Biomedical subjects

K Shigenobu

Publications and source records attributed to K Shigenobu.

At least 127 records · Page 7Linked to original sources

PubMed1993

Effects of beraprost on the transmembrane potentials of guinea-pig ventricular muscles during normoxia and hypoxia-reoxygenation.

1. The present study was performed to determine whether beraprost, a new stable analogue of prostacyclin, may exert beneficial effects on the transmembrane action potentials during normoxia and hypoxia-reoxygenation in isolated right ventricular muscles of the guinea-pig. 2. Under normal oxygenation, beraprost (0.01-100 mumol-1) had no effects on the electrophysiological parameters. 3. Hypoxic conditions induced a decrease in action potential duration (APD) without affecting other action potential parameters. Beraprost inhibited this hypoxia-induced decrease in APD. However, beraprost had no effect on the decrease in contractile force induced by hypoxia, whereas it significantly improved the recovery of contractile force after reoxygenation. 4. Pinacidil-induced shortening of APD was not antagonized by beraprost. 5. Hypoxia significantly decreased the myocardial adenosine triphosphate (ATP) level, which was also prevented by beraprost. 6. These results suggested that beraprost may inhibit the hypoxia-induced shortening of APD by some mechanisms which contribute to the maintenance of muscle ATP level.

Action Potentials↗

PubMed1993

Developmental changes in action potential properties of the guinea-pig myocardium.

Developmental changes in action potential properties were examined in electrically driven (1 Hz) left atria and right ventricles from foetal, neonatal and adult guinea-pig hearts, using standard micro-electrode recording techniques. In both left atria and right ventricles, the overshoot, resting potential and maximum upstroke velocity of the action potential increased progressively with age until birth, and then remained almost unchanged. Action potential duration (APD) changed markedly with age during foetal and neonatal periods. In left atria, APD at 50% repolarization initially decreased until foetal day 50, and then increased until the adult period. In right ventricles, APD initially increased until approximately foetal day 45, then decreased for 5 days following birth, thereafter it increased again. In addition, after-hyperpolarization was observed only in left atria of younger foetuses. Thus we have demonstrated that in the guinea-pig myocardium developmental changes in action potential properties occur more extensively during the foetal period than during the postnatal period.

Action Potentials↗

PubMed1993

Effects of long-term oral administration of NZ-105, a novel calcium antagonist, with or without propranolol in spontaneously hypertensive rats.

A new calcium antagonist, NZ-105 ((+/-)-2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2-yl)-4- (3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol) (10 mg kg-1, p.o.), showed slow-onset hypotensive effect in spontaneously hypertensive rats (SHRs). The tachycardia evoked by NZ-105 was completely prevented when combined with a beta-adrenoceptor blocker, propranolol (20 mg kg-1), which did not affect the hypotensive response to NZ-105. In long-term administration experiments for 12 weeks with SHRs, the systolic blood pressure in the control group increased with age and the heart rate was stable throughout the period. NZ-105 (10 mg kg-1 day-1) alone and its combined treatment with propranolol (20 mg kg-1 day-1) maintained the systolic blood pressure and heart rate at a low level compared with the control group. The hypotensive action of NZ-105 were reproducible after repeated dosing for 12 weeks. Long-term administration of propranolol affected neither the elevation of the systolic blood pressure nor the heart rate substantially. The heart weight per body weight was significantly reduced after the chronic combination of both drugs, suggesting that the cardiac hypertrophy accompanying hypertension was prevented.

Administration, Oral↗

PubMed1993

Inotropic effects of ryanodine and calcium antagonists on embryonic and hatched chick myocardium.

Effects of extracellular Ca2+ and inotropic agents on contractile force were examined in myocardial preparations from embryonic and hatched chicks. Measurement of contractile force was performed in an organ bath with whole hearts for the young embryo (5 to 6 days old) and with isolated strips from the right ventricles for the old embryos (16 to 18 days old), hatched chicks (within 24 hours after hatching) and 1 week old chicks. The extracellular Ca2+ concentration-contractile force curve was in a lower concentration range in young embryonic hearts when compared with older ones. 2 mM Ca2+ and 8 mM Ca2+ produced about 60% maximum contraction in preparations from young embryos and the older ages, respectively. The sensitivity to nicardipine and diltiazem was similar among all ages examined under 2 mM Ca2+. When the two drugs were applied to preparations from the older ages under 8 mM Ca2+, the sensitivity was lower than that of the young embryo under 2 mM Ca2+. Ryanodine produced a negative inotropic response at all ages but the effect was smaller in the young embryo when compared with those of older ages. Mn2+ produced a negative inotropic effect at all ages. In the older three ages, Mn2+ produced a late augmentation of the contractile force in addition to the initial negative inotropic response, while such augmentation was not observed in the young embryo. In conclusion, the chick myocardium was shown to undergo developmental changes in excitation-contraction mechanisms including increase in sarcoplasmic reticulum function during the embryonic period, and thus provides an interesting model for studies on excitation-contraction mechanisms.

