Biomedical subjects
Publications and source records attributed to K Tsuchida.
The synthesis of a new series of dihydropyridines containing a nitrooxy moiety at the 3-ester position is described. The antihypertensive activity of the compounds was examined and compared with that of nifedipine; some of them were relatively potent. The structure-activity relationship is also discussed.
A patient with Stanford type A acute aortic dissection who developed severe cerebral dysfunction after surgery using retrograde cerebral perfusion through the superior vena cava was examined. The patient was able to regain normal brain function with no neurological deficit. Postoperative venography taken through the superior vena cava showed the presence of competent venous valves at the venous angles. This suggests that the valves interrupted cerebral perfusion, decreasing blood flow to less than that required. After consideration of the possible causes of brain damage incurred during surgery for aortic aneurysm using retrograde cerebral perfusion, it was concluded that this patient was able to recover normal brain function because the surgery was performed under profound hypothermia.
A 68-year-old man who necessitated IABP support for acute myocardial infarction suffered from IABP entrapment after its perforation. We washed intra-balloon space several times with heparinized normal saline, and finally could successfully remove it without surgery. It appears that the washing method (Lambert's method) for IABP entrapment could be done with lower risk especially for severe cases.
The mammalian tachykinin system consists of three distinct peptides, substance P, substance K, and neuromedin K, and possesses three corresponding receptors. In this investigation we examined intracellular signal transduction of the individual tachykinin receptors by transfection and stable expression of these receptor cDNAs in Chinese hamster ovary cells. The three receptors commonly showed a rapid and marked stimulation in both phosphatidylinositol (PI) hydrolysis and cyclic AMP formation in response to tachykinin interaction. Direct linkage of the three receptors to both phospholipase C and adenylate cyclase was evidenced by the finding that tachykinin, added together with GTP, activated these enzyme activities in membrane preparations derived from tachykinin receptor-expressing cells. The stimulation of cyclic AMP formation was less efficient than that of PI hydrolysis in receptor-expressing cells as well as their membrane preparations (about 1 order of magnitude difference in the effective peptide concentrations). However, the stimulatory responses of the PI hydrolysis and cyclic AMP formation in both receptor-expressing cells and their membrane preparations were induced in complete agreement with the tachykinin binding selectivity of each subtype of the receptors. This investigation demonstrated unequivocally that the tachykinin receptors have the potential to couple directly to both phospholipase C and adenylate cyclase and to stimulate PI hydrolysis and cyclic AMP formation.
Two abundant fatty acid-binding proteins (MFB1 and MFB2) were isolated from the midgut cytosol of larval Manduca sexta. As isolated, MFB1 and MFB2 were found to contain bound fatty acids in a 1:1 molar stoichiometric ratio. Immunological screening demonstrated that MFB1 and MFB2 were restricted to the midgut in a gradient distribution, with MFB1 more concentrated in the anterior two-thirds of the midgut and MFB2 more concentrated in the posterior two-thirds of the midgut. MFB1 exchanged fatty acid more readily than did MFB2. MFB1 was about 2% and MFB2 about 12% of the cytosolic protein in the midgut. cDNA clones for MFB1 and MFB2 both encode proteins of 131 amino acids that are rich in lysine and acidic residues. Analysis of the amino acid sequence alignment of the MFBs with six mammalian fatty acid-binding proteins revealed a number of shared features: 9 conserved glycines, presumably important in turns of the beta-strands; a basic amino acid in a position corresponding to the residue reported to participate in binding the carboxyl group of the fatty acid (Arg in MFB1 and Lys in MFB2); and conservation of many of the residues important in binding the aliphatic portion of the fatty acid.
Intraperitoneal injection of (+)-3-[3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), a sigma receptor agonist, significantly reduced the striatal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) measured by in vivo microdialysis. These reductions were significantly greater at (+)-3PPP doses of 12 and 24 mg/kg than at 1 mg/kg. The levels of 5-hydroxyindoleacetic acid (5HIAA) were increased by the injection of (+)-3PPP in dose of 24 mg/kg, but were not affected at lower doses. BMY-14802, a sigma antagonist, alone at doses of 15 mg/kg and 30 mg/kg did not affect the levels of DA, DOPAC, HVA and 5HIAA. Pretreatment with 30 mg/kg BMY-14802 reversed the reduction of the levels of DA induced by 12 mg/kg (+)-3PPP. Although neither 30 mg/kg BMY-14802 nor 12 mg/kg (+)-3PPP affected the levels of striatal 5HIAA, combined treatment with both produced a significant elevation. These findings clearly demonstrate that sigma receptors may regulate DA release from the striatal presynapse.
