Biomedical subjects

K Shigenobu

Publications and source records attributed to K Shigenobu.

At least 73 records · Page 4Linked to original sources

PubMed1998

Effects of ryanodine and cyclopiazonic acid on skinned fibers of ventricular myocardium from neonatal and adult rats.

1. We examined the effects of ryanodine and cyclopiazonic acid (CPA) on Ca2+ release from myocardial sarcoplasmic reticulum (SR) with skinned fibers of neonatal rat ventricular myocardium. 2. Both ryanodine and CPA concentration dependently reduced the caffeine-induced tension in skinned fibers with functional SR preserved; 1 microM ryanodine and 20 microM CPA reduced the caffeine-induced tension to less than 20% of control values. 3. Both agents had no effect on the Ca(2+)-tension relation of skinned fibers without functional SR. 4. These results suggest that ryanodine and CPA inhibit Ca2+ release from the SR and Ca2+ uptake into it in neonatal myocardia. 5. Thus, less-negative inotropic effects of ryanodine and CPA on neonatal myocardia compared with those on adult myocardia (Agata et al., 1993; Tanaka and Shigenobu, 1989) could not be ascribed to lack of drug effects on the SR per se.

Animals↗

PubMed1998

Role of sarcoplasmic reticulum in myocardial contraction of neonatal and adult mice.

Changes in action potential parameters by and inotropic responses to nicardipine, verapamil, ryanodine and cyclopiazonic acid were examined in isolated ventricular myocardial preparations from neonatal and adult mice. The action potential of both neonatal and adult mice had a unique configuration with little evidence of a plateau at depolarized membrane potential; the action potential duration was significantly larger in neonatal preparations. Nicardipine had no effect on action potential parameters in the adult while it significantly shortened the action potential duration at 50% repolarization in the neonate. Ryanodine significantly shortened the action potential duration at 80% repolarization at both ages: the shortening was significantly larger in the adult when compared with the neonate. The contraction of ventricular preparations from adult mice were relatively resistant to nicardipine and verapamil. Nicardipine or verapamil, even at 10(-5) M, only decreased the contractile force to 70% of control values; the decrease was much less than that reported in other experimental species such as chick, guinea pig or rabbit. In the neonate, 10(-5) M nicardipine or verapamil decreased the contractile force to 30% of control values. Ryanodine had a potent negative inotropic effect both in the neonate and adult; the effect was significantly larger in the adult. Cyclopiazonic acid produced a decrease in contractile force and prolongation of the time required for relaxation; both effects were significantly larger in the adult. These results suggest that the contraction of the adult mouse myocardium is highly dependent on SR function and less dependent on transsarcolemmal Ca2+ influx when compared with the myocardium of the neonatal mouse and that of other species.

Age Factors↗

PubMed1998

Temperature-sensitive effects of potassium channel openers on isolated guinea pig myocardium and aorta.

The effects of K+ channel openers, NIP-121, cromakalim, and pinacidil, on isolated myocardium and aorta were investigated at two different temperatures, 23 degrees C and 37 degrees C. In right ventricular myocardium, NIP-121 shortened the action-potential duration with little influence on other action-potential parameters at 37 degrees C, but not at 23 degrees C. In whole-cell clamped ventricular myocytes, NIP-121 induced a glibenclamide-sensitive outward current at 37 degrees C but not at 23 degrees C. No difference in tissue adenosine triphosphate (ATP) concentration was detected between ventricular myocardia incubated at 37 degrees C and at 23 degrees C. In aortic preparations precontracted with norepinephrine, NIP-121, cromakalim, and pinacidil produced endothelium-independent relaxation at 37 degrees C, which was antagonized by glibenclamide. The vasorelaxant effects were greatly reduced at 23 degrees C. Thus we demonstrated that the effects of K+ channel openers on the myocardium and vascular smooth muscle are temperature sensitive.

Action Potentials↗

PubMed1998

Glibenclamide-sensitive hypotension produced by helodermin assessed in the rat.

