Biomedical subjects

S Sakurada

Publications and source records attributed to S Sakurada.

At least 109 records · Page 6Linked to original sources

PubMed1993

Increase in plasma thyroid hormone levels during the previous heat exposure time in heat-acclimated rats.

The present study was conducted to investigate day-night variations of plasma thyroid hormone and energy substrate levels in rats after acclimation to heat loaded for several hours at a fixed time per day. The heat-acclimated rats were exposed to an ambient temperature of 33 degrees C for 5 h in the last half of the dark phase for 16 consecutive days, while the control rats were kept at 24 degrees C for the same period. After completing the schedule, plasma levels of triiodothyronine (T3), free T3 (FT3), thyroxine (T4), free T4 (FT4), cortisol, triglyceride, nonesterified fatty acid, total protein, and glucose were measured at 3-h intervals between 00:00 and 18:00 (dark phase, 03:00-15:00). The plasma levels of T3 and FT3 of the heat-acclimated rats were higher than those of the controls in the last half of the dark phase. Similar differences were observed for T4 and FT4 levels. The plasma cortisol level was consistently higher in the heat-acclimated rats than in the control rats. There were no particular differences in energy-substrate levels between the two groups at any time of the day. These results indicate that heat exposure at a fixed time per day alters the pattern of day-night variations of plasma thyroid hormone levels in rats. It is noteworthy that the plasma levels of thyroid hormones, especially T3 and FT3, increased during the period when the rats had been previously exposed to heat.

Acclimatization↗

PubMed1993

[Central effects of iohexol and iopamidol, non-ionic contrast media].

Central effects of intravenously (i.v.)-administered iohexol were compared with those of iopamidol in a series of tests. Mannitol was used as a reference. As assayed by the primary screening test based on Irwin's method, i.v. administration of mannitol resulted in a score of 0 in ddY mice and a score of 0.6 in ICR mice in the startle response. These results were not different from the data of both iohexol and iopamidol. Iopamidol at a dose of 1750 mgI/kg produced an inhibitory effect on the spontaneous locomotor activity. Iohexol at a dose of 7000 mgI/kg potentiated the duration of thiopental-induced narcosis. Hypothermia was caused by high doses of both iohexol and iopamidol. Electric stimulus increased the mortality of mice pretreated with high doses of iohexol and iopamidol. Both drugs had no notable activities in the anticonvulsant, electroencephalic, muscle relaxant and antinociceptive tests. These results indicate that both iohexol and iopamidol do not necessarily possess a similar pharmacological action. Judging from the LD50 of approximately 15000 mgI/kg for both drugs, they seem unlikely to have a specific pharmacological action on the central nervous system.

Animals↗

PubMed1993

Relationship between body core and peripheral temperatures at the onset of thermoregulatory responses in rats.

The relationships between body core temperature and environmental temperature (T(a)) at the onset of tail skin vasodilation, thermally-induced salivary secretion and cold-induced thermogenesis were examined in rats. Hypothalamic temperature (Thy) was measured as an index of body core temperature. Internal body heating and cooling were made using an intravenous thermode chronically implanted in the inferior vena cava at various T(a)s. External heating and cooling were made by changing T(a) at a constant rate, while Thy was controlled at constant levels with the thermode. Internal heating induced tail skin vasodilation but not thermally-induced salivary secretion, and internal cooling induced cold-induced thermogenesis. External warming caused tail skin vasodilation and thermally-induced salivary secretion, but external cooling failed to induce cold-induced thermogenesis. There were significant correlations between Thy and T(a) at the onset of tail skin vasodilation, thermally-induced salivary secretion and cold-induced thermogenesis. When T(a) was taken as an indicator of thermal input from the skin, the ratios of the potency of inputs from the body core and skin were estimated to be between 8:1 and 6:1 at the onset of tail skin vasodilation, 8:1 at the onset of thermally-induced salivary secretion, and 5:1 for the control of cold-induced thermogenesis. These results suggest that, in rats, the contribution of thermal input from the skin to the onset of thermoregulatory responses is relatively small.

Animals↗

PubMed1993

Alteration of nyctohemeral changes in body core temperature by repeated cold exposure given at a fixed time daily in rats [corrected].

