摘要:

N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) has a structure which differs from those of other known blood glucose-lowering agents including sulfonylureas. It has been shown that oral administration of A-4166 exerts blood glucose-lowering effects in animal in vivo studies. In the present study, we investigated the effects of A-4166 on insulin and glucagon secretion at several glucose concentrations using isolated perfused rat pancreas preparations. Both 3.0 and 30 µmol/l A-4166 signigicantly stimulated insulin secretion as compared with basal levels at glucose concentrations of 8.0 and 11.0 mmol (p < 0.01 and p < 0.05, respectively). In contrast, glucagon secretion was not affected by administration of A-4166 up to 30 µmol/l at these glucose concentrations. At a glucose concentration of5.6 mmol/l, neither 0.3nor 3.0µmol/lA-4166 produced significant changes in insulin and glucagon secretion. However, A-4166 at 30 µmol/l significantly stimulated insulin secretion and inhibited glucagon secretion as compared with basal levels (p < 0.01 and p < 0.01, respectively). We conclude that A-4166 at 3.0 and 30 µmol/l directly stimulates insulin secretion but has little effect on glucagon secretion in isolated perfused rat pancreas at glucose concentrations of 8.0 and 11.0 mmol/l. these results, taken together with previously published data, suggest that oral administration of A-4166 could be a useful strategy for stimulating endogenous insulin secretion in non-insulin-dependent diabetic pati

ISSN:0031-7012    

DOI:10.1159/000139181

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Blood pressure, heart rate, and left ventricular function were measured in conscious diabetic Sprague-Dawley rats subjected to 5 weeks of deoxycorticosterone acetate (DOCA) treatment which was started 1 week following intravenous injection of streptozotocin (STZ) (60 mg/kg) to induce diabetes mellitus. It was found that chronic administration of DOCA in nondiabetic animals caused an increase in blood pressure and functional parameters of left ventricle, and a decrease in heart rate and plasma insulin levels. Normotensive diabetic rats exhibited hyperglycemia, hypoinsulinemia, and a lower body weight as compared with control animals but did not show significant abnormalities in cardiovascular function. DOCA-hypertensive STZ-diabetic rats had similar hyperglycemia, milder hypoinsulinemia, and a significantly lower rate of left ventricular relaxation and systolic blood pressure compared with the nondiabetic DOCA-hypertensive animals. It is concluded that the addition of DOCA hypertension to intact 6-week STZ-diabetic Sprague-Dawley rats results in the occurrence of cardiac dysfunction.

ISSN:0031-7012    

DOI:10.1159/000139182

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Effects were determined of chronic administration and withdrawal of a highly selective ĸ-opioid receptor agonist, U-50,488H, on methionine-enkephalin levels in central and peripheral tissues of male Sprague-Dawley rats. Rats were rendered tolerant to and physically dependent on U-50,488H by twice daily injections of 25 mg/kg of this compound for 5 days. Rats deemed abstinent were injected with this drug for 4 days and sacrificed on 5 th day. Methionine-enkephalin concentration increased in the hippocampus of U-50,488H-tolerant-dependent rats, whereas in abstinent rats, its level was elevated only in the hypothalamus. Levels of methionine-enkephalin in the pituitary gland of U-50,488H-tolerant-dependent or abstinent rats were unchanged. Among peripheral tissues, methionine-enkephalin concentration decreased in the adrenal gland of U-50,488H-tolerant-dependent rats. In the U-50,488H-abstinent rats, methionine-enkephalin concentration was elevated in the heart. In tissues of morphine- and U-50,488H-tolerant-dependent and abstinent rats methionine-enkephalin concentrations were affected differentially, suggesting inherent differences in µ- and ĸ-opiate-mediated tolerance-dependence and abstinence process

ISSN:0031-7012    

DOI:10.1159/000139183

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The effects of Madopar (levodopa plus benserazide) on the cataleptic behavioral response to haloperidol and on the locomotor activity in mice were quantitatively compared before and after the administration of 3-O-methyldopa (30MD). The intraperitoneal administration of 30MD (200-400 mg/kg) alone did not modify the haloperidol (1.0 mg/kg s.c.)-induced catalepsy. Madopar, depending on the dose regimen, markedly antagonized the haloperidol-induced catalepsy. Pretreatment with 30MD tended to reverse the antagonistic property of Madopar on the cataleptic behavior in response to haloperidol. The ability of 30MD to significantly inhibit Madopar effects was observed in the locomotor testing paradigm; the locomotor hyperactivity in Madopar-treated animals was significantly inhibited by a prior intraperitoneal injection of 30MD. The results from our animal experiments may provide further evidence that impediment of 30MD formation is meaningful in the treatment of Parkinson’s disease with Madopar or levodop

ISSN:0031-7012    

DOI:10.1159/000139184

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The effect of NG-monomethyl-L-arginine (NMMA), an inhibitor of nitric oxide synthase, on the development of tolerance to the analgesic and hypothermic actions of U-50,488H, a highly selective ĸ-opiate agonist, was determined in the rat. Male Sprague-Dawley rats were rendered tolerant to the pharmacological actions of U-50,488H by twice daily intraperitoneal injections of the drug (25 mg/kg) for 4 days. To determine the effect of NMMA on tolerance to U-50,488H, NMMA was administered 10 min prior to each injection of U-50,488H. Multiple injections of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic actions. NMMA (2, 4 and 8 mg/kg) inhibited the development of tolerance to the analgesic but not to the hypothermic action of U-50,488H. Multiple injections of U-50,488H resulted in a slower gain in body weight which was not modified by treatment with NMMA. The results indicate that inhibition of nitric oxide synthase can selectively block the tolerance to its analgesic action in the rat