A case of aneurysm of the descending thoracic aorta with dominant left vertebral artery and poor cross-collateral circulation is reported. We believe that in such a patient perfusion of the dominant left subclavian artery is a safe method to prevent vertebrobasilar ischemia during thoracic aortic aneurysm operation under normothermia.
The effects of various vasorelaxant agents on aortas from control and genetically diabetic rats were examined. The concentration-response curves for the isoproterenol (ISO)-induced relaxation of both aortic strips with and without endothelium are shifted to the right in diabetic rats. The relaxation responses of diabetic aorta to forskolin and vasoactive intestinal peptide did not differ from those of controls. The relaxation responses of diabetic aorta to cromakalim and nicorandil did not differ from those of controls. These results indirectly indicate that ISO-induced relaxation responses of the aortic strips from genetically diabetic rats decreased, and that this decreased relaxation response of the strips to ISO may be due to decreased density or affinity of beta adrenoceptors on the endothelium and vascular smooth muscle.
We investigated the role of sigma receptors in the expression of behavioral sensitization induced by cocaine. Rats received intraperitoneal injections of either 20 mg/kg cocaine or saline once daily for 14 consecutive days. Cocaine-treated rats became sensitized. After a 5-day abstinence period, a challenge dose of (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine ((+)-3-PPP), a sigma receptor agonist, was administered. (+)-3-PPP at doses of 12 and 24 mg/kg induced significantly more frequent rearing and more potent stereotypy consisting of repetitive head movement and sniffing in cocaine-sensitized rats than in saline-pretreated rats. These enhanced responses to (+)-3-PPP lasted for at least a month. The enhanced responses to (+)-3-PPP were attenuated by 30 mg/kg BMY 14802, a putative sigma antagonist, and also attenuated by 100 mg/kg (+/-)-sulpiride, a D2 dopamine antagonist. These findings show that repeated administration of cocaine produces lasting supersensitivity of simga receptors, which may induce subsequent activation of dopaminergic transmission.
1. The effects of phorbol esters on canine Purkinje fibers were examined using conventional microelectrode techniques. 2. 12-O-Tetradecanoylphorbol-13-acetate (TPA) and 4-beta-phorbol-12,13-dibutyrate (PDB), which are specific activators of protein kinase C (PKC), decreased the action potential amplitude and the maximum rate of depolarization (Vmax) at 3 x 10(-7) M or higher. These phorbol esters had little effect on the resting potential. 3. PDB (1-3 x 10(-7) M) also reduced the contractile force, accompanied with initial increase (in 5 out of 8 experiments), whereas TPA did not decrease it to any significant extent. 4. An inactive analog of phorbol esters, 4-alpha-phorbol-12,13-didecanoate (PDD), decreased the action potential amplitude and Vmax, and slightly increased the action potential duration. However, PDD failed to produce any inotropic effect. 5. Post-rest potentiation of the contractile force after a rest from stimulation for 30 sec was inhibited in the presence of 3-10 x 10(-7) M TPA or 3 x 10(-7) M PDB. 6. Isoproterenol 10(-7) M augmented the action of PDB 3 x 10(-7) M. 7. These results suggest that activation of PKC may modulate myocardial Ca2+ homeostasis and influence the excitation-contraction process.