The effects of cold exposure for several hours at a fixed time once a day on nyctohemeral variations of hypothalamic temperature (Thy), heat balance, and feeding and locomotor activities were examined in rats. The cold-exposed group was subjected to an ambient temperature of 3 degrees C for about 5 h in the last half of the dark phase daily for 10 or more than 21 consecutive days, while the control rats were kept constant at 24 degrees C. The 10-d cold exposure had little effect on nyctohemeral changes in Thy and locomotor activity. However, after completing a 3- to 4-week cold exposure schedule, the levels of Thy, heat loss, heat production, and feeding and locomotor activities of the cold-exposed rats significantly decreased for 1-2 h during the period of the previous cold exposure time. These decreases lasted for at least 2 d after the end of the cold exposure schedule. These results suggest that the patterns of nyctohemeral changes in body core temperature and feeding and locomotor activities were altered after repeated cold exposure at a fixed time once a day in rats.

Animals↗

PubMed1992

A selective and extremely potent antagonist of the neurokinin-1 receptor.

Sendide [Tyr6,D-Phe7,D-His9]-substance P(6-11) has been examined by measurements of ligand binding to crude membrane fractions and by functional tests on the spinally mediated behavioral response. Sendide potently displaced [3H]-labeled substance P (SP) binding to mouse spinal cord membranes in a competitive manner. In vivo, sendide, intrathecally co-injected with SP, competitively antagonized SP-induced scratching, biting and licking. The behaviors elicited by physalaemin, septide and [Sar9, Met(O2)11]-SP were also reduced by co-administration of sendide. Large doses of sendide were needed to reduce the action of neurokinin A, D-septide, neurokinin B and eledoisin. The in vitro and in vivo pharmacological profile of sendide demonstrated that it is a selective and extremely potent antagonist of the neurokinin-1 receptor.

Amino Acid Sequence↗

PubMed1992

Inhibition of development of Kaposi's sarcoma-related lesions by a bacterial cell wall complex.

In vitro and in vivo model systems for the study of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS) were used to evaluate compounds for their potential as therapeutic agents. A sulfated polysaccharide-peptidoglycan compound (SP-PG) produced by bacteria controlled the in vitro growth of acquired immunodeficiency syndrome (AIDS)-associated, KS-derived spindle-shaped cells (AIDS-KS cells) at noncytotoxic concentrations. Angiogenesis induced by AIDS-KS cells in the chicken chorioallantoic membrane assay was blocked by SP-PG, which also inhibited the vascular hyperpermeability response and the angiogenesis associated with the induction of KS-like lesions that develop after subcutaneous inoculation of AIDS-KS cells into nude mice. Suramin, pentosan polysulfate, and interferon alpha, which are currently in use for therapy of KS, were either less effective than SP-PG or much more cytotoxic, or both.

Acquired Immunodeficiency Syndrome↗

PubMed1992

Comparison of opioid properties between D-Arg-containing dipeptides and tetrapeptides.

Since the D-Arg-containing dipeptides, H-Tyr-D-Arg-OMe (TDA) and H-Tyr(Et)-D-Arg-OMe, and D-Arg2-substituted dermorphin N-terminal tetrapeptide analogues, H-Tyr-D-Arg-Phe-Gly-OEt (TDAPG) and H-Tyr(Et)-D-Arg-Phe-Gly-OEt gave different pharmacological responses in vivo, opioid interaction and structure-activity relationships have been investigated in vitro. In the isolated guinea-pig ileum assay, the tetrapeptides were potently inhibitory, their activity markedly exceeding that of the dipeptides. In particular, the first tetrapeptide had twice the activity of morphine, while the potency of the dipeptides was less than one twentieth that of morphine. Also in the opioid receptor binding assay, tetrapeptides had a higher affinity than the dipeptides. IC50 values of tetrapeptides were 8.46 and 23.7 nM, respectively, which were lower than that of morphine. Ethylation of the Tyr residue of TDA much increased the opioid activity whereas that of TDAPG greatly decreased it. All peptides used were extremely stable to aminopeptidase-M and carboxypeptidase-Y and had an inhibitory effect on enkephalin (EK)-degrading enzymes. From these results, it appears that the effects of the tetrapeptides are due mainly to specific interaction with opioid receptors, whereas the dipeptides do not act specifically on the opioid receptors, but are involved in non-opioid mechanisms. The resistance to enzymes and inhibitory effect of the peptides used on the EK-degrading enzymes may also account for their potent and long-lasting opioid-like activities.