Animals↗

PubMed1993

Localization of bone morphogenetic protein-induced bone and cartilage formation on a new carrier: fibrous collagen membrane.

A fibrous collagen membrane (FCM) made of crosslinked reconstituted collagen fibers was applied as a carrier of BMP. The effectiveness of FCM as a BMP carrier was compared with conventionally used insoluble bone matrix (IBM). Partially purified BMP was obtained from a guanidine HCl extract of bovine bone after a three-step chromatographic procedure. The BMP fraction was combined with FCM or IBM and implanted subcutaneously in the back of rats. Bone and cartilage formation were determined by radiographic, histologic, and biochemical analyses after removal at 1, 2, 3 and 4 weeks. After 2 weeks, bone and cartilage formation were evident histologically in IBM-BMP and FCM-BMP. In IBM-BMP, cartilage was formed in the area of presumptive bone. On the other hand, in FCM-BMP, cartilage formation occurred in the space between the fibers of fiber-bundles, while on the surface of the fibers bone formation started independently. Biochemically, the most noteworthy difference between FCM-BMP and IBM-BMP was the marked increase in type II collagen content in FCM-BMP, which contrasted with its decrease in IBM-BMP at 3 weeks. This study demonstrated that FCM definitely functioned as a BMP carrier that led to bone and cartilage formation at distinct sites. Therefore, we conclude that BMP could induce differentiation of immature cells preferentially into either osteogenic cells or chondrocytes depending upon the nature of the carrier which provides the environment for cell differentiation.

Alkaline Phosphatase↗

PubMed1992

Effect of Mn2+ on neonatal and adult rat heart: initial depression and late augmentation of contractile force.

In the present study, we examined the inotropic effect of Mn2+ on adult and neonatal rat myocardia, contraction of which is known to be highly dependent on Ca2+ release from the sarcoplasmic reticulum and trans-sarcolemmal Ca2+ influx, respectively. Mn2+ produced an initial negative inotropic effect followed by a late augmentation of contractile force in both neonatal and adult preparations, accompanied by marked prolongation of the contraction duration. The attenuation of the late augmentation by ryanodine was greater in the adult while the effect of nicardipine was greater in the neonate, which was similar to the effects of the two drugs in the absence of Mn2+. We tentatively concluded that Mn2+ produces late augmentation of the contractile force in neonatal and adult rat myocardia through some action on the general mechanism of force development, rather than by acting specifically on the sarcoplasmic reticulum.

Aging↗

PubMed1991

Potassium channel opening properties of a novel compound, NIP-121, cromakalim and nicorandil in rat aorta and portal vein.

A novel compound, NIP-121, cromakalim and nicorandil caused concentration-dependent relaxation of rat aortas precontracted with 30 mM KCl, with pEC50 (M) values of 8.2, 7.1 and 5.5, respectively. At 60 mM KCl, the vasorelaxation induced by NIP-121 or cromakalim was almost abolished whereas that induced by nicorandil remained. In preparations precontracted with prostaglandin F2 alpha(PGF2 alpha) (10(-5) M), glibenclamide (10(-7) M) and phentolamine (3 x 10(-6), 3 x 10(-5) M) antagonized the relaxation induced by NIP-121 and cromakalim but not that induced by nicorandil. Methylene blue (10(-5) M) showed antagonistic effects against the vasorelaxation induced by nicorandil but not that induced by NIP-121. NIP-121 (10(-7), 10(-6) M) and cromakalim (10(-6), 10(-5) M) significantly increased the 86Rb+ efflux rate in rat aorta. The three compounds inhibited the frequency of spontaneous contractions of the rat portal vein (pIC30; NIP-121 = 8.0, cromakalim = 7.1 and nicorandil = 4.9); glibenclamide and phentolamine antagonized the effects of these compounds. In conclusion, NIP-121 is a more potent K+ channel opener than cromakalim in these tissues. Nicorandil apparently behaves as a K+ channel opener in the rat portal vein, but the vasorelaxation may involve some other mechanisms, such as generation of cyclic GMP.