The effects of helodermin, a basic 35-amino acid peptide isolated from the venom of a lizard salivary gland, on arterial blood pressure and heart rate were examined in the rat, focusing on the possibility that activation of ATP sensitive K+ (K(ATP)) channels is involved in the responses. The results were also compared with those of vasoactive intestinal polypeptide (VIP). Helodermin produced hypotension in a dose-dependent manner with approximately similar potency and duration to VIP. Hypotension induced by both peptides was significantly attenuated by glibenclamide, which abolished a levcromakalim-produced decrease in arterial blood pressure. Oxyhemoglobin did not affect helodermin-induced hypotension, whereas it shortened the duration of acetylcholine (ACh)-produced hypotension. These findings suggest that helodermin-produced hypotension is partly attributable to the activation of glibenclamide-sensitive K+ channels (K(ATP) channels), which presumably exist on arterial smooth muscle cells. EDRF (endothelium-derived relaxing factor)/nitric oxide does not seem to play an important role in the peptide-produced hypotension.

Animals↗

PubMed1998

Cardioprotective effects of beraprost sodium against experimental ischemia and reperfusion as compared with propranolol and diltiazem.

We compared the cardioprotective effects during experimental ischemia and reperfusion of beraprost sodium (beraprost), a prostacyclin analog, with those of propranolol and diltiazem. Coronary perfused guinea-pig right ventricular free wall preparations were subjected to 30 min no-flow ischemia with or without drugs, followed by 60 min reperfusion without drugs. In control preparations, decrease in contractile force and increase in resting tension were observed during the no-flow period. On reperfusion, contractile force returned to less than 50% of preischemic values. Beraprost, at 0.1 microM, showed no inotropic effect under normoxic condition and during the no-flow period, but significantly enhanced the recovery of contractile force after reperfusion to about 80% of control values. Propranolol (30 microM) or diltiazem (10 microM) produced similar enhancement of recovery of contractile force after reperfusion, but these two drugs decreased the contractile force under normoxic conditions to less than 20% of control values. Thus, the cardioprotective effect of beraprost was different from those of propranolol and diltiazem in that it was not accompanied by cardiosuppressive effects.

Animals↗

PubMed1998

Changes in cytosolic Ca2+ measured by use of fura-2 and contraction produced by quick stretch and various stimulants in canine cerebral artery.

Mechanical stimulation such as stretch generates myogenic contraction in cerebral arteries. Myogenic contraction of cerebral arteries in response to quick stretch is greatly modified by promoters and inhibitors of Ca2+ handling mechanisms including Ca2+ channel blockers. In the present study, in order to improve our understanding of the role of Ca2+ in the generation of stretch-induced contraction, changes in cytosolic free Ca2+ concentrations ([Ca2+]cyt) and contraction of canine cerebral artery in response to quick stretch were simultaneously measured by use of fura-2. The [Ca2+]cyt-tension relationship in the stretch-induced contraction was compared with those by various stimulants. Quick stretch at a rate of 10 cm/sec with the amount of 40% of the initial muscle length (=100%) produced a myogenic contraction in canine cerebral artery. The arterial [Ca2+]cyt enormously increased after the stretch, which preceded the occurrence of the delayed contraction in response to stretch. [Ca2+]cyt-tension relationships in the stretch-induced contraction changed counterclockwise as those in the contractions induced by high KC1 and pharmacological agonistic stimulants such as 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1). The contraction in response to quick stretch at the maintenance phase was far smaller than those produced by high KC1 or agonistic stimulants at the same changes in [Ca2+]cyt. These findings suggest that in the cerebral artery contraction in response to quick stretch, elevated cytosolic Ca2+ is utilized less efficiently as compared with the contractions elicited by other stimulants. The apparent low Ca2+ sensitivity of stretch-induced contraction in dog cerebral artery might be related to the low efficiency of cytosolic Ca2+ elevated by the Ca2+ release from intracellular storage sites upon stretch.

Animals↗

PubMed1997

Effects of Ca2+ channel antagonists on sinus node: prolongation of late phase 4 depolarization by efonidipine.