Amino Acid Sequence↗

PubMed1992

Different effects of peptidase inhibitors on dermorphin- and on [D-Arg2]dermorphin-induced antinociceptive activity.

The antinociceptive effects produced by the intracerebroventricular (i.c.v.) injection of dermorphin and [D-Arg2]dermorphin were compared in conscious mice, using the combined administration of peptidase inhibitors. Nociception was assessed using a tail pressure assay. Dermorphin-induced antinociception was not potentiated by simultaneous administration of amastatin or captopril as judged from the ED50 values. Co-administration of dermorphin and amastatin gave a longer duration than with dermorphin alone, whereas there was no significant effect on duration with captopril. The antinociceptive activity of dermorphin was significantly enhanced when the heptapeptide was injected simultaneously with both peptidase inhibitors. This result indicates that the heptapeptide sequence is required for the full expression of intrinsic opioid activity of dermorphin. In contrast, co-administration of amastatin brought about a significant enhancement of the antinociceptive activity induced by i.c.v. administration of [D-Arg2]dermorphin, whereas the effect of [D-Arg2]dermorphin was markedly decreased by the concurrent administration of captopril or thiorphan. The potency of captopril was much greater than that of thiorphan. The present results suggest that [D-Arg2]dermorphin may be transformed metabolically to a peptide which has potent antinociceptive activity.

Analgesics, Opioid↗

PubMed1992

Naloxone-reversible effect of spantide on the spinally mediated behavioural response induced by neurokinin-2 and -3 receptor agonists.

[D-Arg1, D-Trp7,9, Leu11]-substance P (spantide) was tested for antagonism against the licking, biting and scratching response induced by various neurokinin (NK) receptor agonists and bombesin (Bom) in mice. When co-administered with substance P (SP) intrathecally, spantide reduced the SP-induced behavioural responses in a dose-dependent manner. The duration of this antagonistic effect was approximately 30 min. Behavioural responses induced by physalaemin (Phy), [pGlu6, L-Pro9]-SP (6-11) (septide), [pGlu6, D-Pro7]-SP (6-11) (D-septide) and eledoisin (Ele) were also dose-dependently decreased by relatively small doses of spantide. Higher doses of spantide were needed to reduce the behavioural responses induced by [Sar9, Met (O2)11]-SP, neurokinin A (NK A) and neurokinin B (NK B). No significant effect of spantide was observed against the behavioural responses elicited by Bom. Pretreatment with naloxone, an opioid antagonist, resulted in a reversible effect on the behavioural reduction of NK-2 and NK-3 receptor agonists produced by spantide. However, the effect of spantide on the NK-1 receptor agonist-induced response was unchanged by naloxone. In homogenates of mouse spinal cord, competition studies confirmed that the binding of the opioid ligand [3H]naloxone was displaced by spantide with a low but measurable affinity. These results suggest that the behavioural response to NK-2 and NK-3 receptor agonists may be partially inhibited by spantide through the activation of opioid system in the mouse spinal cord.

Analgesics↗

PubMed1992

The capsaicin test in mice for evaluating tachykinin antagonists in the spinal cord.

