Evaluation of the protective effects of histamine and 5-hydroxytryptamine receptor antagonists against the lethal toxicity induced by oxygen free radicals in rats.

Generation of oxygen free radicals (OFR) via intravenous administration of xanthine plus xanthine oxidase [X + XO], to Inactin(R) anesthetized rats produced intense respiratory distress. This effect led to death of more than 90% of the animals within a 120 min observation period. Several reports documented that the two autocoids, 5-hydroxytryptamine (5-HT) and histamine (H), can induce pulmonary and bronchiolar constriction and pulmonary edema. Hence, our present studies were conducted to investigate whether antagonists of 5-HT and histamine could provide protection from the lethal toxicity of the free radicals. Pretreatment of the rats with pyrilamine and cimetidine, H1 and H2 receptor antagonists, respectively, prolonged the duration of survival, but it failed to enhance net survival rate. In contrast, pretreatment of the rats with nonspecific 5-HT antagonists, methysergide and cyproheptadine, and a selective 5-HT(2) receptor antagonist, ketanserin, markedly enhanced the survival rate to 80-90%. These observations are consistent with data showing that 5-HT levels in the systemic arterial blood doubled within 5-10 min after administration of [X + XO]. These studies support the view that OFR-mediated respiratory distress is caused predominantly by 5-hydroxytryptamine and to a lesser extent by histamine.

Utility of check dams in dilution of fluoride concentration in ground water and the resultant analysis of blood serum and urine of villagers, Anantapur District, Andhra Pradesh, India.

High levels of fluoride (beyond 1.5 ppm) in ground water as source of drinking water are common in many parts of Andhra Pradesh, India, causing fluorosis. The study carried out in endemic Nalgonda District, Andhra Pradesh, has indicated that the fluoride-rich ground water present in the wells located down stream and close to the surface water bodies is getting diluted by the low-fluoride surface water. Encouraged by this result, check dams were constructed upstream of the identified marginally high fluoride bearing ground water zones in Anantapur District to reduce fluoride levels as an alternate solution for safe drinking water. In this paper, an attempt is made to study the utility and effect of these check dams in dilution of fluoride concentration in drinking water and its resultant impact on the health aspects of certain villagers of Anantapur District through the analysis of their blood serum and urine. Ground water samples from three fluoride-affected villages, blood and urine of males and females from the same villages were collected and analyzed for fluoride using ion selective electrode method. The results indicated that the fluoride levels in blood serum and urine of males in the age group of 5-11 years are found to be the highest. The concentration of fluoride in ground water is directly proportional to the concentration of fluoride in blood serum and urine. The concentration of fluoride in ground water with depth of the aquifer is a function of lithology, amount and duration of rainfall, rate of infiltration, level of ground water exploitation in the area etc. The construction of check dams upstream of the identified marginally high fluoride waters will not only cause additional recharge of ground water but also reduces the fluoride concentration eventually improving the health of the villagers.

Effects of salt rich diet in the obese Zucker rats: studies on renal function during isotonic volume expansion.

Obese Zucker rats (OZR) are hyperinsulenemic, hyperglycemic and dyslipidemic and develop salt dependent hypertension. Since salt sensitivity is considered to be due to impaired handling of renal sodium excretion, these studies were conducted in the obese and lean Zucker rats (LZR) anesthetized with Inactin to evaluate renal function under basal conditions and during acute isotonic fluid volume expansion (VE). Mean Arterial blood pressure (MBP), heart rate (HR), renal blood flow(RBF) and glomerular filtration rate (GFR) were not significantly different between the lean Zucker rats fed normal diet or that fed salt rich diet(8% NaCI). However, basal UV and UNaV were significantly greater in the LZR fed high salt. During VE essentially identical increases occurred in GFR, UV and UNaV in both the lean groups. In the OZR fed salt rich diet also, there were no significant changes in the heart rate, RBF and GFR. However, arterial blood pressure of the OZR fed salt rich diet was significantly greater than that of the OZR on the normal diet as well as that of both the lean groups. Also, as in the LZR, basal UV and UNaV were significantly greater in the salt fed obese rats. During volume expansion there were no impairments in the ability of the obese groups fed normal or salt rich diet to eliminate sodium and water during volume load. In fact, the net sodium and water excretions during and 60 min after VE in both the obese groups were significantly greater than that of corresponding lean groups. Furthermore, these values in the OZR fed salt rich diet were significantly greater than that of the obese rats on normal salt diet perhaps due to the contribution of pressure natriuretic mechanisms'. These data demonstrate that although OZR are salt sensitive, the renal mechanisms that would collectively respond to acute isotonic VE were fully functional. An unexpected and a novel finding in these studies is that the salt rich diet, in addition to increasing arterial blood pressure also significantly lowered plasma of insulin levels and enhanced glucose and cholesterol levels in the obese Zucker rats.

