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Biomedical subjects

Y Shiraki

Publications and source records attributed to Y Shiraki.

At least 55 records · Page 3Linked to original sources
PubMed1981

The hypotensive mechanisms of the new anti-anginal drug, N-(2-hydroxyethyl)nicotinamide nitrate (SG-75) in beagle dogs.

The hypotensive mechanisms of N-(2-hydroxyethyl) nicotinamide nitrate (SG-75, Nicorandil) were studied in anesthetized dogs. Intravenous injections of SG-75 (0.03-1 mg/kg) decreased systemic blood pressure (SBP) and increased peripheral (coronary, renal, mesenteric and femoral) blood flow (PBF) dose-dependently. The duration of the PBF increase, however, was much shorter than that of the SBP decrease. When peripheral vascular beds were perfused by means of a pump under a constant perfusion pressure near the SBP, the duration and magnitude of the SBP decrease and the PBF increase were equal. In doses of 0.03-0.3 mg/kg i.v., SG-75 did not significantly affect pulse pressure, heart rate, aortic blood flow, left ventricular pressure (LVP) and LVdP/dt max. Intra-arterial injections of SG-75 (0.003-1 mg) increased coronary, renal, mesenteric and femoral blood flow dose-dependently, without affecting SBP and cardiac function. In heart-lung preparations the drug (0.1-2 mg) did not cause cardiodepression. No hypotensive effect was observed following the administration of SG-75 (3 mg) into the cisterna magna. The results indicate that the hypotensive effect of SG-75 may be due mainly to its peripheral mechanisms, relating to vasodilation.

Animals↗
PubMed1979

The actions of 5-hydroxytryptamine and histamine on the isolated ileum of the tree shrew (Tupaia glis).

1. Contractions to 5-hydroxytryptamine (5-HT) and histamine of longitudinal muscle from the isolated ileum of the tree shrew (Tupaia), guinea-pig and rat were investigated by constructing dose-response curves and studying the effects of various antagonists. 2 In the Tupaia and rat ileum the contraction to 5-HT was reduced by methysergide but not affected by tetrodotoxin (TTX), morphine, hexamethonium (C6) or atropine. The response of guinea-pig ileum to 5-HT was not significantly inhibited by methysergide or C6, but was blocked by TTX, morphine and atropine. 3 Histamine-induced contraction of Tupaia and guinea-pig ileum was antagonized by diphenhydramine but not by TTX, morphine, C6 or atropine. Histamine was almost without effect on the rat ileum.

Animals↗
PubMed1979

Comparative studies with 5-hydroxytryptamine and its derivatives in isolated, blood-perfused small intestine and ileum strip of the rat.

The mode of actions of 5-hydroxytryptamine (5-HT) and its derivatives, tryptophan (TP), 5-hydroxytryptophan (5-HTP) and 5-hydroxyindole acetic acid (5-HIAA) was studied on the isolated, blood-perfused small intestine and isolated ileum strip of rats. In the isolated, blood-perfused intestinal preparations, 5-HT and 5-HTP injected into the superior mesenteric artery caused a monophasic fast contraction, while TP and 5-HIAA had no effects on the intestine. The contractile responses to 5-HT and 5-HTP were abolished by tetrodotoxin (TTX), hexamethonium (C6) and morphine, but were resistant to blockade of either atropine, methysergide or phentolamine. On the other hand, in the ileum strip preparations, 5-HT contracted the ileum, but its derivatives had no effects on the ileum. TTX, C6, morphine and atropine failed to prevent the contractile response to 5-HT, whereas methysergide effectively antagonized the response. The present results indicate that 5-HT acts by exciting intramural neuronal elements or by directly contracting the smooth muscle of the intestine. 5-HTP seems to act in the same manner as 5-HT.

Animals↗
PubMed1979

Pharmacological studies on a new thymoleptic antidepressant, 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32).

