INFLUENCE OF SEROTONIN ON THE HUMAN URETER - AN IN-VITRO PHARMACOLOGICAL STUDY

The influence of serotonin (5-hydroxytryptamine, 5-HT) on human ureteral smooth muscle was explored in a series of in vitro experiments. 5-HT evoked a dose-dependent contraction of the ureter, The effect of 5-HT was unaltered by blockade of 5HT(3) and 5HT(4) receptors and muscarinic cholinergic receptors. The 5HT(2) receptor antagonist ketanserin (KT; 10(-5)-10(-4) M) and mixed 5HT(1)/5HT(2) receptor antagonist methysergide (MS; 5 x 10(-5) M) inhibited the effect of 5-HT. Since the antagonist dissociation constant at 5HT(2) receptors for both KT and MS is found to be approximately 10(-9) M, it is concluded that this contractile effect may have been mediated by some other, as yet uncharacterized 5-HT receptor. We believe that 5-HT is a potential neurotransmitter in the human upper ureteral smooth muscle

8-OH-DPAT STIMULATES GASTRIC-ACID SECRETION THROUGH A VAGAL-INDEPENDENT, ADRENAL-MEDIATED MECHANISM

Serotonin (5-hydroxytryptamine, 5-HT) is a neuroendocrine component of the gastrointestinal tract. 5-HT1A receptors exist both in the brain and have been demonstrated autoradiographically in high density in the rat stomach. However, the physiologic role of 5-HT1A receptors in modulating gastric function is not known. The effect of the selective 5-HT1A receptor agonist, (+/-)-8-hydroxy-2-(n-dipropylamino)tetralin (8-OH-DPAT), on gastric acid secretory function was compared to 5-HT in acute, urethane-anesthetized gastric-fistulated rats during pentagastrin infusion. 5-HT inhibited, but 8-OH-DPAT stimulated, gastric acid secretion in a dose-dependent manner. Bilateral cervical vagotomy or celiac ganglionectomy did not reverse the effect of 8-OH-DPAT on acid secretion. However, the enhancement of acid by 8-OH-DPAT was attenuated by acute adrenalectomy or close intra-arterial administration of spiperone, but not idazoxan. Thus, the data suggest that the selective 5-HT1A receptor agonist 8-OH-DPAT may augment gastric secretory function via an adrenal-dependent mechanism

Pharmacological analysis of 5-hydroxytryptamine effects on human isolated ureter

5-Hydroxytryptamine (5-HT) induced concentration-dependent contractions in human isolated ureteral strips in vivo. On the basis of available selective 5-HT agonists and antagonists, we have further investigated the receptors involved. At concentrations from 10 nM to 1 mM, 5-HT induced concentration-dependent contractions. Significant contractions were not observed with 5-HT1A agonist 8-OH-DPAT (10(-9)-10(-4) M), 5-HT1D alpha agonist sumatriptan (10(-9)-10(-4) M), 5-HT2 agonist DOI (10(-9)-10(-4) M), 5-HT3 agonist 2-methyl 5-HT(10(-9)-10(-3) M) and 5-HT4 agonist renzapride (10(-9)-10(-3) M) on the human isolated ureter. On the other side, a 5-HT1-like agonist 5-CT (10(-9)-10(-3) M) produced contractions on the isolated samples. The E-max developed by 5-CT was significantly smaller than that of the 5-HT (29% of 5-HT). Methithepin, the less selective 5-HT1/2 antagonist (10(-9)-10(-6) M), 5-HT3 antagonist, ondansetron. (10(-9)-10(-5) M) and 5-HT4 antagonist DAU 6285 (10(-8)-10(-6) M) did not antagonise the contractile responses to 5-HT. 10(-7) M ketanserin antagonised 5-HT induced contractile responses in ureteral strips. Additionally, combined administration of 5-HT4 antagonist DAU 6285 (10(-6) M) and 5-HT1/2 antagonist methithepin (10(-6) M) caused a rightward shift of the CRC of 5-HT yielding pEC(50) values of 4.68 +/- 0.15. 5-HT-induced contractile responses that were not abolished by TTX and atropine, thus supporting the suggestion that in the human, the contractile responses to cumulative addition of 5-HT of the ureter are not mediated by excitation of cholinergic neurons. In the present study the receptor mediating the contractile response to 5-HT in the human upper ureter could not be clearly designated 5-HT1-like, 5-HT2, 5-HT3 or 5-HT4. This study suggests that contractile response to 5-HT in the upper segments of the human ureter appear to be mediated by an atypical 5-HT receptor subtype. (C) 1999 Academic Press

Effect of verapamil on responses to endothelin-1 in aortic rings from streptozotocin-induced diabetic rats.

In this study, we investigated the constrictor responsiveness to endothelin-l (ET-1, 10-30 nM) of aortic rings (under 1 g resting tension in Krebs-Bicarbonate solution) from 8-weeks streptozotocin (STZ, 65 mg kg(-1), i.p)-induced diabetic rats and vehicle-treated control rats. The maximum ET-1-induced contraction of the aorta in diabetic rats was increased by 150%, but the EC50 of ET-1 remained unchanged. Although in both groups, verapamil reduced the constrictor responses to ET-1 (diabetic group P < 0.001, control group P < 0.05), there were not any significant differences between PD2 values. These results suggest that verapamil inhibits ET-1-induced Ca2+ entry through the L-type channel and this effect did not change in diabetes mellitus. (C) 1999 Academic Press

The role of calcium entry on the relaxation response of rho-kinase inhibitor in rabbit renal artery.

