Ketanserin

Ketanserin, a serotonin receptor antagonist (S2), lowered blood pressure in patients with essential hypertension; at three months 72% (13/18) had a successful reduction in pressure. No marked orthostatic changes were noted. Older patients responded better when standing. Compared with metoprolol, ketanserin provided no significant difference in response at three months. With ketanserin, the heart rate was reduced only in the supine position, whereas it was reduced in the supine and standing positions with metoprolol. Response to ketanserin could not be predicted from baseline renin, aldosterone, or cortisol levels in blood, nor were there any changes in these factors or in plasma hydroxyindole levels with therapy. Ketanserin was generally well tolerated. Cholesterol values were significantly reduced with ketanserin, and there were no adverse hematologic or biochemical changes. Ketanserin should have a significant role in managing hypertension.

Several lines of evidence suggest that a disturbance of serotonin neuronal pathways may contribute to the pathogenesis of anorexia nervosa (AN). This study applied positron emission tomography (PET) to investigate the brain serotonin 2A (5HT2A) receptor, which could contribute to disturbances of appetite and behavior in AN. To avoid the confounding effects of malnutrition, we studied 16 women recovered from AN (REC AN, >1 year normal weight, regular menstrual cycles, no bingeing or purging) compared with 23 healthy control women (CW) using [18F]altanserin, a specific 5-HT2A receptor antagonist on PET imaging. REC AN women had significantly reduced [18F]altanserin binding relative to CW in mesial temporal (amygdala and hippocampus), as well as cingulate cortical regions. In a subset of subjects (11 CW and 16 REC AN), statistical parametric mapping (SPM) confirmed reduced mesial temporal cortex 5HT2A receptor binding and, in addition, showed reduced occipital and parietal cortex binding. This study extends research suggesting that altered 5-HT neuronal system activity persists after recovery from AN and may be related to disturbances of mesial temporal lobe function. Altered 5-HT neurotransmission after recovery also supports the possibility that this may be a trait-related disturbance that contributes to the pathophysiology of AN.

Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine...

Background Serotonin receptors may play an important role in the pathophysiology of affective disorders. We studied type-2 serotonin (5-HT2) receptors in the brain of patients with major depression. Method Using positron emission tomography (PET) and the selective radioligand [18F]altanserin, we investigated 5-HT2 receptor distribution in eight drug-free unipolar depressed patients and 22 healthy subjects. Data were analysed using Statistical Parametric Mapping 95. Results In depressed patients, [18F]altanserin uptake was significantly reduced in a region of the right hemisphere including the posterolateral orbitofrontal cortex and the anterior insular cortex. A trend to similar changes was found in the left hemisphere. No correlation was found between the uptake and the Hamilton rating scale score. Conclusions Pathophysiology of depression may involve changes in 5-HT2 receptor in brain regions selectively implicated in mood regulation.

Serotonin (5-hydroxytryptamine, 5-HT) is a vasoconstrictor and mitogen whose levels are elevated in diabetes. Previous studies have shown the presence of 5-HT2A, 5-HT2B, and 5-HT1B receptors in vascular smooth muscle cells (VSMCs). There are currently no data regarding 5-HT2B and 5-HT1B receptor activation of the JAK/STAT pathway in VSMCs and resultant potential alterations in 5-HT signaling in diabetes. Therefore, we tested the hypothesis that 5-HT differentially activates the JAK/STAT pathway in VSMCs under conditions of normal (5 mM) and high (25 mM) glucose. Treatment of rat VSMCs with 5-HT (10−6 M) resulted in time-dependent activation (∼2-fold) of JAK2, JAK1, and STAT1, but not STAT3 (maximal at 5 min, returned to baseline by 30 min). The 5-HT2B receptor agonist BW723C86 and the 5-HT1B receptor agonist CGS12066A (10−9–10−5 M, 5-min stimulation) did not activate the JAK/STAT pathway. Treatment with the 5-HT2A receptor antagonist ketanserin (10 nM) inhibited JAK2 activation by 5...

Porcine Pseudomonas adult respiratory distress syndrome (ARDS) has been shown to respond to combination therapy of 150 mg of cimetidine, 12.5 mg/kg of ibuprofen, 10 mg/kg of diphenhydramine, 0.2 mg/kg of ketanserin, and 30 mg/kg of methylprednisolone (CIDKM or Poly-5) given at 20 and 120 minutes after the onset of a continuous infusion of liver Pseudomonas aeruginosa, 5 X 10(8) colony-forming units (CFU) ml at 0.3 ml/20 kg/min. The present study was designed to determine the minimal, effective therapy by selective deletion of individual agents from CIDKM. Eight groups were studied: saline control (S, n = 9), Pseudomonas control (P, n = 8), and the following Pseudomonas plus treatment groups (each n = 5): CIDKM (cimetidine, ibuprofen, diphenhydramine, and ketanserin), CID (cimetidine, ibuprofen, and diphenhydramine), IC (ibuprofen and cimetidine), ID (ibuprofen and diphenhydramine), and CD (cimetidine and diphenhydramine). Pseudomonas alone produced severe ARDS with significant (p le...

