Changes in free amino acids in peripheral blood (PB) lymphocytes and polymorphonuclear (PMN) leukocytes after treatment with diazepam.

The effect of single and chronic (15 days) i.p. injections (1.0 and 8.0 mg/kg) of diazepam (DZ) on free amino acid profile in peripheral blood (PB) lymphocytes and polymorphonuclear (PMN) leukocytes of male Wistar Albino rats were investigated. Depletion of some free amino acids was observed in the lymphocytes (mixed T- and B-lymphocytes) and PMN leukocytes (91-95%) neutrophils especially after chronic DZ-treatment. A dose-dependent depletion in the lymphocyte amino acids, Tau, Gly, Ala, Met and Ile, was found after both acute and chronic DZ-treatment. A similar depletion of Tau, Asp, Glu and Met appeared in the PMN leukocytes after single doses as well as chronic DZ-treatment. These results suggest that administration of 1.0-8.0 mg/kg of DZ in single dose or after chronic administration may interfere with the transport of certain important amino acids and/or protein turnover in PB lymphocytes and PMN leukocytes. On the other hand, the basic amino acids Lys, His and Arg were significantly increased in PMN leukocytes after chronic administration of 1.0 mg/kg DZ. It was suggested that the increased levels of the basic amino acids in the neutrophils may interact with the intracellular changes in pH that normally accompany the respiratory burst.

Counteraction of nifedipine-induced hyperglycaemia by metformin.

Nifedipine-induced hyperglycaemia in rats was counteracted by concurrent administration of metformin (500 mg/kg p.o.). However, glibenclamide (5 mg/kg p.o.) did not change the hyperglycaemic effect of nifedipine. It is suggested that nifedipine-induced hyperglycaemia was not related to pancreatic effect and might be attributed to extra pancreatic mechanism by preventing the action of insulin in the tissues. Therefore, counteraction of nifedipine-induced hyperglycaemia by metformin, may play a role in diabetic patients treated with nifedipine.

Interaction between diazepam and oral antidiabetic agents on serum glucose, insulin and chromium levels in rats.

This study was undertaken to investigate the effect of diazepam in the presence and absence of glibenclamide, metformin or their combination on serum levels of glucose, insulin and chromium in rats. Results indicated that diazepam (10 mg/kg i.p.) induced marked hyperglycaemic effects in hyperglycaemic rats. This effect was associated with significant reductions in serum chromium levels and insignificant reduction in serum insulin levels. Diazepam-induced hyperglycaemia was counteracted by concurrent administration of glibenclamide (5 mg/kg orally), metformin (500 mg/kg orally) or their combination. The effect of diazepam on serum chromium level was counteracted partially by administration of glibenclamide and augmented in the presence of metformin or its combination with glibenclamide. It is concluded that the diazepam-induced hyperglycaemia, as well as the hypoglycaemic effect of glibenclamide, might be related to changes in serum chromium levels.

Short-term effect of angiotensin-converting enzyme inhibitor enalapril in incipient diabetic nephropathy.

The short-term effect (2 weeks) of angiotensin-converting enzyme inhibitor (enalapril) on renal hemodynamics and urinary albumin excretion was investigated in eleven normotensive patients with incipient diabetic nephropathy (IDN). Six patients had had elevated baseline glomerular filtration rate (GFR) and each responded to enalapril with a decline in the GFR, from a mean of 160.7 to 134 ml/min/1.73 m2, (p less than 0.05). Their respective filtration fraction values also decreased from a mean of 27.8 to 23.8% (p less than 0.01). Such renal hemodynamic change was accompanied by a decrease in urinary albumin excretion (33 to 19 micrograms/min, p less than 0.05). The remaining 5 patients had displayed normal baseline GFR (mean, 109.6 ml/min/1.73 m2), responded to enalapril with minimal change in the GFR (115.2 ml/min/1.73 m2) and showed no significant improvement in their microalbuminuria. It is concluded that enalapril is effective in lowering glomerular filtration pressure and ameliorating microalbuminuria in the normotensive patient with IDN only when the baseline GFR is elevated.

Influence of bromocriptine on free amino acids in the kidneys and heart of the rat.

