Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective putative 5-HT1A receptor agonist, has been investigated in the rat. Comparisons were made with clonidine, a centrally acting hypotensive agent with negligible affinity for 5-HT receptors. In conscious, spontaneously hypertensive (SH) rats, 8-OH-DPAT caused dose-related and sustained falls in blood pressure and heart rate that were unaffected by depletion of brain 5-HT by p-chlorophenylalanine. 8-OH-DPAT caused hypotension and bradycardia in anesthetized normotensive rats. In pithed rats, 8-OH-DPAT neither lowered blood pressure nor affected the cardiovascular response to spinal sympathetic stimulation or to phenylephrine. The response to 8-OH-DPAT was blocked selectively by intracisternal injection of 8-methoxy-2-(N-2-chloroethyl-N-n propyl) amino tetralin (8-MeO-CIEPAT), a putative irreversible 5-HT1A receptor antagonist, and was abolished in animals whose central monoamine transmitter stores were depleted selectively by combined treatment with DL-alpha-monofluoromethyl-dopa and dopamine. The cardiovascular response to 8-OH-DPAT was inhibited selectively by metergoline, methiothepin, and 8-MeO-CIEPAT; it was nonselectively inhibited by (+/-)-pindolol, (+/-)-cyanopindolol, buspirone, yohimbine, idazoxan, and WY 26392; and was unaffected by prazosin and cis-flupenthixol. These results establish that the cardiovascular response to 8-OH-DPAT in the rat is centrally mediated and point to the putative 5-HT1A receptor as the key site involved. An indirect link involving a catecholaminergic mechanism is suggested by the fact that alpha 2-adrenoceptor antagonists are also inhibitory despite 8-OH-DPAT having no direct agonist effects at alpha 2-adrenoceptors per se.
J Cardiovasc Pharmacol 1987 Mar
PMID:Cardiovascular response to 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in the rat: site of action and pharmacological analysis. 243

Serotonin (5-hydroxytryptamine; also called 5-HT) modifies cardiovascular activity by central as well as peripheral sites of action. When 5-HT is injected within the central nervous system, depending upon the dose and site of administration, either a pressor or a depressor effect is observed. Recent findings suggest that this depressor effect may be mediated by central "5-HT1-like" receptors, since certain compounds that exhibit a high affinity for the 5-HT1A binding site can reduce blood pressure by a central action in both hypertensive and normotensive animals. Peripherally, 5-HT elicits vasodilatation (both directly and indirectly via presynaptic sympathoinhibition and release of vasodilator substances from endothelium) or vasoconstriction (with associated amplification of noradrenaline response) of mainly "large" conductance arteries mediated by, respectively, "5-HT1-like" and 5-HT2 receptors. Of the various antagonists at 5-HT receptors, it is only ketanserin that effectively lowers arterial blood pressure. However, since it is unlikely that the very low concentrations of 5-HT in plasma exert a significant influence on the maintenance of peripheral vascular resistance, the blockade of 5-HT2 receptors by ketanserin does not seem to explain the reduction of blood pressure in hypertension. Indeed, apart from the undoubtedly potent 5-HT2 receptor blockade, ketanserin also has alpha 1-adrenoceptor antagonist, central vasomotor depressant, and "direct" vasodilator properties, which can explain its antihypertensive action.
J Cardiovasc Pharmacol 1987
PMID:Serotonin agonists and antagonists in experimental hypertension. 244 59