Effects of various Ca2+ channel antagonists on the action potential configuration of rabbit sino-atrial node tissue were examined with standard microelectrode techniques. All Ca2+ channel antagonists decreased the maximum rate of phase 0 depolarization (Vmax) and increased the cycle length. The potency order to increase the cycle length was nisoldipine = verapamil > nifedipine = clentiazem > efonidipine > diltiazem. The potency order to decrease Vmax and to shift the threshold potential to a positive direction was the same as that to increase the cycle length, indicating that the major mechanism of negative chronotropism was inhibition of the L-type Ca2+ current. All Ca2+ channel antagonists except efonidipine shifted the maximum diastolic potential to the positive direction, decreased the action potential amplitude and prolonged the action potential duration. The effects of nifedipine were slightly weaker than those of other drugs when compared at equally bradycardiac concentrations. These differences may reflect differences in drug effects on currents other than the L-type Ca2+ current. A characteristic feature of efonidipine was selective suppression of the later phase of pacemaker depolarization with no effect on action potential amplitude and duration. Similar suppression of the later phase was observed with 50 microM Ni2+, which is reported to inhibit the T-type, but not L-type, Ca2+ current. Thus, efonidipine appears to suppress selectively the later phase of pacemaker depolarization through inhibition of both L- and T-type Ca2+ currents, which may be the underlying mechanism for its reported potent negative chronotropic but weak inotropic activity.

Action Potentials↗

PubMed1997

Two-dimensional millisecond analysis of intracellular Ca2+ sparks in cardiac myocytes by rapid scanning confocal microscopy: increase in amplitude by isoproterenol.

Two dimensional images of myocardial Ca2+ sparks, non-propagating local rises in cytoplasmic Ca2+ concentration, were obtained at 4 msec intervals with a rapid-scanning confocal laser microscope, Nikon RCM 8000, and fluo-3. Spontaneous Ca2+ sparks were observed at apparently random sites throughout the cytoplasm of rat ventricular cells. The duration of sparks was 30 to 40 msec and the time to peak intensity about 10 msec. Ryanodine (1 microM) completely inhibited Ca2+ sparks while nicardipine (3 microM) had no effect. Isoproterenol (1 microM) had no effect on the frequency and distribution of Ca2+ sparks but significantly increased their amplitude. These results suggest that myocardial Ca2+ sparks are the result of spontaneous release of Ca2+ from the sarcoplasmic reticulum and that beta-adrenergic stimulation may result in functional modification of the ryanodine receptor channel.

Adrenergic beta-Antagonists↗

PubMed1997

Target cell-induced calcium signals in human natural killer leukemia cells as revealed by confocal fluorescence microscopy.

The target cell-induced calcium response in natural killer (NK) cells was examined using indo-1 (a ratiometric fluorochrome), a newly developed video-rate ultraviolet laser-scanning confocal microscope system, and a human NK leukemia cell line, YTN. Susceptible target cells (JY cells), but not unsusceptible target cells (K562 cells), increased the intracellular calcium concentration ([Ca]i) in almost all indo-1-loaded YTN cells with a lag time, although the kinetics of increase in [Ca]i differed in individual YTN cells. The increase in [Ca]i was completely blocked by 2 mM EGTA and partially (around 50%) blocked by 10 microM nicardipine, the extents of inhibition of calcium response correlating well with those of inhibition of cytotoxic activity. Thus, the calcium response in YTN cells observed in this study may constitute a critical step in the manifestation of cytotoxic activity.

Biological Transport↗

PubMed1997

Cardioprotective effect against ischemia-reperfusion injury of AHC-52, a dihydropyridine compound with inhibitory effect on Cl- but not Ca2+ current.

We examined the effects of a dihydropyridine compound, AHC-52, on guinea pig myocardium. In ventricular cardiomyocytes, AHC-52 (1 microM) had no effect on the basal peak inward and steady state currents, but inhibited the isoprenaline-induced time independent Cl- current. In coronary perfused right ventricular preparations, no-flow ischemia induced decreases in developed tension which recovered only to about 50% of initial values after reperfusion. AHC-52 (0.1 microM) had no effect on developed tension under normal conditions and during ischemia, but significantly improved the recovery of developed tension after reperfusion to about 80% of preischemic values. Thus, AHC-52 inhibits Cl- channels in cardiac muscle and may have protective effects against ischemia-reperfusion injury.