Animals↗

PubMed1991

The antihypertensive property of NIP-121, a novel potassium channel opener in rats.

The antihypertensive effects of NIP-121, a novel potassium channel opener, were examined in comparison with cromakalim and its active enantiomer, lemakalim. In experiments by direct blood pressure measurements, orally administered NIP-121 dose-relatedly decreased arterial blood pressure in conscious spontaneously hypertensive rats (SHRs), and the ED20 values (the doses to produce 20% decrease of the mean blood pressure) of NIP-121 and cromakalim were 0.010 and 0.11 mg/kg, respectively, NIP-121 thus being about ten times more potent than cromakalim. The duration of the hypotensive effect by NIP-121 was longer than that by cromakalim. The hypotensive effect of NIP-121 was stronger in SHRs than in normotensive rats. All three drugs showed tachycardia that was antagonized by a beta-blocker, propranolol. Intravenously administered NIP-121 also showed a more potent hypotensive action with longer duration than cromakalim in conscious SHRs. The ED20 values for hypotension by NIP-121, cromakalim, and lemakalim were 0.017, 0.040, and 0.016 mg/kg, respectively. The intravenous hypotensive potency of NIP-121 but not cromakalim was similar to that of p.o. administration. The repeated treatments with NIP-121 (0.025, 0.05, and 0.1 mg/kg p.o. once a day) for 15 days did not modify the degree of the hypotensive action. In the anesthetized SHRs, pretreatment with glibenclamide but not other antagonists (atropine, propranolol, diphenhydramine + cimetidine, or indomethacin) suppressed the decrease in blood pressure induced by NIP-121.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1991

Action potential shortening and negative inotropic effects of a novel potassium channel opener, NIP-121, as compared with cromakalim in guinea pig ventricular myocardium.

The potencies of NIP-121, a new potassium channel opener, to shorten action potential duration and to decrease the contractile force was examined using isolated guinea pig right ventricular free wall and papillary muscle preparations, respectively; and they were compared with those of cromakalim. NIP-121 was about 10 times more potent than cromakalim with respect to both effects. This potency ratio in cardiac muscle was about the same as that observed in rat aorta and portal vein. These cardiac effects of both agents were antagonized by glibenclamide.

Action Potentials↗

PubMed1990

Role of beta-adrenoceptor-adenylate cyclase system in the developmental decrease in sensitivity to isoprenaline in foetal and neonatal rat heart.

1. The inotropic and chronotropic sensitivity to noradrenaline and isoprenaline (Iso) of foetal and neonatal rat heart decreases as the heart becomes sympathetically innervated. In the present study, we have examined adenylate cyclase (AC) activation and beta-adrenoceptor binding to determine whether a developmental decrease in sensitivity was demonstrable in the beta-receptor-AC system of atrial and ventricular membranes from the 15 day foetus and 1 day and 7 day neonates. 2. While the maximum activation of AC by Iso increased with age, the sensitivity expressed in terms of pD2 values decreased from the 15th foetal day to the first day after birth in the atria, and from the first day to the 7th day after birth in the ventricle. 3. In contrast, activation of AC by forskolin was almost identical at all ages both in atria and ventricle. 4. The maximum equilibrium binding of [3H]-dihydroalprenolol decreased with age, the dissociation constant being about the same at all ages in both the atria and ventricle. 5. In conclusion, we have demonstrated a developmental decrease in the sensitivity of AC to Iso in myocardial membrane fractions consistent with the developmental decrease in chronotropic and inotropic sensitivity to beta-adrenoceptor agonists. Although a reduction in beta-adrenoceptor number partly accounts for the decrease in sensitivity, some other factors such as decreased coupling to AC may largely be responsible.

Adenylyl Cyclases↗

PubMed1990

Rat heart organ culture for the study of trophic substances involved in the maintenance of normal sensitivity to norepinephrine: possible involvement of cAMP and search for other factors.

In organ culture conditions, in the absence of in vivo factors, the newborn rat right atria acquire a high sensitivity to agonists similar to that seen before sympathetic innervation and after denervation. In the present study, we examined the effects of various extracts and substances on the development of supersensitivity to norepinephrine (NE) to obtain information on the in vivo factors that regulate myocardial sensitivity. Addition of rat serum, right atrial extract, superior cervical ganglionic extract, vas deferens extract, carbachol, insulin, cortisone, thyroxin, and neuropeptide Y in the culture medium did not prevent the development of supersensitivity. Addition of NE completely inhibited the development of supersensitivity. This effect of NE was blocked by sotalol but not by phentolamine. Addition of calcitonin gene related peptide, forskolin, and 8-bromo-cAMP partially inhibited the development of supersensitivity. These results are consistent with the view that NE released from sympathetic nerve terminals in the newborn atria maintains myocardial sensitivity at normal level by acting on beta-adrenergic receptors, and that the effect may be partially mediated by a rise in intracellular cAMP concentration.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1990

[Electrocardiogram in pulmonary heart disease--clinical evaluation of right chest leads].

