothelium and additional treatment with methylene blue or AA861 suppressed the response further. Tranylcypromine or diphloretin phosphate, an antagonist of PGI2, attenuated the peptide-induced relaxation. In mesenteric veins, the relaxation induced by bradykinin was slightly reduced by removal of the endothelium; indomethacin reversed the relaxation to a contraction in the strips with or without endothelium. Des-Arg9-[Leu8]bradykinin, a bradykinin B1 antagonist, did not alter the relaxation due to bradykinin in coronary arteries but reduced the response of mesenteric veins. It appears that bradykinin-induced relaxation is associated exclusively with EDRF in dog coronary arteries, with both PGI2 and EDRF in the renal arteries, and only with PGI2 liberated from endothelial and subendothelial tissues in the mesenteric veins. The release of PGI2 and EDRF may be mediated by activation of B1 and B2 receptor subtypes, respectively.

Animals↗

PubMed1987

Age-related changes in the response to vasoconstrictor and dilator agents in isolated beagle coronary arteries.

Responses to vasoactive agents were compared in helical strips of coronary arteries isolated from beagles of 30 days, 3 months, 2 years and 12 years old. Serotonin contracted the arterial strips dose-dependently, the contraction being greater in the arteries of proximal portion than in the distal arteries. The contraction increases with age from 3 months to 12 years, although EC50 values did not differ. Angiotensin II contracted distal coronary arteries to a greater extent than the proximal ones. Age did not alter the peptide-induced contraction. In prostaglandin F2 alpha-contracted coronary arteries, acetylcholine-induced relaxations, dependent on endothelium, were less in the arteries from senescent beagles than in those from adult beagles (2 years old). Histamine relaxed the infant beagle arteries to a lesser extent than the adult and senescent beagle arteries. Histamine-induced relaxations were attenuated selectively by cimetidine. Relaxations caused by adenosine and prostaglandin I2 did not differ in coronary arteries from beagles of different ages. It may be concluded that greater responsiveness to serotonin of senescent beagle coronary arteries is due preferentially to increased function of serotonergic receptors rather than impaired function of the arterial endothelium responsible for the release of relaxing factor(s), although some impairment of the function is supposed, on the basis of interferences with acetylcholine-induced relaxation in the aged beagle arteries. Histaminergic H2 receptor function appears to develop in beagle coronary arteries until 3 months of age.

Acetylcholine↗

PubMed1987

Senescent beagle coronary arteries in response to catecholamines and adrenergic nerve stimulation.

With advancing age from 2 to 12 years, relaxations induced by norepinephrine and epinephrine were suppressed or reversed to contractions in large and medium-size coronary arteries isolated from beagles. Norepinephrine-induced contractions in the senescent beagle arteries treated with propranolol were greater than those in the young beagle arteries and were inhibited by prazosin but not by yohimbine. Relaxant responses to isoproterenol were less in the arteries from old beagles than in the young beagle arteries. The magnitude of relaxations induced by norepinephrine and epinephrine was greatest in small arteries from old beagles, followed by medium and large arteries, in that order. Transmural electrical stimulation tended to produce a contraction in the old beagle arteries and a relaxation in the strips from young beagles. It appears that alpha 1 adrenoceptor function increases with advancing age in beagle coronary arteries of large and medium sizes, and beta receptor function declines. Vasoconstriction mediated by alpha 1 receptors is postulated to be related inversely to the distance from the coronary orifice in senescent beagles, and vice versa with vasodilatation mediated by beta receptors.

Aging↗

PubMed1987

Elevated vascular angiotensin converting enzyme in chronic two-kidney, one clip hypertension in the dog.

The possible role of the vascular angiotensin converting enzyme (ACE) in the development of two-kidney, one clip (2-K, 1C) hypertensive dogs was studied in different blood vessels. Vascular ACE activity per mg protein differed in a variety of blood vessels; the activity appeared to vary inversely with the outer diameter of arteries. The systemic blood pressure in mongrel dogs increased after partial occlusion of the left renal artery, and the hypertension lasted for 8 months. Plasma renin activity (PRA) was raised only for the first 4 weeks after the operation and then returned to the original level in the chronic stage of hypertension. Plasma ACE activity did not alter during the experimental period. In contrast, ACE activities in the jejunal, pulmonary and renal arteries, aorta, lung and cerebral cortex, significantly increased in the chronic hypertensive stage (8 months after occlusion). The production of angiotensin II (ANG II) from ANG I was significantly greater in isolated arteries from 8-month hypertensive dogs than in those from normotensive dogs when assessed by the contractile responses to ANG I and ANG II. These results indicate that acceleration by increased vascular ACE activity of the production of ANG II in the vascular wall may contribute to the maintenance of hypertension in the chronic stage of 2-K, 1C hypertensive dogs having normal PRA and plasma ACE activity.

