Angiotensin II type 1 receptor-mediated inhibition of K+ channel subunit kv2.2 in brain stem and hypothalamic neurons.
Angiotensin II (Ang II) has powerful modulatory actions on cardiovascular function that are mediated by specific receptors located on neurons within the hypothalamus and brain stem. Incubation of neuronal cocultures of rat hypothalamus and brain stem with Ang II elicits an Ang II type 1 (AT1) receptor-mediated inhibition of total outward K+ current that contributes to an increase in neuronal firing rate. However, the exact K+ conductance(s) that is inhibited by Ang II are not established. Pharmacological manipulation of total neuronal outward K+ current revealed a component of K+ current sensitive to quinine, tetraethylammonium, and 4-aminopyridine, with IC50 values of 21.7 micromol/L, 1.49 mmol/L, and 890 micromol/L, respectively, and insensitive to alpha-dendrotoxin (100 to 500 nmol/L), charybdotoxin (100 to 500 nmol/L), and mast cell degranulating peptide (1 micromol/L). Collectively, these data suggest the presence of Kv2.2 and Kv3.1b. Biophysical examination of the quinine-sensitive neuronal K+ current demonstrated a macroscopic conductance with similar biophysical properties to those of Kv2.2 and Kv3.1b. Ang II (100 nmol/L), in the presence of the AT2 receptor blocker PD123,319, elicited an inhibition of neuronal K+ current that was abolished by quinine (50 micromol/L). Reverse transcriptase-polymerase chain reaction analysis confirmed the presence of Kv2.2 and Kv3.1b mRNA in these neurons. However, Western blot analyses demonstrated that only Kv2.2 protein was present. Coexpression of Kv2.2 and the AT1 receptor in Xenopus oocytes demonstrated an Ang II-induced inhibition of Kv2.2 current. Therefore, these data suggest that inhibition of Kv2.2 contributes to the AT1 receptor-mediated reduction of neuronal K+ current and subsequently to the modulation of cardiovascular function. (+info)
Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats.
Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons. (+info)
Leptin and reproduction.
In the few years since leptin was identified as a satiety factor in rodents, it has been implicated in the regulation of various physiological processes. Leptin has been shown to promote sexual maturation in rodent species and a role in reproduction has been investigated at various sites within the hypothalamo-pituitary-gonadal axis. This review considers the evidence that leptin (or alteration in amount of body fat) can affect reproduction. There is evidence that leptin plays a permissive role in the onset of puberty, probably through action on the hypothalamus, where leptin receptors are found in cells that express appetite-regulating peptides. There is little evidence that leptin has a positive effect on the pituitary gonadotrophs and the gonads. There is also very little indication that leptin acts in an acute manner to regulate reproduction in the short term. It seems more likely that leptin is a 'barometer' of body condition that sends signals to the brain. Studies in vitro have shown negative effects on ovarian steroid production and there are no reports of effects on testicular function. Leptin concentrations in plasma increase in women during pregnancy, owing to production by the placenta but the functional significance of this is unknown. A number of factors that affect the production and action of leptin have yet to be studied in detail. (+info)
Developing hypothalamic dopaminergic neurones as potential targets for environmental estrogens.
Environmental chemicals which mimic the actions of estrogen have the potential to affect any estrogen responsive tissue. The aim of the present study was to investigate their potential to mimic the effects of 17beta-estradiol (E2) on developing primary rat hypothalamic dopaminergic (DA) neurones maintained in a chemically defined medium. We now show that both E2 and octylphenol (OP), but not the non-aromatizable androgen, dihydrotestosterone, enhanced the uptake of [3H]DA by the cultured cells, whereas they had no effect on the uptake of [14C]GABA. Although the sensitivity of responses may change with the age of the developing cultures, the dose response curves for E2 and OP were typically 'bell-shaped', with a rise in response followed by a decline to control levels with increasing concentrations. Effects were seen as low as 10(-14) M for E2 and 10(-11) M for OP. Responses to E2 (10(-12) M) and OP (10(-9) M) were reversed in the presence of the antiestrogen, ZM 182780 (10(-5) M). This study thus provides direct evidence, using a mechanistic rather than toxicological end-point, in support of the hypothesis that inappropriate exposure to environmental estrogens at critically sensitive stages of development, could potentially perturb the organisational activities of estrogen on selected neuronal populations in the CNS. (+info)
The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin.