1. At concentrations lower than 10(-5) M, A23187 did not affect the contractile force in canine Purkinje fibers, but at 2 x 10(-5) M, decreased it significantly. 2. X-537A (10(-6) M) slightly increased the contractile force. The increase was not modified by 10(-7) M pindolol. 3. At 20 min after application both ionophores (2 x 10(-5) M) affected little or no changes in the action potential configurations, except for a marked shortening of the action potential duration. A delayed afterdepolarization and an aftercontraction occurred. 4. The electrophysiological effects were potentiated with an increase in extracellular Ca2+ and further by isoproterenol (1-3 x 10(-7) M). 5. A post-rest potentiation was depressed in the presence of these Ca2+ ionophores. 6. When the stimulation frequency was stepped up from 120 to 180 beats/min, the negative staircase of the contractile force was reversed to positive one in the presence of A23187, high Ca2+ and isoproterenol. 7. These results indicate that in canine Purkinje fibers, X-537A produces cellular Ca2+ overload, but A23187 alone does not cause it. Mechanical and electrophysiological effects induced by these ionophores are potentiated by addition of high Ca2+ and isoproterenol.
Experiments were designed to investigate the effects of aging and hyperglycemia on relaxation of the aorta for both endothelium-dependent and -independent agents in Wistar (control) and WBN/Kob (genetically diabetic) rats. The concentration of glucose in serum was elevated significantly in aged (90-92 wk) but not young (13-15 wk) WBN/Kob rats. Endothelium-dependent relaxations of both control and WBN/Kob rats to acetylcholine were reduced by aging. The relaxations induced by acetylcholine in aortic strips were significantly attenuated in both young (nondiabetic) and aged (diabetic) WBN/Kob rats, compared with those from age-matched control vessels, respectively. The concentration-response curves for sodium nitroprusside in aortic strips from both aged control and aged WBN/Kob rats were shifted to the left when compared with those from young rats, respectively. However, the maximal relaxation responses to sodium nitroprusside showed no difference among all vessels studied. The relaxations induced by sodium nitroprusside in aortic strips from both young and aged WBN/Kob rats were similar to those from age-matched control rats, respectively. The relaxations induced by atrial natriuretic peptide showed no difference among all vessels studied. In genetically diabetic rats, functional changes in endothelium occurred before elevation of the levels of glucose in the serum. Thus impaired endothelium-dependent relaxation may play an important role in the high incidence of vascular complications in diabetes mellitus.
We investigated the effects of CD-349, a dihydropyridine derivative, on isoproterenol (Iso)-induced relaxation in rabbit aorta precontracted with endothelin-1 (ET-1). The Iso (10(-8)-10(-5) M)-induced relaxation responses in rabbit aorta precontracted with 1-2 x 10(-7) M ET-1 were augmented by pretreatment with CD-349 (10(-9)-10(-5) M) in a concentration-dependent manner. The effects of CD-349 on Iso-induced relaxation of the aortic strips precontracted with ET-1 were inhibited by treatment with methylene blue (10(-5) M) and oxyhemoglobin (10(-5) M), whereas they were augmented by treatment with N omega-nitro-L-arginine (10(-4) M). The Iso-induced relaxation responses were also augmented by pretreatment with 8-Br-guanosine 3',5'-cyclic monophosphate (cGMP) (3 x 10(-6)-3 x 10(-4) M) in a concentration-dependent manner. However, nifedipine (10(-5) M) and nicardipine (10(-5) M) had no effect on Iso-induced relaxation responses of the aortic strips precontracted with 10(-7) M ET-1. CD-349 also augmented forskolin (10(-8)-10(-5) M)-induced relaxation responses of rabbit aorta in a concentration-dependent manner. CD-349 (10(-7)-10(-5) M) increased the levels of cGMP but not of adenosine 3',5'-cyclic monophosphate (cAMP) in a concentration-dependent manner in rabbit aorta without endothelium. Both CD-349 (10(-5) M) and 8-BrcGMP (3 x 10(-5) M) augmented the Iso-induced elevations of cAMP in rabbit aorta without endothelium. These results indicate that CD-349 and 8-BrcGMP can augment Iso-induced relaxation responses by enhancing the accumulation of cAMP.