3-Mercaptopropionic Acid↗

PubMed1987

Mechanism of histamine actions in human coronary arteries.

Helical strips of human coronary arteries contracted in response to histamine concentration dependently, they relaxed with low concentrations and contracted with high concentrations. Treatment with cimetidine potentiated contraction in the strips with intact and damaged endothelium to a similar extent and attenuated relaxation. Removal of endothelium abolished relaxation and potentiated contraction in the cimetidine-treated strips. Methylene blue increased the contractile response to histamine in the strips with endothelium but did not alter the response in the damaged-endothelium strips. Histamine-induced relaxations in the intact strips were suppressed or abolished by treatment with ETYA, AA861, a lipoxygenase inhibitor, and by chlorpheniramine but were unaffected by indomethacin. Chlorpheniramine also abolished amine-induced contraction. It may be concluded that histamine-induced contraction in human coronary arteries is mediated by H1 receptors in smooth muscle, and relaxation is mediated by H2 receptors in smooth muscle and H1 receptors in endothelium. Also, stimulation of the endothelial H1 receptor liberates vasodilator substance and possibly activates smooth muscle guanylate cyclase to accumulate cellular cyclic guanosine monophosphate.

Adult↗

PubMed1987

[Inhibition by KB-2796, a new Ca2+ entry blocker, of the contractile response of isolated cerebral and peripheral arteries in the dog].

In helical strips of dog cerebral and peripheral arteries, KB-2796 (1-[bis(4-fluorophenyl)-methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), a new Ca2+ entry blocker, inhibited the contractile responses induced by K+, prostaglandin (PG) F2 alpha and serotonin in a non-competitive manner. KB-2796 inhibited the contraction induced by K+ more effectively than those induced by PGF2 alpha or serotonin. In cerebral arteries, the inhibition produced by KB-2796 was more prominent than in peripheral arteries. In renal arteries, serotonin produced contractions in concentrations 200-1,200 times higher than those sufficient to contract the other arteries. KB-2796 inhibited renal arterial contractions induced by serotonin and K+ to a similar extent. In renal arteries depolarized by replacement of the entire amount of NaCl in the bathing medium with KCl, PGF2 alpha produced additional contraction of the artery, whereas serotonin did not contract the artery. These results suggest that KB-2796 inhibits the contractility of cerebroarterial smooth muscle more preferentially than that of other arteries. The contractile response to serotonin of the renal artery appears to be associated with the voltage-dependent influx of Ca2+ as suggested in the cerebral arteries.

Animals↗

PubMed1987

Hypotensive effect of SA446, an angiotensin converting enzyme inhibitor, in 2-kidney, 1-clip renal hypertensive and normotensive dogs.

Hypotensive effects of SA446, an angiotensin converting enzyme (ACE) inhibitor, and effects on the renin-angiotensin system were evaluated in conscious normotensive and 2-kidney, 1-clip renal hypertensive dogs. SA446 (1 mg/kg, p.o.) remarkably inhibited the pressor response to angiotensin (Ang) I between 1 and 6 hr after the administration in normotensive dogs. SA446 significantly decreased blood pressure at 10 mg/kg, p.o., in normotensive dogs. During repeated administration of SA446 (100 mg/kg/day, p.o.) for 13 weeks, the blood pressure was lowered, and the pressor response to Ang I and plasma ACE activity were strongly inhibited. ACE activities in the aorta and kidney were also inhibited. Plasma renin activity and plasma Ang I concentration increased by repeated SA446 application, while plasma aldosterone concentration decreased. The hypotensive effect of SA446 (5 mg/kg, p.o.) was more potent in 2-kidney, 1-clip renal hypertensive dogs than in normotensive dogs. SA446 had longer inhibitory effects on the pressor response to Ang I and more potent hypotensive effects than captopril. The hypotension caused by SA446 appears to be associated mainly with an inhibition of ACE in plasma and also in the vascular wall.

3-Mercaptopropionic Acid↗

PubMed1987

Possible role of vascular angiotensin converting enzyme in the genesis of hypertension.

This study was designed to evaluate changes in angiotensin converting enzyme (ACE) activity in 2-kidney, 1-clip renal hypertensive dogs. Blood pressure increased and remained elevated for eight months after partial clamping of the left renal artery. Plasma renin activity was increased for one month after surgery, but then returned to the pre-clamping level. SA-446, a potent ACE inhibitor, reduced blood pressure in 8 M-hypertensive dogs. Plasma ACE activities was not altered during the course of hypertension, but vascular ACE activities in the pulmonary and mesenteric arteries and the aorta were significantly increased in 8 M-hypertensive dogs. These results may indicate that ACE plays an important role in the maintenance of chronic phase of 2-kidney, 1-clip renal hypertension and that suppression of vascular ACE activities might be a mechanism underlying the hypotensive effect of ACE inhibitors.

Animals↗