A clinical study was made to evaluate the usefulness of electrocardiograms in right precordial leads (V3r or V4R) for the diagnosis of cardiac complications among patients with chronic pulmonary disease. Walsh and colleagues reported that the change of direction in the terminal vector of QRS loop in the vector cardiogram is useful for the evaluation of chronic pulmonary heart disease. They showed that the terminal vectors of QRS loops tend to deviate to the right and/or posterior direction in the early stage of chronic pulmonary heart disease. We utilized the electrocardiograms in the right precordial leads to detect the second R waves, which are thought to reflect the terminal vectors of QRS loops in the vectorcardiograms. When the electrocardiograms in the right precordial leads were compared, the second R waves in leads V3R or V4R were more frequently observed among patients with chronic pulmonary heart disease than those without. However, in the same two groups, the frequency of second R waves in leads V5R or V6R didn't differ. We conclude that the second R waves in leads V3R or V4R in a patient with chronic lung disease suggest the presence of chronic pulmonary heart disease as a complication.

Adult↗

PubMed1989

Effect of ryanodine on neonatal and adult rat heart: developmental increase in sarcoplasmic reticulum function.

Negative inotropic responses to nicardipine, MnCl2 and ryanodine of isolated papillary muscles were compared between 1-day-old neonatal and adult rats. All of the drugs produced dose-dependent negative inotropic responses at both ages. Nicardipine and MnCl2 were effective at lower concentrations in the neonate when compared to the adult, while ryanodine was more effective in the adult. Attenuation of the positive inotropic effect of isoproterenol by nicardipine was greater in the neonate, while that by ryanodine was greater in the adult. The relaxation phase of contraction was shortened by isoproterenol and prolonged by ryanodine in adult preparations, but there were no changes in the neonatal preparations. In the adult, increasing the stimulus frequency resulted in a decrease in contractile force (negative force-frequency relationship) at control conditions, while it produced rather slight increases in contractile force in the presence of ryanodine. In the neonate, increases in the stimulus frequency resulted in an increase in contractile force (positive force-frequency relationship) both in the presence and absence of ryanodine. It was concluded that contraction of the adult rat myocardium is highly dependent on Ca2+ release from the sarcoplasmic reticulum, while that of the neonatal myocardium is more dependent on trans-sarcolemmal Ca2+ influx. It was also speculated that the negative force-frequency relationship is produced by some factor(s) closely related to sarcoplasmic reticulum function.

Alkaloids↗

PubMed1989

Endothelium-dependent vasodilator effects of platelet activating factor on rat resistance vessels.

1. To elucidate the mechanisms of the powerful and long-lasting hypotension produced by platelet activating factor (PAF), its effects on perfusion pressure in the perfused mesenteric arterial bed of the rat were examined. 2. Infusion of PAF (10(-11) to 3 x 10(-10) M; EC50 = 4.0 x 10(-11) M; 95%CL = 1.6 x 10(-11) - 9.4 x 10(-11) M) and acetylcholine (ACh) (10(-10) to 10(-6) M; EC50 = 3.0 +/- 0.1 x 10(-9) M) produced marked concentration-dependent vasodilatations which were significantly inhibited by treatment with detergents (0.1% Triton X-100 for 30 s or 0.3% CHAPS for 90 s). 3. Pretreatment with CV-6209, a PAF antagonist, inhibited PAF- but not ACh-induced vasodilation. 4. Treatment with indomethacin (10(-6) M) had no effect on PAF- or ACh-induced vasodilatation. 5. These results demonstrate that extremely low concentrations of PAF produce vasodilatation of resistance vessels through the release of endothelium-derived relaxing factor (EDRF). This may account for the strong hypotension produced by PAF in vivo.

Acetylcholine↗

PubMed1989

Platelet-activating factor: lack of direct action on guinea pig myocardium and possible transmitter release from cardiac sympathetic nerve endings at high concentrations.