The subdivision of serotonin (5-HT) receptors into three classes, designated 5-HT1, 5-HT2, and 5-HT3, has been based on radioligand binding studies and experiments in isolated tissues. As a result of radioligand binding studies, two types of 5-HT recognition sites have been postulated. One site specifically labeled by [3H]5-HT was termed 5-HT1, and the other one labeled by [3H]spiperone or [3H]ketanserin was designated 5-HT2. The pharmacological properties of the latter sites are obviously identical to those of the majority of the classical "D" receptors, whereas a smaller proportion of "D" receptors resemble the 5-HT1 type. Hence, according to the current definition, 5-HT1 and 5-HT2 receptors mediate effects previously ascribed to "D" receptors. Three subtypes of 5-HT1 binding sites, designated 5-HT1A, 5-HT1B, and 5-HT1C, can now be distinguished by improved binding assay with rather selective radioligands. The identity of a given 5-HT binding site with a 5-HT receptor was suggested by correlating the agonists' and antagonists' affinities for the binding site with their potencies to produce certain effects. This was further confirmed by the development of rather selective agonists and antagonists. A third class of 5-HT receptors, the "M" receptors, which are now designated 5-HT3 in order to distinguish them from muscarinic cholinoceptors, were identified in functional in vitro experiments. They are present on terminals of sympathetic and parasympathetic nerves and on afferent nerve fibers. All three receptor classes are involved in cardiovascular regulation.
J Cardiovasc Pharmacol 1987
PMID:Classification of serotonin receptors. 244 65

This study investigated the central hypotensive effects of drugs that possess a high affinity for central 5-hydroxytryptamine (5-HT1A) binding sites; (+)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), N,N-dipropylcarboxamidotryptamine (DP-5-CT), erythro-1-(1-[2(1,4-benzodioxan-2-yl)-2-hydroxyethyl]- 4-piperidyl)-2-benzimidazolinone (R28935) and urapidil proved to possess high affinity and selectivity for central 5-HT1A binding sites, labeled by [3H]8-OH-DPAT. (+)8-OH-DPAT (0.1-10 micrograms/kg) given through the left vertebral artery of chloralose-anesthetized cats, lowered blood pressure by a biphasic dose-response curve. When given systemically, 10- to 100-fold higher doses of (+)8-OH-DPAT were necessary to obtain the same hypotensive effect when compared with central administration. Besides 8-OH-DPAT, R28935, DP-5-CT and urapidil also lowered blood pressure by a central mechanism in doses that were ineffective when given systemically. The central hypotensive effect of 0.3 micrograms/kg (+)8-OH-DPAT, 3 micrograms/kg DP-5 CT, and 3 micrograms/kg R28935 could be blocked by 100 micrograms/kg (-)pindolol, indicating that central 5-HT1A receptors are involved. High doses of (+)8-OH-DPAT (3-10 micrograms/kg) can also lower blood pressure by activating central alpha 2-adrenoceptors. The hypotensive effect of 300 micrograms/kg urapidil given through the vertebral artery could not be blocked by (-)pindolol. These results indicate the involvement of central 5-HT1A receptors in the mechanism of the central hypotensive activity of (+)8-OH-DPAT, DP-5-CT, and R28935.
J Cardiovasc Pharmacol 1988 Apr
PMID:Central 5-HT1A receptors and the mechanism of the central hypotensive effect of (+)8-OH-DPAT, DP-5-CT, R28935, and urapidil. 245 46

Simultaneous recordings of cardiac, splanchnic, and renal nerve activity, blood pressure, heart rate, and femoral arterial conductance were made in anaesthetised paralysed cats. Cumulative dose-response curves were constructed for either cinanserin or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in animals that had received a maximal hypotensive dose of prazosin that had, in addition to decreasing blood pressure, decreased heart rate and background activity in all three nerves. Cinanserin failed to further affect these parameters. However, 8-OH-DPAT caused further falls in blood pressure and heart rate and virtually abolished the remaining activity in all nerves. Part of the extra decrease in heart rate was shown to be due to an increase in vagal tone. It was concluded that if a drug has both an agonist action at the putative 5-HT1A receptors and an antagonist action at alpha 1-adrenoceptors, it is a more potent hypotensive agent than if it only blocks alpha 1-adrenoceptors. These observations do not support a role for 5-HT2 receptors in the maintenance of blood pressure.
J Cardiovasc Pharmacol 1988
PMID:Are drugs that act both on serotonin receptors and alpha 1-adrenoceptors more potent hypotensive agents than those that act only on alpha 1-adrenoceptors? 245 11