Some pharmacological actions of 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole (FS-32), a newly synthesized indazole derivative, were investigated in comparison with imipramine. FS-32 showed anti-reserpine activity in a dose-dependent manner, whereas imipramine exhibited a bell-shaped dose-response pattern. Catecholaminergic potentiation was demonstrated with FS-32. The results obtained from a norepinephrine potentiation test in vitro suggest that FS-32 may act in a manner qualitatively different from the tricyclic antidepressant. FS-32 produced a definite suppressive effect on isolation-induced fighting without affecting coordinated motor activity and on the duration of afterdischarge elicited by electrical stimulation to the amygdala or the hippocampus without producing a slow wave pattern in the EEG. Similar effects on fighting behavior and the afterdischarge were shown under imipramine with a slight motor incoordination and with a slow wave pattern, respectively. FS-32 produced practically no peripheral anti-cholinergic action, while it antagonized central cholinergic activity. FS-32 tended to produce an increase in chatecholamine content in the brain without MAO or COMT inhibitory activity. Norepinephrine uptake was inhibited by FS-32, but less than by imipramine. These pharmacological properties suggest a potential clinical utility of FS-32 as an antidepressant possessing thymoleptic activities.

Acetylcholine↗
PubMed1978

A device for recording left ventricular contraction and electrocardiogram in nonworking isolated perfused rat heart.

Using the isolated Langendorff rat heart preparation perfused at a constant flow rate (about 6 ml.min-1 pro heart) with a modified Krebs-Henseleit solution, methods for recording left ventricular cavity pressure and electrocardiogram (ECG) changes were devised. Stable levels of mechanical activities were reached 60--90 min after start of perfusion and were maintained for at least 4 hr. When either norepinephrine (0.05--0.15 microgram) was injected into the aortic bulb of the heart, sensitive changes in the measurable cardiac parameters were observed and changes in ECG patterns were particularly characteristic. Our results indicate that this experimental model may be useful for evaluating numerous functions of the isolated heart.

Animals↗
PubMed1975

Positive and negative chronotropic response of the S-A node to oxyfedrine.

Direct perfusion of the sinus node artery under a constant pressure of 100 mmHg was carried out in vagotomized dogs. "Selective" injection of L-3-methoxy-omega-(1-hydroxy-1-phenylisopropylamino) propiophenone hydrochloride (oxyfedrine) into the sinus node artery induced three types of chronotropic response; a pronounced sinus tachycardia, an initial bradycardia followed by sustained tachycarcia, or a definite sinus bradcardia alone. The paradoxical sinus bradycardia induced by oxyfedrine was more pronounced at higher doses of the compound, whereas it was nver produced by the injection of isoproterenol. The oxyfedrine-induced sinus tachycardia, which occurred even in reserpinized preparations, was not suppressed by the treatment with tetrodotoxin, hexamethonium or bretylium, but it was selectively inhibited by propranolol. Atropine, tetrodotoxin or hexamethonium did not prevent the occurrence of sinus bradycardia induced by oxyfedrine, and physostigmine failed to enhance the response. The present study indicates that the oxyfedrine-induced tachycardia is mediated mainly by a direct stimulating action on adrenergic beta-receptors, while the bradycardia appears to be induced by a direct depressant action on the S-A node.

Animals↗
PubMedDate not supplied

Modulation of vibrissa-evoked cortical potentials after infraorbital nerve crush in rats.

Cortical potentials evoked by unilateral stimulation of the major vibrissae were recorded in 12 rats subjected to unilateral crush of the infraorbital nerve. Immediately after nerve crushing, the latency of the initial positive potential evoked at contralateral scalp sites by stimulating the vibrissae of the nerve-crushed side was increased. In contrast, the latency of the ipsilaterally evoked potential was shortened. The relative amplitude of the negative component to the positive one of the evoked potentials tended, immediately after the nerve crush, to be smaller on the contralateral cortex (N/P-contra) and greater on the ipsilateral cortex (N/P-ipsi). These changes disappeared largely by the 2nd post-operative week. It is suggested that reduction of the tactile signals transmitted through the crossed pathway is responsible for the prolonged latency and the smaller N/P-contra. Shortening of the ipsilateral latency and the enhanced N/P-ipsi may be due to liberation of the ipsilateral sensory system from inhibition by the contralateral one.