This study was performed to clarify the role of extracellular and intracellular Ca2+ on rho-kinase enzyme inhibition-induced relaxation in rabbit renal arteries. The response to rho-kinase inhibitor (Y-27632) was studied in isolated renal artery segments precontracted with phenylephrine in the presence of voltage-gated calcium channel blocker nifedipine and in the absence of intracellular or extracellular Ca2+. Cumulative addition of rho-kinase inhibitor Y-27632 (10(-8)-10(-5) M) produced a concentration-dependent relaxation in renal artery rings precontracted with phenylephrine. Preincubation with nifedipine (1 mu M) resulted in a significant increase in relaxation response to rho-kinase inhibitor Y-27632 compared with preincubation with DMSO; the solvent of nifedipine. The maximal relaxation to Y-27632 in renal arteries precontracted with phenylephrine was significantly increased in the Ca-free Krebs containing 100 mu mol/l ethylene glycol tetraacetic acid (EGTA) but after depletion of intracellular stores with 20 mmol/l caffeine and 1mmol/l EGTA in Ca2+ free Krebs there was no significant difference between the relaxation to Y-27632 from control response in 2.5 mmol/l Ca2+ Krebs in the renal artery. These results suggest the involvement of extracellular Ca and L-type voltage-operated Ca2+ channels in phenylephrine-induced rho-kinase activation (Fig. 3, Ref. 20). Full Text in PDF www.elis.sk

Acute effect of rosiglitazone on relaxation responses in hypercholesterolemic corpus cavernosum

Thiazolidinediones (TZDs) improve vascular endothelial dysfunction through non-genomic effects of peroxisomal proliferator-activated receptor gamma. This study investigated the acute effect of one of the TZD, rosiglitazone, on endothelium-dependent relaxation response of corpus cavernosum (CC) in hypercholesterolemic rabbits. New Zealand rabbits were divided into two groups randomly as control and cholesterol groups. Hypercholesterolemia was induced by feeding rabbits with 2% cholesterol diet (w/w) for 6 weeks. Endothelium-dependent and -independent relaxation response of CC were evaluated in the presence of rosiglitazone by organ bath studies with cumulative doses of acetylcholine (Ach) and sodium nitroprusside (SNP). Maximal relaxation (Emax) response to Ach significantly decreased owing to hypercholesterolemia in CC tissues. However, in vitro incubation of rosiglitazone with different concentrations (0.1, 1 and 10 mu M) did not improve the Ach-dependent Emax responses in hypercholesterolemic rabbit CC. Surprisingly, rosiglitazone caused a significant decrease in Ach-dependent relaxation in healthy CC. Emax responses to SNP did not differ in the presence of rosiglitazone in both the control and hypercholesterolemic groups. Rosiglitazone does not improve hypercholesterolemia-induced endothelial dysfunction in CC tissues while it dose-dependently impairs endothelium-dependent relaxation in healthy CC tissue

Serotonin causes acute gastric mucosal injury in rats, probably via 5HT1D receptors.

5-HT-induced acute gastric mucosal injury was assessed in rats by using 5HT1, 5HT2, 5HT3, 5HT4 or muscarinic receptor related drugs. Rats were treated with antagonists i.p. and 30 minutes later either vehicle, 5-HT (20 mg/kg) or other agonists were administered s.c. The stomachs were removed 4 hours after the last injection and mucosal integrity was assessed by light microscopy using a histological ulcer index (HUI). The HUI was found to be significantly increased following 5-HT administration (1.57 +/- 0.3) when compared with controls (0.14 +/- 0.1). 5HT1 agonist 5-carboxamidotryptamine (20 mg/kg) produced acute gastric erosion and increased the HUI (P < 0.05). The HUI in the animals receiving 5-HT1D agonist sumatriptan (7 mg/kg) was found to be 1.62 +/- 0.24. 5HT2 antagonist ketanserine (2.5-15 mg/kg), 5HT3 antagonist ondansetron (1-5 mg/kg), 5HT4 antagonist DAU 6285 (1-10 mg/kg) and atropine (1.5-30 mg/kg) exerted no effect whereas 5HT1/2 antagonist metitepine (0.05-0.5 mg/kg) caused a dose dependent inhibition of the effect of 5-HT. The results from this study demonstrate that 5-HT causes acute gastric mucosal injury and this injury is probably due to the activation of the 5-HT1D receptors

The role of circadian rhythm on the pharmacokinetic of methotrexate in streptozotocin-induced diabetes mellitus rats

Chronopharmacokinetic studies have been conducted both in animals and humans. Anticancer agents are of great interest due to their narrow therapeutic range and large pharmacokinetic variability. It was reported that the pharmacokinetics of MTX showed a circadian rhythm in rats and humans. Since diabetes-induced physiological changes can affect pharmacokinetics of drugs, it was reported that MTX blood concentration in diabetic rats was higher than that of the control groups. The present study was designed to elucidate whether these diabetes-induced changes in pharmacokinetics occurred during the day and thus administered MTX at four different times in streptozotocin-induced diabetes mellitus (SIDM) rats. Blood samples were drawn at 5, 15, 30, and 60 min after IV infusion of MTX in both the SIDM and control groups. Control and SIDM Area under the concentration-time curve (AUC) values showed a significant circadian rhythm with a peak located in mid-dark phase at 14:00. Clearance values were significantly low at 14:00 in the diabetic group when compared to other periods and the control group. The MTX AUC was increased when treatment with dexamethasone was given to suppress the endogenous production of corticosterone in both control and SIDM rats. These results suggest that the extent of MTX pharmacokinetics varies with the time of day in the SIDM rats and these variations might be related to changes in corticosterone concentrations