A capsaicin test involving peripheral nociception, which produces behaviour similar to that elicited by formalin, is described in mice. Capsaicin was injected subcutaneously (s.c.) into the dorsal surface of a hindpaw and the time the animals spent licking the paw was recorded. Doses of capsaicin of 6.25-1600 ng induced nociception, during a period of 5 min, starting immediately after injection and disappearing completely at 10 min. Intrathecally (i.t.) administered [D-Arg1,D-Trp7,9,Leu11]substance P (spantide), a tachykinin antagonist and [D-Phe7,D-His9]substance P (6-11), a selective antagonist of substance P (SP), inhibited the capsaicin-induced behaviour, in a dose-dependent manner. This licking behaviour was also inhibited by intrathecal administration of SP antiserum but not by somatostatin (SOM) antiserum. Intrathecal pretreatment with capsaicin resulted in a marked reduction of the licking response, following subcutaneous injection of capsaicin into the paw. Capsaicin-induced licking was not affected by intrathecal administration of cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-(OBz)-Thr], a SOM antagonist and by intrathecal pretreatment with cysteamine, a SOM depletor. This nociceptive test may allow discrimination between SP- and SOM-mediated responses in the spinal cord of the mouse.

Analgesics↗

PubMed1992

Antinociceptive mechanisms of [D-Arg2]-dermorphin tripeptide analogs.

These studies examined the antinociceptive effects and mechanisms of opioid activity of synthetic dermorphin tripeptide analogs containing D-Arg as the second amino acid, H-Tyr-D-Arg-Phe-NHCH3 and H-Tyr-D-Arg-Phe-N(CH3)2. Both tripeptides, administered i.c.v., i.t. and s.c. in mice, produced a potent and long-lasting antinociceptive activity as compared with morphine. In the guinea pig isolated ileum (GPI) assay, the IC50 value of both peptides was lower than that of morphine on the electrically induced contractions of the GPI. In radioligand binding studies with rat brain membrane synaptosomes, both tripeptides bound with high affinity to [3H]DAMGO-labeled mu-type sites, whereas they bound with no or negligible affinity to [3H]DPDPE-labeled delta sites and [3H]U-69593-labeled kappa sites. In the enzymatic degradation using high-performance liquid chromatography, both tripeptides showed good enzymatic stability after 25 hr of incubation with solubilized enzymes of mouse brain or spinal cord, in contrast to a rapid degradation of Met-enkephalin. The in vitro and in vivo pharmacological profile of [D-Arg2]-dermorphin tripeptide analogs demonstrates that they are potent and selective agonists at the mu opioid receptor. A high resistance of the tripeptides to enkephalin-degrading enzymes may largely contribute to their prolonged opioid activity.

Amino Acid Sequence↗

PubMed1991

Effect of heat acclimation on diurnal changes in body temperature and locomotor activity in rats.

1. The present study was performed to examine the effects of heat exposure hours hours at a fixed time once a day on diurnal variations of deep body temperature, heat balance and locomotor activity in rats. 2. The heat-exposed group (HE) was subjected to an ambient temperature of 33.5 degrees C for about 5 h in the last half of the dark phase daily for at least 10 consecutive days, while the control rats were constantly kept at 24 degrees C. 3. After the completion of the heat exposure schedule, hypothalamic temperature (Thy), heat loss, heat production and locomotor activity of HE rats significantly decreased for 3-4 h during the period of previous heat exposure time and formed a characteristic trough in the dark phase, which was never observed in the control rats or in the HE rats before the start of the heat exposure schedule. 4. The troughs of Thy, heat loss and heat production in the dark phase were persistent for at least 2 days after the end of the heat exposure schedule. The reductions of locomotor activity in this period were, however, observed only on the first day after stopping the heat exposure schedule. 5. These results suggest that the time memory for heat exposure was formed in heat-acclimated rats and was persistent for at least 2 days after the removal of heat exposure. It is also concluded that the reduction in metabolic heat production contributed to the fall of Thy during the period of heat exposure.

Acclimatization↗

PubMed1991

Mechanism of vasoconstriction in the rat's tail when warmed locally.