Animals↗
PubMedDate not supplied

Cardiovascular effects of a new coronary vasodilator N-(2-hydroxyethyl)nicotinamide nitrate (SG-75): comparison with nitroglycerin and diltiazem.

The cardiovascular effects of a newly developed nicotinamide derivative, N-(2-hydroxyethyl)nicotinamide nitrate (SG-75), were examined in anesthetized, open-chest or closed-chest dogs and compared with those of nitroglycerin and diltiazem. When administered intra-arterially, SG-75 (0.003-1 mg) increased coronary, renal, mesenteric, and femoral blood flows in a dose-dependent fashion, without affecting systemic blood pressure or cardiac function. The coronary vasodilator response to SG-75 was not influenced by intra-arterial administration of propranolol, atropine, diphenhydramine, or dipyridamole. SG-75 (0.03-1 mg/kg) administered intravenously decreased systemic blood pressure and peripheral (coronary, renal, mesenteric, and femoral) vascular resistance and increased peripheral blood flow in a dose-dependent manner. In doses of 0.03-0.3 mg/kg, this drug did not significantly affect pulse pressure, heart rate, right atrial pressure, aortic blood flow, left ventricular (LV) pressure, LV dP/dt, or myocardial oxygen consumption. The results indicate the SG-75 has desirable characteristics as an antianginal agent.

Animals↗
PubMedDate not supplied

Cardiohaemodynamic effects of long-term intravenous administration of N-(2-hydroxyethyl)nicotinamide nitrate (SG-75), a potent coronary vasodilator: comparison with glyceryl trinitrate.

1. Cardiohaemodynamic changes have been studied in beagle dogs treated with intravenous injections of either 300 micrograms/kg of N-(2-hydroxyethyl)nicotinamide nitrate (SG-75) or 30 micrograms/kg of glyceryl trinitrate three times a day for 1-2 months. Throughout the experimental period, no significant changes in general behaviour, body weights and plasma levels of enzymes and substrates were observed in either the SG-75-or glyceryl-trinitrate-treated groups. 2. At 1 and 2 months after the start of chronic drug administrations, the dogs were anaesthetized and measurements were made of resting systemic blood pressure, pulse pressure, heart rate, right atrial pressure, coronary blood flow, aortic blood flow, left ventricular (LV) pressure and LVdP/dt: there were no significant differences between non-treated dogs and dogs treated chronically with SG-75 or glyceryl trinitrate. 3. The effects of the acute intravenous administration of SG-75 and glyceryl trinitrate were examined in dogs pretreated intravenously with SG-75 (300 micrograms/kg) and glyceryl trinitrate (30 micrograms/kg), respectively, three times a day for 1-2 months. The depressor and coronary vasodilator responses to the two drugs remained unchanged in comparison with those in non-treated dogs. 4. These results indicated that, with the doses used, neigher SG-75 nor glyceryl trinitrate produced changes in sensitivity or tolerance after long-term intravenous administration.

Animals↗
PubMedDate not supplied

Alpha-adrenoceptor antagonistic effects and antihypertensive activity of SGB-1534 in conscious normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive dogs: comparison with prazosin.

In conscious normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive dogs, alpha-adrenoceptor antagonistic and antihypertensive actions of SGB-1534, given orally, were compared with those of prazosin. SGB-1534 and prazosin did not markedly influence systemic blood pressure (SBP) and heart rate (HR) in normotensive dogs. These alpha 1-adrenoceptor antagonists inhibited SBP and HR increases induced by i.v. adrenaline in a dose-dependent manner. In DOCA-salt hypertensive dogs, persistent hypotension, accompanied by a reflex tachycardia, occurred after oral administration of SGB-1534 and prazosin. The hypotensive activity of SGB-1534 was much more potent in magnitude and duration than that of prazosin. In isolated canine mesenteric and femoral arteries, SGB-1534, compared to prazosin, elicited a more potent inhibition on the contractile response to a relatively selective alpha 1-adrenoceptor agonist, phenylephrine. It appears that the antihypertensive activity of SGB-1534, like prazosin, is nearly in parallel with its alpha 1-adrenoceptor antagonistic effect.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Tissue angiotensin-converting enzyme blockade by MC-838 (altiopril calcium) infused intravenously to miniature pigs: comparison with captopril.