The effects of bromocriptine, sulpiride or their combination on free amino acids in the kidneys and the heart after acute and chronic treatment of rats were investigated, using an automatic LKB Amino Acid Analyzer. Bromocriptine at a single dose of 4 or 10 mg/kg (i.p.) did not affect the level of any amino acid; however, at a dose of 20 mg/kg it significantly elevated the content of taurine in the kidney from 7.00 +/- 0.30 to 9.70 +/- 0.1 and in the heart from 22.9 +/- 1.7 to 30 +/- 1.2 mumol/g wet tissue (P less than 0.05, N = 7). It also increased glutamic acid in the heart from 3 +/- 0.1 to 4.5 +/- 0.25 mumol/g wet tissue (P less than 0.05, N = 7). Chronic oral treatment of rats with bromocriptine (20 mg.kg-1.day-1) for 5 weeks significantly elevated the level of taurine in the kidney from 7.2 +/- 0.3 (control) to 11.1 +/- 0.90 and in the heart from 23.1 +/- 1.7 to 38.8 +/- 1.8 mumol/l g wet tissue. It also increased cardiac glutamic acid content from 3 +/- 0.1 to 4.8 +/- 0.24 mumol/g wet tissue (P less than 0.01, N = 7). Concurrent administration of sulpiride (20 mg/kg) significantly suppressed bromocriptine-induced increases in taurine and glutamic acid in both organs, suggesting an activation of D2 receptors by bromocriptine. Due to the similarities between bromocriptine and the affected amino acids in renal and cardiac actions, it is suggested that mobilization of taurine and glutamic acid may at least in part contribute towards bromocriptine-induced renal and cardiac actions.

Role of Na+/K+-stimulated adenosine triphosphatase in the action of dopaminergic-D2 receptors of the liver in rats.

The dopamine receptor agonist, bromocriptine, in a dose of 10 mg/kg i.p. for 14 days, in rats caused a significant increase in liver Na+/K+-ATPase activity, whereas sulpiride, a dopamine receptor antagonist, in a dose of 10 mg/kg, i.p. for 14 days, in rats, caused a significant decrease in liver Na+/K+-ATPase activity. Injection of bromocriptine and sulpiride simultaneously in a group of rats, under the same conditions and using the same doses caused a complete block of both stimulatory activity of bromocriptine and inhibitory activity of sulpiride on liver Na+/K+-ATPase activity. It is suggested that Na+/K+-ATPase may have a role in the action of dopaminergic-D2 receptors.

Role of cyclic AMP in the action of dopaminergic D2 receptors of some endocrine glands in rats.

Short-term and long-term effects of bromocriptine mesylate (10 mg/kg i.p.) on cyclic AMP contents of the liver and some endocrine glands have been investigated in the presence and absence of sulpiride (10 mg/kg i.p.). Results revealed that bromocriptine caused significant elevations in the cyclic AMP contents of the liver and reduction in its adrenocortical content. Bromocriptine effect on the adrenal cortex was antagonized by sulpiride, whereas its effect on the liver was not changed. Bromocriptine did not change the cyclic AMP content in the thyroid gland or the ovary.

Effects of bromocriptine on cyclic-GMP contents of some endocrine glands and liver in rats.

Cyclic GMP contents of the thyroid gland and ovary were significantly increased in response to single and multiple treatments of bromocriptine, an effect which was antagonized by sulpiride. Liver and adrenocortical cyclic GMP levels have not been changed by bromocriptine although sulpiride alone induced a significant reduction. The data may indicate the presence of D2 receptors in ovary and thyroid gland that are related to cyclic GMP.

Effect of bromocriptine on lipid plasma levels in rats.

Results show that bromocriptine induced marked alterations in plasma levels of cholesterol and lipids in response to acute and chronic administrations in rats. Two hours after an I.P. dose of 10 mg/kg, bromocriptine mesylate caused significant reductions in plasma levels of total high density lipoprotein (HDL) and high density lipoprotein cholesterol (HDL cholesterol). At a dose of 20 mg/kg, bromocriptine mesylate induced significant elevations in plasma levels of total cholesterol, total HDL, HDL cholesterol, total low density lipoproteins (LDL), and low density lipoprotein cholesterol (LDL cholesterol). Injected at a dose of 4 or 10 mg/kg daily for 14 consecutive days, bromocriptine mesylate caused significant increases in plasma levels of total cholesterol, LDL cholesterol and total LDL whereas the levels of HDL cholesterol, total HDL triglycerides (TG) were reduced. At a dose of 20 mg/kg all parameters were significantly increased. Marked hyperglycaemia was noticed in response to doses of 10, 15 and 20 mg/kg injected daily for 14 consecutive days or 2 hrs after a single administration of 15 mg/kg. Plasma insulin activity was reduced 2 hours after injection of bromocriptine at a dose of 15 mg/kg Likewise, a significant reduction in plasma insulin activity was observed in response to daily I.P. injections of bromocriptine at a dose of 15 mg/kg. Hyperglycaemic and hypoinsulinaemic effects of bromocriptine (acute and chronic) were markedly decreased when sulpiride, a dopaminergic D2 antagonist, was injected at an I.P. dose of 10 mg/kg before bromocriptine. Plasma ACTH activity was significantly increased in response to bromocriptine (15 mg/kg I.P.) in acute and chronic experiments. This effect was markedly diminished when sulpiride was injected prior to bromocriptine. In conclusion, bromocriptine induced marked elevations in plasma levels of total cholesterol and lipids which are likely to be related to hyperglycaemic and hypoinsulinaemic effects.