Animals↗

PubMed1997

Arthroscopic studies of variants of the anterior horn of the medical meniscus.

The objective of this study was to arthroscopically analyse the morphology and dynamics of variants of the anterior horn of the medial meniscus of the knee (VAMM) and to then consider the pathological significance of these variants. VAMM was defined as knees in which the anterior horn of the medial meniscus is not attached to the tibia. Between April 1992 and March 1995, arthroscopy was performed on 953 knees of 903 patients. At the time of this examination, observation and probing were performed to determine the condition of the synovium, the synovial plica, the cartilage in all compartments, the meniscus, the cruciate ligaments, and the popliteal tendon. In particular, detailed examination was made of the anterior horn of the medial meniscus with regard to the point of insertion to the tibia and the degree of movement in knee flexion/ extension. Cases of VAMM diagnosed on the basis of the arthroscopic findings were classified into the following four categories: the ACL (anterior cruciate ligament) type, where the anterior horn of the medial meniscus was attached to the ACL; the transverse ligament type, where the anterior horn of the medial meniscus was attached to the transverse ligament; the coronary ligament type, where the anterior horn of the medial meniscus was attached to the coronary ligament; and the infrapatellar fold type, where the anterior horn of the medial meniscus was attached to the infrapatellar synovial fold. These patients were then analyzed with regard to the arthroscopic findings and the intra-articular lesions other than VAMM. In 98 (10.9%) of the total patients, 103 knees were classified as VAMM. Classification of those 103 knees using the above criteria showed 39 ACL type knees, 51 transverse ligament type knees, 11 coronary ligament type knees, and 2 infrapatellar fold type knees. The arthroscopic findings indicated that the anterior horn of the medial meniscus was not attached directly to the tibia in any of these knees. Probing and flexion/extension of the knee revealed hypermobility at the anterior horn of the medial meniscus. In this study, anterior knee pain syndrome was diagnosed in 12 (11.7%) of the 103 VAMM knees. In addition, there was no clear history of trauma in 20 of 23 knees found to have an isolated medial meniscus tear. In these cases, even detailed arthroscopic observation proved the causes of the symptoms or injury. On the basis of these findings, we surmised that the anterior portion shows hypermobility at the time of flexion/extension of the knee, regardless of the type of VAMM. In this study, we discussed the possibility that the existence of VAMM may become the cause of pain or injury to the meniscus.

Adolescent↗

PubMed1997

Changes in electrophysiological and mechanical responses of the rat papillary muscle to alpha- and beta-agonist in streptozotocin-induced diabetes.

To clarify the changes occurring in diabetic animals in the responsiveness of the myocardium to alpha 1- and beta-adrenoceptor agonists, we examined both alpha- and beta-adrenoceptor-mediated electrophysiological and mechanical responses in the depolarized right ventricular papillary muscle of streptozotocin (STZ) induced diabetic rats and age-matched controls. Both methoxamine (10(-7)-10(-4) M) and isoproterenol (10(-9)-10(-6) M) enhanced the slow response action potential in a concentration-department manner. The amplitude and the APD50 (time required for 50% repolarization) of the methoxamine-induced slow response action potential were both markedly increased in STZ-induced diabetic rats in comparison with control rats, whereas those of the isoproterenol-induced slow response were significantly decreased. The methoxamine-induced contraction in depolarized muscle was slightly but not significantly increased in STZ-induced diabetic rats, whereas the isoproterenol-induced contractile response was significantly attenuated. The maximum number of binding sites (Bmax) for [3H]dihydroalprenolol and for [3H]prazosin were both significantly decreased in diabetic rats, compared with age-matched control rats, without any change in the affinity constants. The slow response action potential induced by methoxamine but not isoproterenol was attenuated by IAP (islet-activating factor) treatment (50 micrograms/kg, i.v. for 3 days). These results suggest that an alpha-adrenoceptor-mediated electrophysiological response is unmasked when the beta-adrenoceptor-mediated response is desensitized in the papillary muscle of STZ-induced diabetic rats.