The central nervous system control of food intake has been extensively studied, hence, several neurotransmitter systems regulating this function are now clearly identified, for example, the endocannabinoid and serotoninergic systems. The former stimulates feeding while the latter inhibits it. Oleamide (Ole) is a cannabimimetic molecule affecting both systems. In this work, we tested the orexigenic and anorectic potential of Ole when administered into the nucleus accumbens shell (NAcS), a brain region that has been related to the orexigenic effects of cannabinoids. Additionally, we tested if Ole administered into this nucleus affects the activity of the hypothalamic nuclei involved in feeding behaviour, just as other cannabinoids do. We found a hyperphagic effect of Ole that is mediated through CB1 activation. The combination of Ole and the CB1 antagonist, AM251, produced a hypophagia that was fully blocked by SB212084, a 5-HT2C receptor antagonist. We also show that blockade of 5-HT...

To examine the role of 5-HT2 receptors in the central cardiorespiratory network, and in particular the respiratory modulation of parasympathetic activity to the heart, we used an in vitro medullary slice that allowed simultaneous examination of rhythmic inspiratory-related activity recorded from hypoglossal rootlet and excitatory inspiratory-related neurotransmission to cardioinhibitory vagal neurons (CVNs) within the nucleus ambiguus (NA). Focal application of ketanserin, a 5-HT2 receptor antagonist, did not significantly alter the frequency of spontaneous excitatory postsynaptic excitatory currents (EPSCs) in CVNs in control conditions. However, ketanserin diminished spontaneous excitatory neurotransmission to CVNs during hypoxia. The inhibitory action of ketanserin was on 5-HT3 mediated EPSCs during hypoxia since these responses were blocked by the 5-HT3 receptor antagonist ondansetron. In addition, a robust inspiratory-related excitatory neurotransmission was recruited during re...

Alpha-methyl-5-HT is widely used as a high-affinity 5-HT(2) receptors agonist, though some studies have postulated that this drug also activates other serotonergic receptors. In the present work, we found that a wide range of concentrations of alpha-methyl-5-HT induced biphasic responses (contraction followed by relaxation) in guinea pig tracheal rings. The relaxing phase caused by 32microM alpha-methyl-5-HT was blocked by 0.1microM propranolol. Furthermore, during an ongoing histamine-induced contraction, alpha-methyl-5-HT (0.1-100microM) produced a concentration-dependent relaxation starting at 10microM. This relaxation was fully abolished by 0.1microM propranolol or 1microM ICI 118,551 (a selective beta(2)-adrenoceptor antagonist). Additionally, in electrophysiological recordings, 32microM alpha-methyl-5-HT also enhanced the membrane K(+) currents of single tracheal myocytes, an effect reverted by propranolol and ICI 118,551, and mimicked by 0.1microM salbutamol. Thus, we conclud...

The cardiovascular effects of the selective 5 HT2-serotonergic antagonist Ketanserin (cumulative doses of 0.01, 0.04, 0.16, 0.64 and 2.5 mg.kg-1 i.v. at 30 min intervals) were investigated in closed-chest, anesthetized dogs with spontaneously beating hearts (n = 7) and in dogs with a fixed heart rate (n = 7). Besides, the effects of Ketanserin (0.04 mg.kg-1 i.v.) during serotonin infusion (median: 20 micrograms kg-1.min-1 i.v.) were studied (n = 7). Ketanserin, starting at 0.04 mg.kg-1, lowers arterial blood pressure through a decrease in systemic vascular resistance. The increase in heart rate after the injection of 0.16 mg.kg-1 and higher doses is likely reflexogenic in nature and secondary to the decrease in systemic vascular resistance. Ketanserin also induces a positive inotropic effect, starting at a dose of 0.16 mg.kg-1 as indicated by the increase in LV dP/dt max, LV dP/dt max/P and maximum aortic blood flow velocity at constant heart rate and in the presence of no change or...

Sensory processing deficits are a hallmark of schizophrenia and can be demonstrated by recording auditory evoked potentials (AEPs) elicited in response to closely paired click stimuli. In nonschizophrenic humans, as well as in rats, the amplitude of the response to the second click is reduced (filtered) compared with the first. In contrast, schizophrenics, or rats treated with amphetamine, generate AEPs that have smaller amplitudes and show little or no reduction in the response to the second click. We sought to evaluate the role of 5-hydroxytryptamine2 5-HT2 receptors in auditory filtering. Male Sprague-Dawley rats were implanted with a skull screw electrode to permit chronic recording of AEPs from a point approximating human vertex. During subsequent recording sessions, pairs of clicks (a conditioning click followed by a test click) were presented 500 msec apart. Parameters of N40, a dominant midlatency component of the AEP, were examined to evaluate the effects of a 5-HT2 recepto...