Effect of phenylephrine with and without atropine on QT dispersion in healthy normotensive men.

The present study examined if changes in cardiac after-load would affect QT interval dispersion. QT dispersion (QTd) on the 12-lead electrocardiogram is believed to be a noninvasive measure of electrical inhomogeneity in the heart and has recently been identified as a sensitive predictor of sudden cardiac death. In experimental models, an increase in cardiac afterload has been shown to alter action potential durations through mechanoelectrical feedback.

Influence of thyroid hormone on 5-HT(1A) and 5-HT(2A) receptor-mediated regulation of hippocampal BDNF mRNA expression.

The aim of the present study was to determine the influence of thyroid hormone, T3, on the regulation of hippocampal BDNF expression by 5-HT receptor agonists. Chronic T3 administration prior to treatment with the 5-HT(1A) agonist, 8-OH-DPAT, significantly decreased BDNF mRNA in the dentate gyrus region of the hippocampus. Administration of 8-OH-DPAT did not alter hippocampal BDNF mRNA expression in naive, euthyroid rats.

Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine.

The clinical efficacy of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) is normally attributed to their ability to increase brain 5-HT function although recent preclinical findings indicate that their selectivity for 5-HT over noradrenaline may be less evident in vivo. The present study investigated the effects of the SSRI, paroxetine, on extracellular levels of noradrenaline. Microdialysis was carried out in the hippocampus of the awake rat.

Affinity of (+/-)-pindolol, (-)-penbutolol, and (-)-tertatolol for pre- and postsynaptic serotonin 5-HT(1A) receptors in human and rat brain.

There is considerable interest in the use of drugs that selectively block presynaptic (somatodendritic) serotonin 5-HT(1A) receptors for the adjunctive treatment of major depressive disorder. The 5-HT(1A)/beta-adrenoceptor ligands (+/-)-pindolol, (-)-tertatolol, and (-)-penbutolol are currently under clinical investigation, and knowledge of their affinity at different populations of central 5-HT(1A) receptors is needed. Here we have determined the affinity of these drugs for presynaptic and postsynaptic 5-HT(1A) receptors in postmortem human and rat brain using receptor autoradiography and the selective 5-HT(1A) radioligand [(3)H]WAY-100635.

Neuroanatomical targets of anxiogenic drugs in the hindbrain as revealed by Fos immunocytochemistry.

It is speculated that specific hindbrain transmitter pathways centred on the periaqueductal gray and locus coeruleus are an important integrative neural substrate for the expression of anxiety and the somatic symptoms and cardiovascular changes that accompany severe anxiety states, such as in panic disorder. Here we investigated the effects of various drugs, known to induce panic in humans and to be anxiogenic in animals, on Fos expression in the periaqueductal gray, locus coeruleus and other parts of the rat hindbrain. The drugs tested were the benozodiazepine inverse agonist FG-7142, the alpha(2)-adrenoceptor antagonist yohimbine, the non-selective 5-hydroxytryptamine(2C) receptor agonist m-chlorophenyl piperazine, the adenosine antagonist caffeine and the cholecystokinin analogue BOC-CCK(4).

Neurochemical and electrophysiological studies on the functional significance of burst firing in serotonergic neurons.

We have previously described a population of 5-hydroxytryptamine neurons which repetitively fires bursts of usually two (but occasionally three or four) action potentials, with a short (<20 ms) interspike interval within a regular low-frequency firing pattern. Here we used a paradigm of electrical stimulation comprising twin pulses (with 7- or 10-ms inter-pulse intervals) to mimic this burst firing pattern, and compared the effects of single- and twin-pulse electrical stimulations in models of pre- and postsynaptic 5-hydroxytryptamine function. Firstly, we measured the effect of direct electrical stimulation (2 Hz for 2 min) of rat brain slices on efflux of preloaded [3H]5-hydroxytryptamine.

Repeated electroconvulsive shock promotes the sprouting of serotonergic axons in the lesioned rat hippocampus.