The vascular response of the tail to local warming was investigated in urethan-anesthetized rats whose colonic temperature was maintained at 39.5 degrees C with an intravenous thermode at an ambient temperature of 23 degrees C. The tail, covered with thin latex tubing, was immersed in temperature-controlled water initially kept at 35 degrees C. The tail was warmed by raising the water bath temperature from 35 to 44 degrees C at a constant rate. Tail blood flow (BF), mean arterial blood pressure (BP), and tail skin temperature (Tsk) were measured before and during the local warming. Tail vascular conductance (VC) was computed as 100 x tail BF/BP. When Tsk exceeded 37 degrees C, tail BF and VC significantly decreased from the levels at Tsk of 35 degrees C, and significant reductions in tail BF and VC occurred until Tsk reached 42 degrees C. Surgical deafferentation of the tail, chemical sympathectomy with 6-hydroxydopamine (100 mg/kg), and alpha-blockade with phentolamine (7 or 40.1-45.5 mg/kg) or phenoxybenzamine (5 mg/kg) failed to stop the decrease in tail BF and VC during the local warming. These results suggest that a reflex via the central nervous system and the alpha-adrenergic sympathetic nervous system is not indispensable for heat-induced vasoconstriction (HIVC). It is therefore assumed that, at least in the rat's tail, HIVC predominantly originates from a local vascular response to high temperature.

Animals↗

PubMed1991

Temperature regulation during acute heat loads in rats after short-term heat exposure.

Eleven rats were kept at an ambient temperature of 33.5 degrees C (HC) for 4-5 consecutive days, 9 additional rats were subjected to 33.5 degrees C for approximately 5 h daily (HI) for the same period, and 12 controls (Cn) were kept at 24 degrees C. After the exposure, the rats were placed in a direct calorimeter, where the wall temperature was set at 24 degrees C, and subjected to direct internal heating (6.2 W.kg-1, 30 min) through an intraperitoneal electric heater. After the first heat load and when thermal equilibrium had been attained again, the rats were subjected to indirect external warming by raising the jacket water temperature surrounding the calorimeter from 24.0 to 38.8 degrees C in 90 min. Hypothalamic (Thy) and colonic temperatures (Tco), evaporative and nonevaporative heat loss, and metabolic heat production (M) before the acute heat loads did not differ among the groups. During heat loads, the latent times for the onsets of the rises in tail skin temperature and evaporation were significantly longer, and Thy and Tco at the start of increases in heat losses tended to be higher, in the HC than in the Cn. M significantly decreased in all groups, but the magnitude and duration of reduction in M were significantly greater in the HC than in the Cn. There were no differences between the thermoregulatory responses to heat loads of the HI and Cn. These results suggest that in HC the threshold core temperature for heat loss response and the upper critical temperature have already shifted to a higher level and that HC respond to heat stress more strongly with the reduction of M than Cn. Short-term intermittent heat exposure had little effect on the thermoregulatory mechanisms in rats.

Acclimatization↗

PubMed1991

Differential effects of substance P analogs on neurokinin 1 receptor agonists in the mouse spinal cord.

Effects of five substance P (SP) analogs on the licking, biting and scratching response induced by neurokinin (NK) 1 receptor agonists such as SP, physalaemin and (p-Glu6,Pro9)-SP (6-11) (septide) were studied after intrathecal injections in mice. Septide brought about a SP-like behavioral response, and was approximately 25 times more potent than the D-Pro9 analog, D-septide. When administered simultaneously with NK-1 receptor agonists, a putative SP antagonist, spantide inhibited SP-, physalaemin- and septide-induced behavioral response in a dose-dependent manner with ED50 values of 1.0, 0.65 and 1.3 nmol/mouse, respectively. Septide-induced response was significantly reduced by lower doses of (D-Arg1, D-Pro2,4, D-Phe7, D-His9, Leu11)-SP than (D-Phe7, D-His9, Leu11)-SP (6-11). In contrast, (D-Arg1, D-Pro2,4, D-Phe7, D-His9)-SP (0.5-1.0 nmol) and (D-Phe7, D-His9)-SP (6-11) (0.5-2.0 nmol) inhibited only SP-induced behavioral response, but not physalaemin- or septide-induced response. The results of this study indicate that NK-1 receptor agonists are not necessarily affected to a same degree by SP analogs containing D-His. These findings may be interpreted as indicative of the existence of different NK-1 receptor subtypes.

Analgesics↗

PubMed1990

N-terminal substance P fragments inhibit the spinally induced, NK 1 receptor mediated behavioural responses in mice.