Action Potentials↗

PubMed1997

Myocardial action potential prolongation by calcium channel activation under calcium free-EGTA conditions in guinea-pigs: developmental and regional variations.

Prolongation of action potentials upon the addition of various cAMP increasing agents under Ca2+ free-EGTA condition, which was previously suggested to be produced by persistent Na+ influx through Ca2+ channel due to lack of Ca(2+)-mediated inactivation, was examined in isolated myocardial preparations from neonatal and adult guinea-pigs. Application of isoproterenol under Ca2+ free-EGTA condition produced prolongation of the action potential duration in both neonatal and adult preparations from various regions of the heart. Both in the neonate and adult, the prolongation in the right ventricular free wall and atrial preparations was smaller than that in preparations from other parts of the ventricle. In all regions of the heart except the right ventricle, the prolongation by isoproterenol was greater in the adult than in the neonate, no developmental difference was observed in the right free wall. In right ventricular free-wall preparations, the prolongation produced by forskolin and isobutyl-methylxanthine in the adult was larger than in neonatal ones. Our present results suggest regional and developmental difference in contribution of Ca(2+)-mediated inactivation of Ca2+ channels to the repolarization of guinea-pig myocardium. The developmental changes were similar to but much smaller than, those observed in the rat myocardium.

1-Methyl-3-isobutylxanthine↗

PubMed1997

Difference in the endothelium mediated effects of A23187 on thoracic aorta between neonatal and adult guinea pigs.

Developmental changes in the functional properties of thoracic aorta were examined in neonatal and adult guinea-pigs. Norepinephrine-induced contractions of the neonatal aortic rings were markedly enhanced by removal of the endothelium, whereas those of the adult rings were only slightly enhanced. Carbachol induced endothelium-dependent relaxation to a similar extent in both neonatal and adult aortic rings precontracted with 30 microM norepinephrine. A23187 induced endothelium-dependent relaxation in the adult aortic rings precontracted with 30 microM norepinephrine, whereas it failed to induce the relaxation in the neonatal aortic ring. Sodium nitropurusside induced endothelium-independent relaxation to a similar extent in both neonatal and adult aortic rings precontracted with 30 microM norepinephrine. The endothelium-dependent relaxation induced by carbachol and by A23187 were inhibited either by NG-nitro-L-arginine or by methylene blue, but not by indomethacin, indicating that both the relaxations were mediated by nitric oxide, but not by prostacyclin. These results suggest that, although the neonatal endothelium of the guinea-pig aorta is capable of releasing nitric oxide, the mechanisms underlying the synthesis and/or release of nitric oxide may be different between the neonatal and adult endothelium.

Animals↗

PubMed1997

Endothelium mediated vasorelaxant effects of Ca(2+)-ATPase inhibitors on thoracic aorta from neonatal and adult guinea pigs.

Vasorelaxant effects of Ca(2+)-ATPase inhibitors were examined in the isolated adult and neonatal guinea pig thoracic aorta focusing on the functional alterations of endothelial cells with development. Cyclopiazonic acid produced an endothelium-dependent vascular relaxation in the adult aorta preconstricted with norepinephrine, whereas no relaxant response was obtained by the compound in the neonatal preparation. Endothelium-dependent vascular relaxation was also produced by another Ca(2+)-ATPase inhibitor, thapsigargin, in the adult aorta, but not in neonatal ones. The endothelium-dependent vascular relaxations produced by both Ca(2+)-ATPase inhibitors were suppressed either by NG-nitro-L-arginine or by methylene blue, suggesting that nitric oxide (NO) mediated the endothelium-dependent vascular relaxations. The present results suggest the possibility that mechanisms underlying the synthesis and/or release of NO change with development in the guinea pig aortic endothelial cells.

Aging↗

PubMed1997

Glibenclamide-sensitive mechanism is involved in helodermin-produced vasodilatation in rat mesenteric artery.