This study reports the effect of repeated electroconvulsive shock on the sprouting of 5-hydroxytryptamine neurons in the partly lesioned rat dorsal hippocampus. We have adopted a 5-hydroxytryptamine homotypic collateral sprouting model to examine whether electroconvulsive shock administration altered the rate of 5-hydroxytryptamine axonal reinnervation of the dorsal hippocampus. The 5-hydroxytryptamine innervation of hippocampus originates from the median raphe via the cingulum bundle and the fimbria-fornix.

Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension.

Therapeutic strategies against free radicals have mostly focused on the augmentation of antioxidant defenses (eg, vitamins C and E). A novel approach is to prevent free radical generation by the enzyme system xanthine oxidase. We examined whether the inhibition of xanthine oxidase with allopurinol can improve endothelial function in subjects with type 2 diabetes and coexisting mild hypertension compared with control subjects of a similar age.

Serotonergic regulation of mRNA expression of Arc, an immediate early gene selectively localized at neuronal dendrites.

Arc (activity regulated, cytoskeleton associated protein) is an effector immediate early gene that is selectively localized in the neuronal dendrites. Elevation of brain 5-HT by the combined administration of the monoamine oxidase inhibitor, tranylcypromine (TCP, 5 mg/kg, i.p.

Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure.

Background: The RALES study showed that spironolactone, added to conventional therapy for chronic heart failure, dramatically reduced mortality. We tested the hypothesis that this benefit was partially due to improvement in endothelial function and/or to amplified suppression of the vascular renin-angiotensin axis.

Methods And Results: We performed a randomized, placebo-controlled, double-blind crossover study on 10 patients with NYHA class II to III chronic heart failure on standard diuretic/ACE inhibitor therapy, comparing 50 mg/d spironolactone (1 month) versus placebo.

Costs associated with symptomatic systolic heart failure.

Objective: To investigate whether the extent of systolic dysfunction is a useful predictor of the costs of healthcare and social support for patients with heart failure.

Design: Cross-sectional study with collection of cost data attributed to management of heart failure in the previous year.

Setting: Four primary-care practices in Scotland.

Effect of 5-HT(1A) receptor ligands on Fos-like immunoreactivity in rat brain: evidence for activation of noradrenergic transmission.

This study investigated the effects of 8-OH-DPAT and various other 5-HT(1A) receptor agonists on brain noradrenergic transmission using Fos-like immunoreactivity (Fos-LI) as a marker of neural activation. Administration of 8-OH-DPAT (0.1 and 1 mg/kg) induced a marked and dose-related increase in the number of cells positive for Fos-LI in the locus coeruleus (LC), the main source of noradrenergic projections to the forebrain.

Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain.

The aim of the present study was to investigate whether changes in brain 5-HT concentrations affect the expression of BDNF mRNA in rat brain. Brain 5-HT concentration in the rat was elevated by combined treatment with tranylcypromine and L-tryptophan, tranylcypromine alone, by a single dose of the 5-HT releasing agent p-chloroamphetamine (PCA) or by the selective 5-HT reuptake inhibitor paroxetine. 5-HT was depleted by either multiple p-chlorophenylalanine (pCPA) or PCA injections.

Role of the medial prefrontal cortex in 5-HT1A receptor-induced inhibition of 5-HT neuronal activity in the rat.

1. We examined the involvement of the frontal cortex in the 5-HT2A receptor-induced inhibition of 5-HT neurones in the dorsal raphe nucleus (DRN) of the anaesthetized rat using single-unit recordings complemented by Fos-immunocytochemistry. 2.

Effects of (-)-tertatolol, (-)-penbutolol and (+/-)-pindolol in combination with paroxetine on presynaptic 5-HT function: an in vivo microdialysis and electrophysiological study.

