Effects of Selective 5-HT2 Receptor Antagonists on some Haemodynamic Changes Produced by Experimental Pulmonary Embolism in Rabbits
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Heparin, aspirin and the selective 5-HT2 antagonists ketanserin and pelanserin partially prevented the platelet-fall, rise en right ventricular pressure and systemic hypotension induced by the intravenous administration of an autologous clot or a suspension of collagen fibrils in rabbits. Whereas platelet-depletion nearly fully prevented the haemodynamic effects of the experimental thromboembolism. Intravenous 5-HT resembled the effects of pulmonary embolism and was only partially antagonized by the 5-HT2 receptor antagonists. These results suggest an additive role for platelet-derived vasoactive factors and thrombin in these experimental models and point out a role for 5-HT receptors eliciting reflex responses in the lung during the embolization.Keywords:
Ketanserin
SUMMARY Ketanserin may influence baroreflex function by blocking 5‐HT 2A receptors and/or α 1 ‐adrenoceptors through central and/or peripheral mechanisms. In the present study, we tested the hypothesis that the baroreflex sensitivity (BRS)‐enhancing effects of ketanserin are mediated by central 5‐HT 2A receptors in spontaneously hypertensive rats (SHR). Using a conjugate of a monoclonal antibody to the serotonin reuptake transporter (SERT) and the toxin saporin (anti‐SERT‐SAP), which specifically eliminates the neurons that express SERT, the effects of ketanserin (0.3 and 3.0 mg/kg, i.g.) on BRS, blood pressure (BP), heart period (HP) and blood pressure variability (BPV) were compared between conscious intact SHR and SHR pretreated with anti‐SERT‐SAP. Immunochemistry showed that, 2 weeks after intracerebroventricular injection of the toxin, 5‐HT expression was strikingly attenuated in the brain, whereas values of BRS, BPV and BP were similar to those in the sham group. In intact SHR, 0.3 mg/kg ketanserin significantly improved BRS (191% control) and reduced BPV without affecting BP; at 3.0 mg/kg, ketanserin significantly increased BRS (197% control) and decreased BPV and BP. In toxin‐pretreated SHR, only the high dose of ketanserin improved BRS (132% control), neither of the ketanserin doses reduced BPV, but both significantly decreased BP. We conclude that the BRS‐enhancing effects of ketanserin are mediated largely by central 5‐HT 2A receptors, whereas the antihypertensive effect of ketanserin persists even after destruction of serotonergic neurons in the central nervous system.
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Ketanserin, a 5HT2-receptor blocking drug was given to 17 patients with essential hypertension. Satisfactory control was achieved in 13 patients. Control was not as satisfactory when given once daily. There was no rebound effect when the drug was ceased. Side-effects were few. Ketanserin was a satisfactory drug to reduce blood pressure in patients with moderate hypertension.
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Cardiovascular effects in the rat of ketanserin, a novel 5-hydroxytryptamine receptor blocking agent
Abstract Following intravenous administration of ketanserin (0.3–10 mg kg−1) to conscious or anaesthetized normotensive and spontaneously hypertensive rats there were dose-dependent blood pressure reductions but no compensatory tachycardia. Intracerebroventricular administration of ketanserin (25–500 μg) had inconsistent and largely insignificant cardiovascular effects. In a dose range where it produces hypotension ketanserin antagonized the pressor responses to adrenaline and noradrenaline as well as to 5-hydroxytryptamine in monoamine depleted and spinalized rats. It is suggested that the hypotensive action of ketanserin in the rat does not involve a central mechanism but a peripheral α-adrenolytic action is implicated.
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Ketanserin
5-HT2 receptor
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Rats pre-treated with the quinazoline-dione derivative Ketanserin (1,25, 2,5 and 5 mg.kg-1, i.p.) (Janssen Pharmaceutica, Beerse, Belgium) present a more prolonged general anaesthesia and a more pronounced incapacity to stand up when injected with pentobarbital (30 to 120 mg.kg-1, i.p.). Cold shivering linked to Ketanserin is also suppressed.
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Male Wistar rats were treated with ondansetron (1 and 2 mg/kg s.c.), ketanserin (0.2, 1 and 5 mg/kg s.c.) or NAN-190 (1, 3 and 5 mg/kg i.p.) 15 min before acetylsalicylic acid (ASA, 400 mg/kg i.p.), and 30 min thereafter the pain threshold was evaluated. The antinociceptive activity of ASA in the hot-plate test was variously affected by ondansetron, ketanserin and NAN-190: at the highest dose (2 mg/kg s.c.) ondansetron abolished it while ketanserin (5 mg/kg s.c.) significantly reduced it, and NAN-190 (1–5 mg/kg) did not significantly modify the effect of ASA. Binding experiments indicate that both ondansetron and ketanserin completely prevented the decrease in the maximum number of 5-HT<sub>2</sub> receptors (B<sub>max</sub>) provoked by ASA. These data indicate that the central antinociceptive activity of ASA is modulated in a different manner by serotonin receptor antagonists, and that 5-HT<sub>2</sub> and 5-HT<sub>3</sub> receptors may exert a pivotal role in nociception, alone or in association.
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1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000 nM. 7. We conclude that 80-86% of the maximum 5-HT-evoked contraction of human temporal artery is mediated through 5-HT2A receptors, the remainder through 5-HT1-like-receptors, regardless of whether or not endothelium is functional. The 5-HT1-like-receptors are more likely to be 5-HT1D beta receptors than 5-HT1D alpha receptors and sumatriptan is a full agonist for these receptors. As found in arteries of other species, SK&F 103829 is a partial agonist for 5-HT2A receptors of human temporal artery.
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To investigate the role of the serotonergic nervous system in blood pressure regulation, 5μg of 5-hydroxytryptamine (5-HT) was given i.c.v. before and after 1 μg of i.c.v. xylamidine or 200μg of i.c.v. ketanserin or 200μg of i.v. ketanserin in conscious Wistar Kyoto rats. Also i.v. (0.5, 1, 2μg) or i.c.v. (1μg) phenylephrine (PHE) were given before and after 1μg of i.c.v. xyla-midine. I.c.v. 5-HT elicited a consistent pressor response of approximately 27mHg and slight decrease in heart rate. MAP and heart rate did not change after xylamidine or ketanserin. Whereas pressor response to i.c.v. 5-HT after i.c.v. ketanserin or i.c.v. xylamidine was suppressed, it did not change after i.v. ketanserin. Neither i.c.v. nor i.v. PHE-induced pressor response was influenced by i.c.v. xylamidine pretreatment. These data suggest that the central 5-HT2 receptor may subserve pressor function in rats.
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5-HT2 receptor
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Ketanserin (3 X 40 mg daily) was administered during 6 weeks in 14 patients with mild to moderate essential hypertension using a double-blind, placebo-controlled, crossover design. Ketanserin decreased (p less than 0.01) the recumbent blood pressure from 159/104 to 153/97 mm Hg and the recumbent heart rate from 75 to 72 beats/min. Platelet aggregation induced by 5-hydroxytryptamine (5-HT), whether or not amplified by threshold doses of collagen, was not inhibited; however, it was reduced in 10 normal volunteers after a single oral dose of 40 mg ketanserin. The results suggest that long-term treatment with ketanserin reduces blood pressure; whereas 5-HT receptor inhibition could not be demonstrated when assessed by platelet aggregation.
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