In light of observed amplificatory interactions between serotonergic and adrenergic stimuli in functional studies on vascular tissue and platelets, we investigated the distinction and possible interactions between alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic and 5-HT1A-, 5-HT1B-, and 5-HT2-serotonergic receptor binding sites. Therefore, the binding affinities of archetypes of adrenergic and serotonergic agonists and antagonists for the various receptors were measured. Only the alpha 1-blocker prazosin revealed great specificity for alpha 1-adrenergic receptors; the other investigated antagonists and agonists showed cross-reactivity with adrenergic and serotonergic receptors in various combinations. Using [3H]ketanserin binding to rat frontal cortex and [3H]prazosin binding to rat cortex tissue as models for 5-HT2-serotonergic and alpha 1-adrenergic receptors, respectively, we did not find cooperative effects of epinephrine on the binding of 5-hydroxytryptamine or ketanserin to 5-HT2 receptors nor of 5-hydroxytryptamine on the binding of epinephrine or prazosin to alpha 1-adrenergic receptors. It was concluded that the various adrenergic and serotonergic receptor subtypes (a) have distinct drug binding properties; (b) occur on various central and peripheral tissues; (c) co-occur on some tissues; (d) each subtype mediates several distinct functions; (e) distinct receptors may mediate similar functions; (f) the drug binding properties of a particular receptor remains the same in different tissues, but purported alpha 2-like receptors on platelets reveal some differences from alpha 2-receptors in the brain and other peripheral tissues; (g) the various receptor subtypes appear to be distinct molecular entities; and (h) in brain tissue there is no evidence for the occurrence of direct adrenergic-serotonergic receptor-receptor interactions at the level of the binding sites.
J Cardiovasc Pharmacol 1988
PMID:Distinction between adrenergic and serotonergic receptor subtypes: specificity of drugs and absence of cooperative interactions between adrenergic and serotonergic receptor binding sites. 245 21

The systemic and regional hemodynamic effects of the centrally acting putative 5-HT1A receptor agonist flesinoxan (3, 10, 30, and 100 micrograms/kg) were investigated in the anesthetized cat and compared with those of 8-hydroxy-2(di-n-prophylamino) tetralin (8-OH-DPAT 3, 10, 30, and 100 micrograms/kg) and clonidine (0.3, 1, 3, and 10 micrograms/kg). Cardiac output (CO) was measured with a precalibrated electromagnetic flow probe placed on the ascending aorta, and regional blood flows and conductances were measured with radioactive microspheres. Flesinoxan and 8-OH-DPAT caused a decrease in blood pressure (BP 44 and 37%, respectively, at 100 micrograms/kg) mainly resulting from an increased peripheral vascular conductance; in the case of 8-OH-DPAT, however, a reduction in CO (34%) also contributed. Clonidine decreased BP (12% at 10 micrograms/kg) by reducing CO (31%). All three drugs decreased heart rate (HR). Flesinoxan and 8-OH-DPAT decreased tissue perfusion in the heart, lungs, gastrointestinal tract, eyes, and skin, but both renal and cerebral blood flows were preserved as a result of increased vascular conductances. These two drugs also redistributed intrarenal blood flow from the outer cortex toward the inner cortex and medulla. Low doses of clonidine tended to increase but higher doses decreased organ blood flows, especially to the heart, lungs, liver, and eyes. Clonidine did not redistribute intrarenal blood flows. These results establish that the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT elicited a systemic and regional hemodynamic profile that differs from that of the alpha 2-adrenoceptor agonist clonidine.
J Cardiovasc Pharmacol 1989 Nov
PMID:Systemic and regional hemodynamic effects of the putative 5-HT1A receptor agonist flesinoxan in the cat. 248 Nov 92