The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) might be enhanced by co-administration of 5-HT1A receptor antagonists. Thus, we have recently shown that the selective 5-HT1A receptor antagonist, WAY 100635, blocks the inhibitory effect of an SSRI on 5-HT cell firing, and enhances its ability to elevate extracellular 5-HT in the forebrain. Here we determined whether the beta-adrenoceptor/5-HT1A receptor ligands (+/-)-pindolol, (-)-tertatolol and (-)-penbutolol, interact with paroxetine in a similar manner.

DD angiotensin-converting enzyme gene polymorphism is associated with endothelial dysfunction in normal humans.

A polymorphism within the angiotensin-converting enzyme (ACE) gene may increase the risk of myocardial infarction in individuals previously thought to be at low cardiovascular risk. The mechanism through which it exerts this effect is unknown but may be due to increased angiotensin II-induced nitric oxide (NO) breakdown and/or reduced bradykinin-mediated NO release. We investigated whether endothelial function was different between different ACE genotypes.

Acute renal failure due to retroperitoneal haematoma: a question of warfarin dispensation.

We report a case of an important and uncommon haemorrhagic complication in a patient receiving warfarin treatment. We reflect on the importance of close monitoring of anticoagulant therapy to prevent haemorrhagic complications and to ensure safety in longterm use.

Alteration in expression of G-protein-activated inward rectifier K+-channel subunits GIRK1 and GIRK2 in the rat brain following electroconvulsive shock.

G-protein-activated inward rectifier potassium channels are coupled to a number of neurotransmitter receptors, including some monoamine receptors. In the present study we have investigated the effect of electroconvulsive shock on gene expression of the G-protein-activated inward rectifier potassium channel subunits G-protein-coupled inward rectifier K+-channel (GIRK1) and GIRK2 in the rat brain using in situ hybridization and immunocytochemistry. Acute electroconvulsive shock (a single shock) increased GIRK2 expression while causing a transient reduction of the messenger RNA abundance of GIRK1 in granule cells of the dentate gyrus.

Delay in presentation of patients with acute stroke to hospital in Oxford.

We identified prospectively all patients (181 patients, 183 episodes) admitted to hospital in Oxford with acute stroke from 1 January to 30 June 1997. Data were inadequate in 30, leaving 153 episodes in 151 patients (63 men, 90 women). Structured interviews were used to investigate the timing of events preceding admission.

Endogenous angiotensin II and baroreceptor dysfunction: a comparative study of losartan and enalapril in man.

Aims: To assess the role of direct ATI receptor antagonism in baroreceptor modulation in man, and to perform a direct comparison of Ang II blockade at the receptor level with that of ACE inhibition.

Methods: Ten healthy male volunteers [mean age (s.d.

6-OHDA denervation substantially decreases DCC mRNA levels in rat substantia nigra compacta.

The function of deleted in colorectal cancer (DCC) protein, a member of the immunoglobulin superfamily of cell adhesion molecules, in the adult CNS is unknown. Recently the transcript encoding DCC has been shown to be expressed in a variety of rat brain regions, including the substantia nigra pars compacta and the striatum, which encompasses the nigrostriatal dopaminergic system. In the present study DCC mRNA expression in substantia nigra, striatum, dentate gyrus and piriform cortex was investigated in adult rats using in situ hybridization histochemistry following unilateral injections of 6-hydroxydopamine (6-OHDA) in the median forebrain bundle.

Abnormal function of potassium channels in platelets of patients with Alzheimer's disease.

Background: Reports of abnormalities of potassium-channel function in various cultured cells of Alzheimer's disease patients led us to attempt to characterise the pharmacological characteristics of the abnormal channel.

Methods: We studied platelets from 14 patients with Alzheimer-type dementia and 14 non-demented controls matched for age and sex. The effects of specific inhibitors of K+ channels on the efflux of rubidium-86 ions, a radioactive analogue of K+, from the platelets were measured.

Aldosterone blunts the baroreflex response in man.

1. Recent animal evidence suggests that aldosterone, like angiotensin II, may possess detrimental autonomic modulating properties. Aldosterone has been shown to impair the baroreflex response in animal models.