Orexin-A and orexin-B (the hypocretins) are recently described neuropeptides suggested to have a physiological role in the regulation of food intake in the rat. We compared the orexigenic effect of the orexins administered intracerebroventricular (ICV) with other known stimulants of food intake, one strong, neuropeptide Y (NPY), and two weaker, melanin-concentrating hormone (MCH) and galanin. Orexin-A consistently stimulated food intake, but orexin-B only on occasions. Both peptides stimulated food intake significantly less than NPY, but to a similar extent to MCH (2 h food intake: NPY 3 nmol, 7.2+/-0.9 g vs saline, 1.5+/-0.2 g, P<0.001, MCH 3 nmol, 3.2+/-0.8 g vs saline, P<0.01, orexin-B 30 nmol, 2. 6+/-0.5 g vs saline, P=0.11) and to galanin (1 h food intake: galanin 3 nmol, 2.0+/-0.4 g vs saline, 0.8+/-0.2 g, P<0.05, orexin-A 3 nmol 2.2+/-0.4 g vs saline, P<0.01; 2 hour food intake: orexin-B 3 nmol, 2.4+/-0.3 g vs saline, 1.3+/-0.2 g, P<0.05). Following ICV orexin-A, hypothalamic c-fos, a maker of neuronal activation, was highly expressed in the paraventricular nucleus (PVN), and the arcuate nucleus (P<0.005 for both). IntraPVN injection of orexin-A stimulated 2 h food intake by one gram (orexin-A 0.03 nmol, 1.6+/-0. 3 g vs saline, 0.5+/-0.3 g, P<0.005). These findings support the suggestion that the orexins stimulate food intake. However, this effect is weak and may cast doubt upon their physiological importance in appetite regulation in the rat. (+info)
Somatostatin inhibits release of thyrotropin releasing factor from organ cultures of rat hypothalamus.
Somatostatin in concentrations of 10(-6) to 10(-8) M inhibited basal release of thyrotropin releasing factor in organ culture of rat hypothalamus. Norepinephrine in doses of 10(-4)--10(-6) M induced release of thyrotropin releasing factor which increased progressively with time and was temperature and dose dependent. This enhanced thyrotropin-releasing-factor release was inhibited by somatostatin at 10(-6)--10(-8) M. (+info)
Comparison of two aquaretic drugs (niravoline and OPC-31260) in cirrhotic rats with ascites and water retention.
kappa-Opioid receptor agonists (niravoline) or nonpeptide antidiuretic hormone (ADH) V2 receptor antagonists (OPC-31260) possess aquaretic activity in cirrhosis; however, there is no information concerning the effects induced by the chronic administration of these drugs under this condition. To compare the renal and hormonal effects induced by the long-term oral administration of niravoline, OPC-31260, or vehicle, urine volume, urinary osmolality, sodium excretion, and urinary excretion of aldosterone (ALD) and ADH were measured in basal conditions and for 10 days after the daily oral administration of niravoline, OPC-31260, or vehicle to cirrhotic rats with ascites and water retention. Creatinine clearance, serum osmolality, ADH mRNA expression, and systemic hemodynamics were also measured at the end of the study. Niravoline increased water excretion, peripheral resistance, serum osmolality, and sodium excretion and reduced creatinine clearance, ALD and ADH excretion, and mRNA expression of ADH. OPC-31260 also increased water metabolism and sodium excretion and reduced urinary ALD, although the aquaretic effect was only evident during the first 2 days, and no effects on serum osmolality, renal filtration, and systemic hemodynamics were observed. Therefore, both agents have aquaretic efficacy, but the beneficial therapeutic effects of the long-term oral administration of niravoline are more consistent than those of OPC-31260 in cirrhotic rats with ascites and water retention. (+info)