ISSN:0031-7012    

DOI:10.1159/000139185

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

High-affinity (104 ± 18 pmol/l) and high-density (204 ± 25 fmol/mg) angiotensin II (All) binding sites have been identified in Xenopus laevis heart membranes. Competition binding of [125I]Sar1, Ile8 angiotensin (SIA) to these receptors by peptide analogs selective for the mammalian All receptor subtypes AT1 and AT2 suggested that the amphibian AII binding sites were more closely related to the AT1 receptor subtype. Also in common with AT1 receptors, dithiothreitol and GTPγS inhibited [125I]SIA binding to Xenopus heart receptors, exhibiting IC50 values of 600 and 0.95 µmol/l, respectively. In addition, Xenopus oocytes injected with Xenopus heart mRNA were capable of mobilizing calcium when exposed to All, demonstrating that Xenopus All receptors are functionally linked to a second-messenger system similar to that coupled to mammalian AT1 receptors. However, in contrast to both AT1 and AT2 receptor subtypes, nonpeptide antagonists DUP 753 and SK&F 108566 (AT1 receptor selective) and PD123319 (AT2 selective) did not bind the Xenopus All receptors, thus establishing that the amphibian receptors were pharmacologically unique. Together, these results demonstrate that Xenopus heart All receptors are functionally similar to mammalian AT1 receptors but are pharmacologically distinct from both AT1 and AT2 recept

ISSN:0031-7012    

DOI:10.1159/000139186

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The present study compared the contractile and relaxant responses of male and female rabbit bladder neck and urethra to field stimulation (FS) and various contractile and relaxant agents, with special attention paid to the involvement of nitric oxide (NO) in the mediation of field-stimulated relaxation. FS at basal tension elicited a frequency-dependent contractile response in all preparations. The maximal response to high frequency FS was significantly greater in the bladder neck strips isolated from male rabbits than in those from female rabbits. There were no significant differences in the response to bethanechol or phenylephrine between strips isolated from males and females. Field-stimulated responses of the strips from male bladder neck and urethra were greater than the response to phenylephrine. The responses of all strips to FS were greater than those to bethanechol. In addition, the response to phenylephrine was generally greatere than that to bethanechol. Phentolamine was a significantly more effective inhibitor of the response of the female bladder neck and urethral strips to FS than of the response of the male strips. The contractile response of all strips to phenylephrine was generally greater than that to bethanechol for both sexes and for both bladder neck and urethral strips. NG-nitro-L-arginine methylester (L·NAME) inhibited totally the field-stimulated relaxation of all strips. Isoproterenol stimulated a slowly developing but significant inhibition of phenylephrine prestimulated contractions. In conclusion, significant differences exist in the magnitude of field-stimulated relaxation between the bladder neck and urethra of both male and female rabbits, and, for all tissues, field-stimulated relaxation could be completely inhibited by pretreatment with L·NAME, an NO synthesis inhibito

ISSN:0031-7012    

DOI:10.1159/000139187

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

The effects of l-glutamine on pulmonary hypertension in the isolated perfused rabbit lung were investigated. Pulmonary hypertension was produced by the thromboxane-A2 mimetic U46619. l-Glutamine at a dose of 0.04 mM produced a sustained increase in pulmonary artery pressure (PAP) and subsequent administration of an equimolar dose of l-arginine did not affect PAP. l-Glutamine at a dose of 0.5 mM transiently increased PAP, which then decreased to baseline (pre-glutamine) values. When endogenous nitric oxide (NO) synthesis was inhibited with NG-nitro-l-arginine methylester, l-glutamine at a dose of 0.04 mM decreased PAP. These results demonstrate that the effect of l-glutamine on PAP during pulmonary hypertension depends upon dose, time and the presence of endogenous NO synthesis. We believe that the results can be explained by two different effects of l-glutamine, namely a direct inhibition of NO release by glutamine and the donation of nitrogen atoms by glutamine for additional NO or other vasodilator synthesis. Since plasma glutamine levels are 0.4-0.7 mM, endogenous l-glutamine may play a modulatory role during pulmonary hypertension.

ISSN:0031-7012    

DOI:10.1159/000139188

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Pretreatment of animals with dilazep, a blocker of adenosine uptake, potentiated the increased concentrations of adenosine in venous blood by 6-fold and raised arterial adenosine concentrations by 3-fold. Pretreatment of animals with erythro-9-)2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor of adenosine deaminase, also potentiated the increased concentrations of adenosine in venous blood by 6-fold and raised arterial adenosine concentrations by 3-fold. Pretreatment with combination of dilazep and EHNA furthermore increased venous adenosine levels by 11 times and arterial adenosine levels by 6 times. These data clearly suggest that hemorrhage induced extensive adenosine release and the released endogenous adenosine was eliminated quickly from plasma by the uptake mechanism and adenosine deaminase.

ISSN:0031-7012    

DOI:10.1159/000139189

出版商:S. Karger AG    

年代:1994

数据来源: Karger