Influence of plasma insulin levels on antinatriuretic and vasoconstrictor actions of angiotensin-II.

The objective of the present study is to investigate whether plasma insulin levels play a role in the antinatriuretic and vasoconstrictor actions of angiotensin-II (Ang-II). We evaluated antinatriuretic function of endogenous Ang-II using an AT1 receptor antagonist, candesartan in anesthetized Sprague-Dawley rats. In control rats, candesartan produced significant increases in natriuresis and diuresis and these effects were abolished in streptozocin (STZ, 55 mg/kg i.p.) treated rats. Replacement of insulin restored these renal effects of candesartan. In a separate group of rats pretreated with an autonomic ganglionic blocker, pressor responses to Ang-II and norepinephrine (NE) before or after L-NNA, a nitric oxide synthase inhibitor were not affected by STZ treatment. However, insulin replacement greatly augmented these responses. These data provide evidence in vivo showing that insulin can enhance both antinatriuretic and vasoconstrictor actions of Ang-II. Hence exaggerated renal and vascular effects of Ang-II in the obese Zucker rats observed in our previous studies may be related to hyperinsulimemia and this phenomena could contribute to salt-sensitivity and development of sustained hypertension.

Effects of fenoldopam, a dopamine D-1 agonist, and clevidipine, a calcium channel antagonist, in acute renal failure in anesthetized rats.

The present studies were conducted to: a) comparatively evaluate the effects of clevidipine, a new dihydropyridine calcium antagonist, and fenoldopam, a dopamine (D-1) receptor agonist on basal renal function, and b) to determine the efficacy of these agents in protecting renal function in an experimental model of ischemia/reperfusion (I/R) induced acute renal failure in rats. Infusions of either clevidipine or fenoldopam (5.0 nmol/kg(-1) min(-1) i.v. for 60 min) produced significant increases in urine flow (UV), urinary sodium excretion (UNaV), and fractional excretion of sodium (FENa) in inactin anesthetized rats. Unlike clevidipine, fenoldopam also produced significant increases in renal blood flow (RBF) and urinary potassium excretion (UKV). In a separate series, unilateral renal failure was induced in anesthetized rats by occluding the left renal artery for 40 min followed by reperfusion. In this model, there was a 70-75% reduction in the GFR that was paradoxically associated with several fold increases in UV, UNaV, and FENa in the vehicle treated group. In two separate groups, infusions of neither clevidipine nor fenoldopam (5.0 nmol/kg(-1) min(-1)) for 60 min beginning 10 min before reperfusion, improved filtration fraction. However, clevidipine treatment markedly improved tubular function in that loss of sodium and water were significantly attenuated and UV and UNaV were restored towards basal levels. In contrast, in the fenoldopam group, tubular function was further deteriorated as evidenced by exacerbated losses of sodium and water. These observations suggest that whereas both clevidipine and fenoldopam were potent natriuretic agents, only the calcium antagonist was effective in preserving renal function in the present experimental model of ischemic renal failure.

Enhanced BK-induced calcium responsiveness in PC12 cells expressing the C100 fragment of the amyloid precursor protein.

Several lines of evidence have implicated the amyloid precursor protein (APP) and its metabolic products as key players in Alzheimer's disease (AD) pathophysiology. The approximately 100 amino acid C-terminal fragment (C100) of APP has been shown to accumulate intracellularly in neurons expressing familial AD (FAD) mutants of APP and to cause neurodegeneration when expressed in transfected neuronal cells. Transgenic animals expressing this fragment in the brain also exhibit some neuropathological and behavioral AD-like deficits. Here, we present evidence that PC12 cells expressing the C100 fragment either via stable transfections or herpes simplex virus-mediated infections show alterations in calcium handling that are similar to those previously shown in fibroblasts from AD patients. This alteration in calcium homeostasis may contribute to the deleterious effects of C100 in PC12 cells. Our data also lend support for a pathophysiological role for C100 since it induces an alteration thought to play an important role in AD pathology.

Ionic and signal transduction alterations in Alzheimer's disease: relevance of studies on peripheral cells.