Helodermin-caused vascular relaxation was simultaneously measured with intracellular Ca2+ concentration ([Ca2+]i) in rat mesenteric artery. Helodermin caused concentration-dependent relaxation in the mesenteric artery preconstricted with norepinephrine (NE). Helodermin-caused relaxation was accompanied by decrease in [Ca2+]i, D-cis-Diltiazem, a Ca2+ channel blocker, also lowered the [Ca2+]i and tension increased by NE. However, helodermin relaxed the artery more efficiently than D-cis-diltiazem, suggesting that the peptide decreased myofilament Ca2+ sensitivity. The vascular relaxation and the corresponding decrease in [Ca2+]i induced by helodermin were partly, but significantly attenuated by glibenclamide. Helodermin-induced vascular responses were mimicked by vasoactive intestinal polypeptide (VIP) or forskolin. Furthermore, helodermin increased cAMP contents in the mesenteric artery. These findings show that vasodilatation induced by helodermin is attributable to lowered [Ca2+]i of arterial smooth muscle partly through the activation of glibenclamide-sensitive K+ channels, and to decrease in the myofilament Ca2+ sensitivity. The increase in the cellular cAMP content probably plays a key role in the peptide-induced vasorelaxation.

Animals↗

PubMed1997

Inhibitory actions of ONO-3708 on the stretch-induced contraction potentiated by hemolysate/oxyhemoglobin studied in dog cerebral artery.

Quick stretch at a rate of 10 cm/sec with the amount of 30% of the slack length ( = 100%) produced a contraction in dog cerebral artery. The stretch-induced contraction was potentiated by 2-3 times in the presence of hemolysate (0.2 mg oxyHb/ml) only when the endothelium was intact. The stretch-induced contraction was also augmented by vasoconstrictor prostaglandins (PGs) such as PGF2 alpha or a stable thromboxane A2 (TXA2) analogue, U46619 (9, 11-dideoxy-11 alpha, 9 alpha-epoxymethano prostaglandin F2 alpha). ONO-3708 (7-[2 alpha, 4 alpha-(dimethylmethano-6 beta-(2-cyclopentyl-2 beta-hydroxyacetamido)-1 alpha-cyclohexyl]-5(z) heptenoic acid), a specific receptor antagonist for thromboxane A2 (TXA2)/prostaglandin (PG) endoperoxide, inhibited the potentiated stretch-induced contraction in the presence of hemolysate by about 50%. The compound completely inhibited the increase of stretch-induced contraction by PGF2 alpha or U46619. A cyclooxygenase inhibitor, acetylsalicylate, or a TXA2 synthetase inhibitor, OKY-046 ((E)-3-[4-(1-imidazolyl methyl)phenyl]-2-propenate) did not affect the potentiated stretch-induced contraction. The amount of PGF2 alpha released from the cerebral artery was not increased by hemolysate. These findings suggest that the potentiation of the stretch-induced contraction by hemolysate/oxyhemoglobin is not attributable to cyclooxygenase metabolites such as vasoconstrictor PGs. ONO-3708 seems to inhibit the potentiated stretch-induced contraction by hemolysate/oxyhemoglobin via mechanisms other than antagonism for cyclooxygenase products.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Comparative effects of gallopamil and verapamil on the mechanical and electrophysiological parameters of isolated guinea-pig myocardium.

The effects of gallopamil, D600, a methoxy derivative of verapamil, on the mechanical and electrophysiological parameters of isolated guinea-pig myocardial preparations were compared with those of verapamil. Both gallopamil and verapamil produced concentration-dependent negative chronotropic and negative inotropic effects in isolated right atrial and right ventricular papillary muscles, respectively. The negative chronotropic and negative inotropic potencies of gallopamil were 7.2 and 4.3 times higher than those of verapamil, respectively. Gallopamil decreased the action potential duration of isolated papillary muscles without substantially affecting other action potential parameters, while verapamil decreased not only the action potential duration but also the maximum rate of rise and amplitude. In voltage-clamped single ventricular myocytes, gallopamil as well as verapamil decreased the L-type Ca2+ current amplitude. The potency orders for the shortening of the action potential duration and inhibitory effects of the L-type Ca2+ current amplitudes were verapamil > gallopamil. These results indicate that gallopamil has higher negative chronotropic and inotropic potency than verapamil as a result of factors other than L-type Ca2+ current inhibition.

Animals↗