N-terminal fragments of substance P (SP) were tested for antagonism against the aversive responses induced in mice by various tachykinin receptor agonists, somatostatin and bombesin. When co-administered with SP intrathecally, low doses (1.0-4.0 pmol) of SP (1-7) or SP (1-8) reduced the SP-induced behavioural responses of scratching, biting and licking. Aversive responses induced by two other neurokinin (NK) 1 receptor agonists, Septide and physalaemin, were also dose-dependently decreased by the simultaneous injection of small doses of SP (1-7) or SP (1-8). Aversive responses induced by 400 pmol of NK A were also significantly reduced by co-administration of SP (1-7) or SP (1-8). No significant effects of the N-terminal fragments were observed against the aversive responses elicited by NK A (300 pmol), eledoisin, NK B, somatostatin or bombesin. These results suggest that the behavioural antagonism produced by SP (1-7) and SP (1-8) may be limited to the NK 1 receptor at the spinal level in mice.

Animals↗

PubMed1990

N-terminal tetrapeptide of dermorphin and D-Arg-substituted tetrapeptides: inactivation process of the antinociceptive activity by peptidase.

Degradation products of the N-terminal tetrapeptide of dermorphin, H-Tyr-D-Ala-Phe-Gly-OH (ALPG) and D-Arg2-substituted tetrapeptide analogs of dermorphin, H-Tyr-D-Arg-Phe-Gly-OH (ARPG), H-Tyr-D-Arg-Phe-Gly-NH2 (TDAPG-NH2) and H-Tyr-D-Arg-Phe-beta-Ala-OH (TDAPA) by enkephalin degrading enzymes were studied by using reversed-phase high-performance liquid chromatography. After 5 and 25 hr incubations of the peptides with solubilized enzymes of mouse brain or spinal cord, liberation of the appreciable Tyr1 residue was observed in ALPG but not in ARPG, TDAPG-NH2 and TDAPA. When ARPG and TDAPG-NH2 were incubated with enzymes for 25 hr, a main degradation product was the N-terminal tripeptide produced from the hydrolysis of Phe3-Gly4 bond. Conversely, TDAPA did not produce the N-terminal tripeptide after 25 hr incubation with enzymes. In the enzyme assay, Tyr1-D-Arg2 bond of ARPG, TDAPG-NH2 and TDAPA was more stable than that of ALPG to the cleavage by aminopeptidase M (AP-M). Phe3-Gly4 bond of ALPG, ARPG and TDAPG-NH2 were easily hydrolyzed by carboxypeptidase Y (CP-Y) within 3 hr incubation, whereas the hydrolysis of Phe3-beta-Ala4 bond of TDAPA by CP-Y was not observed after 3 hr incubation. The present results and previous behavioural data suggest that a potent and prolonged antinociceptive activity of the D-Arg-substituted tetrapeptides is mainly attributed to the stability of Tyr1-D-Arg2 bond against aminopeptidase of peptidases.

Amino Acid Sequence↗

PubMed1990

Spinal antinociception: comparison of a dermorphin tetrapeptide analogue, [D-arginine2, sarcosine4]-dermorphin (1-4) and morphine in rats.

Intracerebroventricular injections of [D-arginine2, sarcosine4]-dermorphin (1-4) (DAS-DER 1-4) and morphine produced a dose-dependent inhibition of the tail-flick response to thermal stimulation. The ED50 value for each drug was 3.23 (1.35-7.73) nmol/rat and 32.0 (13.3-76.6) nmol/rat, respectively. When injected into the spinal subarachnoid space, the ED50 value was 0.035 (0.015-0.086) nmol/rat for the tetrapeptide and 11.9 (5.7-25.2) nmol/rat for morphine, respectively. Antinociception induced by DAS-DER 1-4 and morphine, through the intracerebroventricular and intrathecal routes, was clearly reduced by pretreatment with a small dose of naloxone. After spinal transection, the antinociceptive potency of systemically-administered morphine was significantly reduced while that of DAS-DER 1-4 was unaltered. The activity of DAS-DER 1-4 and morphine was also reversed by naloxone in spinal animals. It is concluded that DAS-DER 1-4, a dermorphin analogue, has a minor supraspinal action but acts mainly at the level of the spinal cord, in contrast to the action of morphine.

Analgesics↗