Several lines of evidence indicate that Alzheimer's disease (AD) has systemic expression. Systemic changes are manifested as alterations in a number of molecular and cellular processes. Although, these alterations appear to have little or no consequence in peripheral systems, their parallel expression in the central nervous system (CNS) could account for the principal clinical manifestations of the disease. Recent research seems to indicate that alterations in ion channels, calcium homeostasis, and protein kinase C (PKC) can be linked and thereby constitute a model of pathophysiological relevance. Considering the difficulties of studying dynamic pathophysiological processes in the disease-ridden postmortem AD brain, peripheral tissues such as fibroblasts provide a suitable model to study molecular and cellular aspects of the disease.

Restoration of TEA-induced calcium responses in fibroblasts from Alzheimer's disease patients by a PKC activator.

Several alterations in fibroblasts of Alzheimer's disease (AD) patients have been described, including alterations in calcium regulation, protein kinase C (PKC), and potassium (K+) channels. Studies have also found reduced levels of the alpha isoform of PKC in brains and fibroblasts of AD patients. Since PKC is known to regulate ion channels, we studied K+ channel activity in fibroblasts from AD patients in the presence of (2S, 5S)-8-(1-decynyl)benzolactam (BL), a novel activator of PKC with improved selectivity for the alpha, beta, and gamma isoforms. We present evidence for restoration of normal K+ channel function, as measured by TEA-induced [Ca2+]i elevations, due to activation of PKC by BL. Representative patch-clamp data further substantiate the effect of BL on restoration of 113pS K+ channel activity. Immunoblotting analyses using an alpha-isozyme-specific PKC antibody confirm that BL-treated fibroblasts of AD patients show increased PKC activation. The present study suggests that PKC activator-based restoration of K+ channels may offer another approach to the investigation of AD pathophysiology, which in turn could lead to the development of a useful model for AD therapeutics.

Impaired odour discrimination on desynchronization of odour-encoding neural assemblies.

Stimulus-evoked oscillatory synchronization of neural assemblies has been described in the olfactory and visual systems of several vertebrates and invertebrates. In locusts, information about odour identity is contained in the timing of action potentials in an oscillatory population response, suggesting that oscillations may reflect a common reference for messages encoded in time. Although the stimulus-evoked oscillatory phenomenon is reliable, its roles in sensation, perception, memory formation and pattern recognition remain to be demonstrated--a task requiring a behavioural paradigm. Using honeybees, we now demonstrate that odour encoding involves, as it does in locusts, the oscillatory synchronization of assemblies of projection neurons and that this synchronization is also selectively abolished by picrotoxin, an antagonist of the GABA(A) (gamma-aminobutyric acid) receptor. By using a behavioural learning paradigm, we show that picrotoxin-induced desynchronization impairs the discrimination of molecularly similar odorants, but not that of dissimilar odorants. It appears, therefore, that oscillatory synchronization of neuronal assemblies is functionally relevant, and essential for fine sensory discrimination. This suggests that oscillatory synchronization and the kind of temporal encoding it affords provide an additional dimension by which the brain could segment spatially overlapping stimulus representations.

Olfactory conditioning in the honey bee, Apis mellifera: effects of odor intensity.

Any odor-guided behavior might require generalization and/or discrimination over a wide range of odorant intensities. Proboscis extension conditioning (PEC) and electroantennogram (EAG) assays were used to investigate stimulus-intensity dynamics during olfactory processing in the honey bee. Experiments that tested generalization involved conditioning to one odorant concentration and either testing with a different odorant or with different concentrations of the same odorant. At low training concentrations, responses to either a novel odorant or to higher concentrations of the same odorant resulted in strong generalization. At higher training concentrations, significantly less generalization was observed to a novel odorant or to lower concentrations of the same odor. EAG analyses indicate that asymmetric generalization could arise due to long-term adaptation of peripheral receptor neurons. Discrimination experiments showed that relatively higher odorant concentrations associated with an appetitive reinforcer could usually be discriminated from a lower concentration that was associated with punishment, but not vice versa. Although sensory modulation in peripheral (sensory) processes might be sufficient to account for discrimination of a high from a low concentration, discrimination of low from high concentrations point to the involvement of central processes.

Nephrogenic adenoma: clinical features and therapeutic considerations.

Nephrogenic adenoma is a benign metaplastic lesion that usually responds to endoscopic treatment. Although occasionally it has been present simultaneously with another malignancy there has been no evidence that a nephrogenic adenoma has ever transformed into a carcinoma. The symptoms of a nephrogenic adenoma can be severe but these lesions can be treated with transurethral surgery. The lesions can occur throughout the bladder and in the urethra. They usually are associated with trauma to the urothelium. Postoperative followup is needed because these lesions tend to have a symptomatic recurrence. An increased awareness of nephrogenic adenoma by urologists and pathologists may lead to its more frequent diagnosis.