The effect of a new orally active angiotensin-converting enzyme (ACE) inhibitor, calcium(-)-N-[(S)-3-[(N-cyclohexyl-carbonyl-D-alanyl)thio]-2-methyl- prolinate (MC-838, altiopril calcium), on cardiohemodynamics and tissue ACE activity was compared with that of captopril in the anesthetized miniature pig. MC-838 and captopril were infused i.v. for 1 or 3 hr at an equimolar rate of 20 and 10 micrograms/kg.hr-1, respectively. When MC-838 was infused i.v., captopril appeared in approximately 40% of MC-838 in serum, indicating that the amount of serum captopril during the equimolar concentration treatment with MC-838 corresponds to half of serum captopril after the dosing of captopril. During the infusion, the drugs did not significantly affect systemic blood pressure (SBP), heart rate (HR), renal blood flow (RBF) and renal vascular resistance (RVR). MC-838 and captopril, in a similar degree, attenuated the vasoconstrictor response to angiotensin-I (A-I) injected into the renal artery (i.a.), and enhanced the vasodilator one to i.a. bradykinin, 3 hr after the onset of the drug infusion. The animals were sacrificed at 1 and 3 hr after the onset of the infusion of MC-838 or captopril, and the ACE activity in serum and some target organs (lung, kidney, heart, brain and aorta) was determined. Effective activities of MC-838 and captopril occurred in the lung and kidney (only at 3 hr for captopril) where higher ACE activity in a variety of tissues was found, to a lesser degree in the serum (only by captopril) and not at all in the brain, heart and aorta.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Antihypertensive action of a novel orally active angiotensin converting enzyme inhibitor altiopril calcium (MC-838) in several hypertensive models of rats: comparison with captopril.

The antihypertensive effects of altiopril calcium (MC-838), calcium(-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methyl- propionyl]-L-prolinate, a novel inhibitor of angiotensin converting enzyme, compared with captopril, were evaluated in conscious rat models of experimental hypertension. MC-838 (3-30 mg/kg p.o.) as well as captopril (3 and 10 mg/kg p.o.) dose-dependently lowered systemic blood pressure (SBP) with no consistent changes in heart rate (HR) in two-kidney renal hypertensive rats (2 KG-RHRs) and spontaneously hypertensive rats (SHRs). However, MC-838 and captopril, unlike hydralazine, did not significantly produce hypotension in DOCA-salt hypertensive rats. The antihypertensive effect of MC-838, compared with captopril, was characterized by a slower onset and longer duration. When compared on a weight basis of 3 mg/kg, the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action was approximately 2 times longer than that of captopril. MC-838, like captopril, attenuated angiotensin-I (A-I)-induced pressor response, and augmented bradykinin (BK)-induced depressor one in SHRs. However, no correlation was observed between the modification of the SBP response to exogenous i.v. A-I or BK, and the SBP lowering caused by MC-838 or captopril given orally. In contrast, there was a close correlation between inhibition of lung angiotensin converting enzyme (ACE) (but not plasma ACE) and SBP reduction induced by the 2 ACE inhibitors in SHRs. When administered orally once a day for 9 weeks in 2 KG-RHRs and SHRs, MC-838 dose-dependently reduced SBP throughout the treatment period. After withdrawal of treatment with MC-838 there was no rebound increase in SBP. These studies indicate that MC-838 is a promising antihypertensive agent.

Angiotensin I↗