Antihypertensive Action and Serotonin-Induced Platelet Aggregation During Long-Term Ketanserin Treatment in Hypertensive Patients
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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.Keywords:
Ketanserin
Crossover study
When the local concentration of serotonin is raised during platelet aggregation, the direct effect of serotonin on vascular smooth muscle is to activate the contractile process. Serotonin also amplifies the constrictor responses to other neurohumoral mediators. Vascular smooth muscle can become hyperreactive to the vasoconstrictor effects of serotonin both acutely (e.g., local cold, hypoxia) and chronically (e.g., atherosclerosis, hypertension). Vasodilator responses to serotonin can be unmasked by blockade of its vasoconstrictor component. The inhibition by ketanserin of the various vasoconstrictor and platelet-aggregating effects of serotonin presumably contributes to the therapeutic effects of the compound.
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Abstract In most vascular beds, receptors mediating contraction to serotonin are of the 5HT 2 type (defined by [ 3 H]‐spiperone binding in brain tissue). Research on vascular serotonin receptors has been prompted by the development of ketanserin, a potent 5HT 2 ‐receptor antagonist. Recent data suggest that ketanserin also possesses α‐receptor antagonist activity and that this property accounts for its antihypertensive activity in spontaneously hypertensive rats (SHR). The multiple blocking activities of ketanserin have prompted a search for more selective 5HT 2 ‐receptor antagonists to elucidate the role of vascular serotonin receptors in blood pressure regulation. Consequently, 1‐(1‐naphthyl)piperazine (1‐NP) and LY53857, an ergoline derivative, have been identified as potent and highly selective 5HT 2 ‐receptor antagonists in vascular tissue. 1‐(1‐napthyl)piperazine and LY53857 show approximately 2,000‐ and 300,000‐fold greater affinity, respectively, for 5HT 2 ‐receptors than for α‐receptors compared to a 60‐fold selectivity of ketanserin. However, neither 1‐NP nor LY53857 lowered blood pressure in the SHR in doses that markedly shifted the pressor response to serotonin but did not antagonize α‐adrenergic receptors. Furthermore, blood pressure reduction in the SHR correlated poorly with the ability of several “5HT 2 ‐receptor antagonists” to bind to 5HT 2 ‐receptors and correlated extremely well with the binding of these agents to α‐receptors. Thus, in SHR, 1) antihypertensive activity of ketanserin occurred in doses that block α‐receptors and not at lower doses that block serotonin receptors, 2) more specific serotonin antagonists that did not block α‐receptors in vivo did not lower blood pressure, and 3) the reduction in blood pressure produced by a series of serotonin receptor antagonists correlated with their ability to block α‐receptors but not 5HT 2 ‐receptors.
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5-HT1 receptor
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Abstract This unit describes assays for measuring the binding of radioligands to two major types of receptors for 5‐hydroxytryptamine (5‐HT or serotonin), 5‐HT 1 and 5‐HT 2 receptors, in homogenates of brain tissue or cloned into cells in culture. The specific receptor subtypes covered are 5‐HT 1A , 5‐HT 1B , 5‐HT 2A , and 5‐HT 2C . In addition, methodology for using quantitative autoradiography to measure radioligand binding to serotonin receptors in brain slices is described. Protocols are provided for characterization of both saturation and competition binding assays, and instructions for data analysis of these assays is also described. In addition, methodology is provided for the quantification (image analysis) of radioligand binding in brain tissue sections to determine receptor density, preparation of rat brain sections for quantitative autoradiography, and thionin staining of thaw‐mounted tissue sections to define certain brain regions.
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SUMMARY 1. The role of serotonin (5HT) in the pathogenesis of ACTH‐induced hypertension in sheep has been examined. 2. The pressor responses to injections of 5HT (0.1–30 μg/kg) were similar in normotensive and hypertensive sheep. 3. Prior treatment with the 5HT 2 receptor antagonist ketanserin had no effect on the development of hypertension produced by ACTH administration.
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Employing C14-glucose and C14-serotonin (5HT) as precursors, we have synthesized desoxyfructo-5HT [1-desoxy-1-(5-hydroxytryptamine)-D-fructose] labelled either in the sugar or 5HT moieties, and examined the uptake of the labelled substrate by washed human platelets. Desoxyfructo-5HT appears to interact with the 5HT uptake site, effectively inhibiting the uptake of H3-5HT. However, our data indicate that contrary to published reports, the entry of desoxyfructo-5HT into platelet vesicles or cytoplasm is negligible.
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A series of photolabile o-nitrobenzyl derivatives of serotonin (caged serotonin) were synthesized: the amine-linked serotonin derivatives N-(2-nitrobenzyl) serotonin (Bz-5HT) and N-(alpha-carboxy-2-nitrobenzyl) serotonin (N-CNB-5HT), and O-alpha-carboxy-2-nitrobenzyl) serotonin (O-CNB-5HT), which has the caging group attached to the phenolic OH group. All the derivatives released free serotonin when excited by 308-nm or 337-nm laser pulses. The time constant of serotonin release from N-CNB-5HT was 1. 2 ms, with a quantum yield of 0.08. This is too slow for rapid chemical kinetic measurements. O-CNB-5HT is suitable for transient kinetic investigations of the serotonin 5-HT(3) receptor. It released serotonin with a time constant of 16 micros and a quantum yield of 0.03. The biological properties of O-CNB-5HT were evaluated, and the applicability of the compound for kinetic studies of the 5-HT(3) receptor was demonstrated. O-CNB-5HT does not activate the 5-HT(3) receptor by itself, nor does it modulate the response of a cell when co-applied with serotonin. When irradiated with a 337-nm laser pulse, O-CNB-5HT released free serotonin that evoked 5-HT(3) receptor-mediated whole-cell currents in NIE-115 mouse neuroblastoma cells.
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