To examine the role of coronary artery spasm in patients with syncope after alcohol ingestion, we performed an intracoronary ergonovine provocation test in 7 male patients (39 to 73 years old, mean 54 years) with alcohol-related syncope which remained unexplained despite noninvasive cardiovascular and neurological examinations. No patients had structural heart disease or significant coronary artery stenosis. Ergonovine was continuously infused into each coronary artery at a rate of 10 micrograms/min for up to 5 min. Coronary artery spasm with ST-segment elevation was induced in 4 of 7 patients. Chest pain before syncope or history of chest pain were not present in 3 of 4 patients with a positive ergonovine test. Multivessel coronary artery spasm was induced in 3 patients. One patient presented with triple vessel coronary artery spasm progressing to near syncope as a result of profound hypotension and ventricular tachycardia during provocation. Coronary artery spasm was promptly relieved by intracoronary isosorbide dinitrate infusion. All patients with a positive ergonovine test were treated with calcium antagonist and did not experience syncope during follow-up. These results suggest that coronary artery spasm is one of the important causes of syncope after alcohol ingestion.
The occurrence of coarctation in patients with right aortic arch is extremely rare. We have encountered a 21-year-old man with anomalous left subclavian artery. He was diagnosed when he was 13. On angiography he exhibited a right aortic arch. The left common carotid artery, right common carotid artery and the right subclavian artery diverged from the proximal side of the coarctation. The left subclavian artery diverged from the distal side. The right brachial arterial pressures measured 158-72 mmHg, while the left brachial arterial pressures measured 98-80 mmHg. Clinical studies revealed no vascular ring and no other anomalies were found in this patient. An attempt at treatment was made with extra anatomical bypass grafting from the ascending aorta to the descending aorta. No pressure difference due to coarctation remained after operation.
Postoperative brain dysfunction was studied for 18 patients who survived more than 30 days after operations of aortic arch aneurysms. The operative procedures were graft replacement in 12 patients, resection with direct or patch closure in 3, and thromboexclusion in 3. Except for thromboexclusion, adjuncts were used: temporary bypass in 1, partial EPC (extracorporeal circulation) in 2, and selective cerebral perfusion during EPC in 12. As for intra-operative monitoring, the temporal artery blood pressures were more than 50 mmHg in all, but the electroencephalogram changed to flat wave just after clamping the aorta in one patient. Postoperative brain dysfunction occurred in 5 patients, including temporary loss of consciousness in 2, lasting loss of consciousness in 1, and paralysis with loss of consciousness in 2. Postoperative brain dysfunction occurred more often in old aged men with atherosclerotic aneurysms. Patients with temporary brain dysfunction had no remarkable change in CT scan, but patients with lasting brain dysfunction had low density areas. It is recommended to prevent this complication as follows: 1) pre-operative evaluation of cerebral vascular disorders, 2) gentle maneuver of atherosclerotic lesions, 3) bilateral cerebral perfusions and intra-operative monitorings, 4) intensive perioperative care of circulation and respiration.
Therapeutic effects of hyperbaric oxygen therapy (HBO) in 50 patients with chronic occlusive arterial diseases were studied with determination of the transcutaneous oxygen pressure (TcPO2), plasma lipid peroxide level, and plasma superoxide dismutase (SOD) level. Necrosis or ulceration was present in 30 patients, rest pain without tissue loss in 6, infection and necrosis in 2, infection of the amputated stump in 2, delayed healing of the amputated stump wound in 8, and delayed union of bone fractures in 2. HBOs were carried out in 2-3 absolute atmospheres for 60 min for 3-40 times (mean, 12.7 times). In combination with HBO, sympathetic denervation was performed in 41 patients, and PGE1 infusions were administered in 46. Of patients with necrosis or ulceration, 16 were healed, 13 were improved, and one was unchanged. Of patients with rest pain, 5 had relief and one was unchanged. All patients with infection were cured. Of patients with delayed healing of amputation wounds, 7 were healed and one required reamputation. All patients with bone fractures obtained bone union. The TcPO2 markedly increased during HBO and remained at a high level for some time after HBO. The lipid peroxide and SOD levels were not changed significantly by HBO.
The effects of phorbol 12,13-dibutyrate (PDBu) on portal veins from hypertensive (SHRSP0 and normotensive (WKY) rats were examined. PDBu contracted the strips from SHRSP and WKY in a concentration-dependent manner. However, both twitch contraction and tonic contraction of strips in response to PDBu were enhanced in SHRSP. Treatment with staurosporine reduced contractile response to PDBu in strips from SHRSP. It appears that the activity of protein kinase C in vascular smooth muscle is increased in SHRSP.