Biomedical subjects

K Shigenobu

Publications and source records attributed to K Shigenobu.

At least 19 recordsLinked to original sources

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↗

PubMed1988

Binding of [3H]befunolol to beta-adrenoceptors in cardiac muscles of fetal and neonatal rat.

Characterization of beta-adrenoceptors was studied in heart muscles of rat fetus and neonate. The results of binding assay with [3H]befunolol, a beta-adrenergic partial agonist, to membrane fractions from rat heart muscles indicate that beta-adrenoceptors contain two different affinity sites. In the presence of 5'-guanylylimidodiphosphate, the low affinity site was reduced, while the high affinity site was not affected. The dissociation constants for both sites did not change during pre- and post-natal development. But the maximum binding sites for both sites decreased slightly but significantly (p less than 0.05) during development. A 10-fold decrease in norepinephrine sensitivity and isoprenaline sensitivity during pre- and post-natal development was not explained by the slight decrease in the maximum binding sites.

Adrenergic beta-Antagonists↗

PubMed1988

Changes in sensitivity of rat heart to norepinephrine and isoproterenol during pre- and postnatal development and its relation to sympathetic innervation.

Possible correlation between sympathetic innervation and sensitivity to adrenergic agonists was examined with developing rat hearts. Chronotropic responses of right atria to tyramine (TYR) was absent until the 15th day of gestation. After the 17th day of gestation, the maximum chronotropism by TYR was equal to that by norepinephrine (NE), indicating the development of functional sympathetic innervation to sinus node during this period. In ventricle, TYR responsiveness was low at birth and increased with age, indicating an increased sympathetic innervation during early postnatal period. Both in atria and ventricle, sensitivity to NE was high in early fetal ages followed by a 10-fold decrease after the onset of sympathetic innervation. Similar changes were observed in the sensitivity to isoproterenol, suggesting the postjunctional nature of this sensitivity change. There was no difference in sensitivities to dibutyryl cyclic AMP and forskolin between ventricles from 1-day- and 1-week-old neonates, suggesting changes in beta-receptor-adenylate cyclase system as a cause of this sensitivity change. The observed parallelism between functional sympathetic innervation and postjunctional sensitivity changes supports the hypothesis that sympathetic nerve exerts trophic influence upon cardiac muscle development to regulate the sensitivity to agonists.

Animals↗

PubMed1988

Kinetic analysis of the positive inotropic action (PIA) of ouabain in isolated perfused rabbit heart. Slow onset of PIA and slow binding to Na+, K+-adenosine triphosphatase.

The positive inotropic action (PIA) of ouabain was analyzed kinetically using isolated perfused rabbit heart. The input function of the ouabain concentration in the perfusate (Ci) into the heart was controlled by changing the volume of the reservoir and the rate of ouabain infusion into the reservoir fixed in front of the heart. The time courses of PIA were measured continuously with different infusion rates. The relationship between Ci and PIA clearly depended on the infusion rate in isolated perfused rabbit heart. The binding kinetics of ouabain to Na+, K+-adenosine triphosphatase (ATPase) in the cardiac homogenate showed two kinds of binding sites. The association rate constant (kappa 1), the dissociation rate constant (kappa-1) and the binding capacity of each site was estimated by the simultaneous fitting method. The occupation curve of the high affinity site corresponded well with the PIA measured in the isolated perfused heart at steady state. These results indicate that ouabain binding to the high affinity site is related to the PIA, and the slow binding process of ouabain to Na+, K+-ATPase may be one of the principal reasons for the infusion-rate dependence of ouabain PIA.

Animals↗

PubMed1988

Cardiac effects of ketanserin, a serotonin antagonist--electrophysiological examinations as a part of toxicity studies.

Cardiac effects of ketanserin were examined mainly electrophysiologically with using rat and guinea pig heart muscle preparations. 10(-6)M ketanserin slightly antagonized the positive chronotropic but not inotropic action of serotonin in spontaneously beating guinea pig atria. Ketanserin, only at the concentration as high as 10(-4)M, produced slight rightward shift of the positive chronotropic but not inotropic dose-response curves for norepinephrine in guinea pig atria. In both rat and guinea pig atria, ketanserin per se produced negative chronotropic effect and slight prolongation of action potential duration (APD) at high concentrations, 0.1 or 0.3 mg/ml. In guinea pig ventricular preparation, 1 mg/ml of ketanserin did not affect the rate of rise of the action potential (+Vmax), action potential amplitude and APD. In rat ventricular free wall preparations, 1 mg/ml of ketanserin produced slight increase in APD without affecting the other action potential parameters. In rat ventricular papillary muscle and septum preparations, 0.3 mg/ml of ketanserin tended to produce a decrease in +Vmax and an increase in APD. However, since these changes were produced only at extremely high concentrations and slight in degree, it was concluded that ketanserin does not produce electrophysiological side effects of clinical relevance.

Action Potentials↗

PubMed1987

Contractile response and electrophysiological properties in enzymatically dispersed smooth muscle cells of rat vas deferens.

Electrophysiological studies were performed on single smooth muscle cells isolated from the vas deferens of the rat. The tissue was preincubated in Ca-free modified Tyrode's solution for 1 h and then transferred to a high-K solution for 1 h. It was next minced and treated with the enzyme solution composed of 600-800 unit/ml collagenase and 40 unit/ml elastase. The procedure yielded about 50% spindle shaped Ca-tolerant cells (100-250 microns in length and about 10 microns in diameter). These cells could contract during the superfusion with the solutions containing 10(-8) to 10(-3) M norepinephrine (NE) or adenosine triphosphate (ATP). The cells isolated from the epididymal portion were more sensitive to norepinephrine than were those from the prostatic part. Their basic electrical properties were studied using tight-seal suction electrode technique. The cells had resting potentials around -40 mV and their input resistance was about 0.8 G omega. Action potentials could be evoked by application of depolarizing current. During whole cell voltage clamp, an inward current followed by an outward current was recorded when 800 ms pulses from a holding potential of -60 mV to test potentials positive than -40 mV were applied. The transient outward current generally recorded in other smooth muscle cells was not seen in these cells. The amplitude of the inward current was Ca dependent and sensitive to a Ca antagonist, nicardipine, indicating that Ca ion is the main carrier of this component of the current. When the pipette was filled with Cs-containing solution, the outward current was abolished.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