Effect of taurine on arterial, uterine and cardiac PGI2 and TXA2 synthesis in the rat.

The influence of taurine (in drinking water for 6 weeks) on PGI2 and TXA2 synthesis by some female rat organs was investigated using radioimmunoassay and platelet antiaggregatory bioassay. Taurine 100 and 200 mg/kg/day increased aortic PGI2 release from 0.59 +/- 0.04 (control) to 0.85 +/- 0.05 and 1.01 +/- 0.06 ng/mg, respectively and that by the myometrium from 0.24 +/- 0.02 (control) to 0.38 +/- 0.01 and 0.50 +/- 0.04 ng/mg wet tissue, respectively (P less than 0.05, n = 6). It did not affect PGI2 and TXA2 production in the heart or TXA2 in the aorta. Taurine 200 mg/kg depressed uterine TXA2 synthesis from 148.6 +/- 9.8 (control) to 85.4 +/- 6.8 pg/mg (P less than 0.05, n = 6). Furthermore taurine 0.4 and 0.8 mM in vitro stimulated PGI2 release by the myometrial and aortic tissues from pregnant rats. The stimulant effect of taurine on PGI2 may be related to its antioxidant effect whereas its inhibitory effect on uterine TXA2 may result from direction of synthesis towards PGI2. It is concluded that endogenous taurine may participate in regulation of PGs synthesis and that prostanoids may contribute to its known actions. On broad basis, taurine-induced release of PGI2 may prove of potential value in those ailments characterised by deficiency in PGI2 release.

Effect of bromocriptine on prostacyclin release and cyclic nucleotides on rat aortic and uterine tissues.

The effect of bromocriptine mesylate on cyclic nucleotides and PGI2 release by rat aortic and uterine tissues was investigated. Treatment of rats with bromocriptine (10 mg kg-1 I.P. daily for 14 days) increased PGI2 release by the thoracic aorta from 0.67 +/- 0.02 to 1.4 +/- 0.03 ng/mg wet tissue (P less than 0.001; n = 6). This increase was antagonized by treatment with sulpiride (15 mg kg-l). Incubation of the arterial tissue with bromocriptine (50 micrograms ml-1) in vitro also stimulated PGI2 release. Mepacrine (160 micrograms ml-1) significantly decreased both basal and stimulated PGI2 release. Incubation of myometrial tissue from pregnant rats with bromocriptine (50 micrograms ml-1) in vitro significantly decreased PGI2 release from 1.25 +/- 0.07 to 0.60 +/- 0.08 ng/mg wet tissue (P less than 0.05, n = 6). It also elevated uterine cAMP from 40 +/- 2 to 64 +/- 3 pmoles/100 mg wet tissue. Both effects were antagonized by sulpiride. Bromocriptine did not affect uterine cGMP or the cyclic nucleotides in the aorta. It is concluded that the increase in aortic PGI2 was mediated via activation of dopamine D-2 receptors that stimulate phospholipase A2 enzyme. The decrease in myometrial PGI2 release may be related to the increase in uterine cAMP resulting from activation of dopamine D-1 receptors. Previous studies suggested a role for PGI2 in implantation in the rat. The results suggest that the inhibitory effect on uterine PGI2 may underlie the reported inhibition of bromocriptine on implantation. On broad basis, the decrease in uterine PGI2 together with the reported luteolytic effect of bromocriptine point to a potential role for the compound in postcoital contraception.

Mechanism of bromocriptine-induced hyperglycaemia.

Results reveal that bromocriptine at a dose of 6 mg/kg. I.P. in mice caused a significant hyperglycaemic effect which was accompanied by a marked increase in liver glycogen. After adrenalectomy, the effect of bromocriptine on serum glucose level was reduced whereas its effect on liver glycogen content was abolished. In rats, administration of bromocriptine (17.5 mg/kg I.P.) induced a significant rise in serum glucose level which was associated with marked reduction in serum insulin activity and increase in serum corticosterone level with no effect on serum triiodothyronine (T3) or thyroxine (T4) levels. It could be concluded that bromocriptine-induced hyperglycaemia might be attributed at least partially to inhibition of insulin release and stimulation of corticosterone secretion.