Microelectrode and mechanical studies were performed with isolated guinea pig myocardium (right ventricular free walls and papillary muscles) to examine the effects of platelet-activating factor (PAF) and lysophosphatidylcholine (LPC). Low concentrations of PAF (10(-8) to 10(-6) M, a range equivalent to the blood concentrations that produce marked hypotension in vivo) had no effects on action potential configuration and contractile force. High concentrations (10(-5) to 10(-4)M) of PAF and LPC per se elicited slow response action potentials with concomitant contraction (restored contraction) in the myocardium depolarized with elevated K+ (25 mM); they also augmented slow responses and restored contractions produced by a low concentration of isoproterenol (10(-8) M). Although these results suggested there was an increase in slow Ca current, the slow responses and restored contractions thus produced were greatly suppressed or abolished by the addition of a beta-adrenoceptor blocking agent, sotalol (10(-5) M), and by pretreatment with reserpine (5 mg/kg i.p., 24 h prior). In accordance with our previous conclusions, the present results suggest that direct cardiac action is not involved in the mechanisms of hypotension produced by PAF. It was also shown that high concentrations of PAF and LPC may act nonspecifically as amphiphilic compounds to induce transmitter release from sympathetic nerve endings, which may in turn augment the Ca current channels in the myocardial cell membrane.

Action Potentials↗

PubMed1989

Developmental increase in the inotropic and cyclic AMP response to isoproterenol in embryonic and newly hatched chicks.

The cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels of ventricles isolated from 15- to 20-day-old chick embryos and 0- to 3-day-old hatched chicks were compared to clarify the mechanism underlying the change in sensitivity to isoproterenol during perinatal developmental stages when the functional sympathetic innervation has been completely achieved. Isoproterenol produced a positive inotropic effect on ventricles isolated from both embryonic and hatched chicks, but the ventricles from the hatched chicks were more sensitive. At both developmental stages sotalol was an equipotent antagonist of isoproterenol. 3-Isobutyl-1-methylxanthine (IBMX) produced an increment in the contractile force of the ventricles at both stages, but the ventricles from the hatched chicks responded to lower doses of IBMX. The reactivity to isoproterenol in increasing cyclic AMP level was significantly higher in the hatched ventricles than in the embryonic ventricles. The results suggest that the different sensitivities to isoproterenol between embryonic and newly hatched chick ventricles may be due to some changes in the process for cyclic AMP production.

1-Methyl-3-isobutylxanthine↗

PubMed1988

Altered responsiveness to autonomic transmitters of hearts from neonatal spontaneously hypertensive rats.

Responsiveness to autonomic neurotransmitters of isolated hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared in 1-day-old and 4-week-old neonates and adults. Chronotropic responses to norepinephrine (NE) and acetylcholine (Ach) were examined using right atrial preparations. There was no difference in the basal beating rate between SHR and WKY at all ages tested. The maximum beating rate produced by NE was higher in SHR only at 1 day after birth; there was no difference in the 4-week-old neonate and the adult. The sensitivity (pD2 values) to Ach was lower in SHR at both 1 day and 4 weeks after birth, but not in the adult. Inotropic responses to NE were examined using right ventricular preparations. The sensitivity was slightly higher in SHR at 1 day after birth, but no difference was observed in the 4-week-old neonate and the adult. These results suggested that the neonatal SHR heart has an increased function due to altered responsiveness to autonomic neurotransmitters, which may play a role in the initiation of hypertension.

Acetylcholine↗

PubMed1988

Organ culture of rat heart: maintained high sensitivity of fetal atria before innervation to norepinephrine.

Changes in sensitivity to norepinephrine (NE) of fetal and neonatal rat right atria placed in organ culture were examined. The high sensitivity to NE of the 17-day fetal atria was maintained during organ culture for 5 days. The pD2 value for NE at the 17th day of gestation was 8.66 +/- 0.09, and that after organ culture for 5 days was 8.62 +/- 0.09. The sensitivity of 1-day-old neonatal artia was significantly lower than that of fetal atria; but when they were cultured for 24 h, there was a 10-fold increase in sensitivity. The pD2 value before culture was 7.59 +/- 0.05, and that after culture was 8.54 +/- 0.04. NE added to the culture medium prevented this increase in sensitivity. Similar changes were observed in the sensitivity to isoproterenol, but not in the sensitivity to forskolin, indicating that these sensitivity changes were of a postjunctional nature and most likely due to some changes in the beta-receptor and (or) its coupling to adenylate cyclase. Therefore, the decrease in myocardial sensitivity to NE observed during the late fetal period is most likely to be caused by factor(s) related to sympathetic innervation.

Animals↗