The vascular effects of serotonin (5-hydroxytryptamine, 5-HT) are complex and heterogeneous. In human forearm, we showed that low doses of 5-HT cause marked but transient vasodilatation followed by a persistent vasodilator response. In in vitro and in animal experiments, 5-HT induced release of nitric oxide (NO) through stimulation of endothelial 5-HT1-like receptors. In the present study, we investigated involvement of the "NO pathway" and possible involvement of the 5-HT1A receptor subtype in 5-HT-induced persistent vasodilator response. In 8 healthy volunteers, we infused 5-HT (0.1, 0.3, and 1 ng/kg/min) and the selective 5-HT1A receptor agonist flesinoxan (15, 45, and 150 ng/kg/min) intraarterially (i.a.) with NG-monomethyl-L-arginine (L-NMMA 30 micrograms/kg/min) or saline. Forearm blood flow (FBF) was measured by automated R-wave-triggered venous occlusion plethysmography. Forearm vascular resistance (FVR) was derived from simultaneously recorded i.a. blood pressure (BP) and FBF. 5-HT dose-dependently decreased FVR (p < 0.001). The persistent vasodilator response to 5-HT appears to be mediated by NO release, as suggested by its complete abolition by L-NMMA (p < 0.001). Flesinoxan decreased FVR slightly, but only at high doses (p < 0.05). The present findings indicate that 5-HT1A receptors are not functionally involved in 5-HT-mediated vasodilatation in human forearm.
J Cardiovasc Pharmacol 1994 Sep
PMID:No functional involvement of 5-hydroxytryptamine1A receptors in nitric oxide-dependent dilatation caused by serotonin in the human forearm vascular bed. 752 2

The central regulation of blood pressure and other cardiovascular parameters may involve the baroreceptor reflex are, including both adrenergic and serotonergic pathways, as well as amino acids, as neurotransmitters. Both adrenergic and serotonergic pathways have been recognized as targets for clinically relevant, centrally acting antihypertensives, such as clonidine, guanfacine, and alpha-methyl-DOPA. The central components of the hybrid drugs urapidil and ketanserin also involve serotonergic pathways and receptors. For urapidil the stimulation of 5-HT1A-receptors is assumed to induce peripheral sympathoinhibition, whereas for ketanserin the central mechanism is unknown in detail. More recently central imidazoline (I1) receptors have been proposed as the major target for the newer antihypertensives rilmenidine and moxonidine. Clonidine, however, is assumed to be mixed I1- and alpha2-receptor agonist. The distinction between central I1- and alpha2-receptors may potentially offer the design of new antihypertensives, acting like clonidine but with fewer side effects. Finally, the amino acid pathways should be considered as potential targets for centrally acting antihypertensives. Experimental compounds on this basis are available but clinical implications appear to be very remote. In the present survey an outline is given of the various pathways, neurotransmitters, and receptors involved in the central regulation of blood pressure. The different types of centrally acting antihypertensives are subsequently discussed on this basis.
Cardiovasc Drugs Ther 1994 Dec
PMID:Different types of centrally acting antihypertensives and their targets in the central nervous system. 774 57

The effects of two centrally acting antihypertensive agents, clonidine (0.1 mg/kg/day s.c.) and flesinoxan (1 mg/kg/day s.c.), on short-term blood pressure variability (BPV) were investigated in conscious spontaneously hypertensive rats (SHRs). The drugs were infused subcutaneously during 24 h and 4 weeks by osmotic minipumps. BPV was characterized by spectral analysis. In conscious SHRs, clonidine significantly and preferentially reduced the low frequency (LF; 0.25-0.75 Hz) oscillations of mean arterial pressure (MAP) in short-term (24 h) and long-term (4 weeks) treatments but significantly decreased MAP level only in short-term treatments. In contrast, flesinoxan significantly reduced MAP level whatever the duration of infusion but decreased LF-MAP only in short-term treatments. These results show that centrally mediated inhibition of sympathetic tone by stimulation of either alpha2-adrenoceptors or 5-HT1A (serotonin) receptors can reduce BPV. This effect is independent of the modifications in BP level. The effects of the drugs on baroreceptors may also contribute to the decrease in BPV. The dual properties of clonidine (alpha2-adrenoceptors and imidazoline receptors) may account for its differential effects on BP level and BPV.
J Cardiovasc Pharmacol 1997 Aug
PMID:Effects of clonidine and flesinoxan on blood pressure variability in conscious spontaneously hypertensive rats. 926 53


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