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)

Serotonin (5-HT) plays a major role as a neurotransmitter in the brain and large amounts are found in blood platelets. 5-HT release can be induced by action potentials invading the nerve terminals and by platelet aggregation. The targets of 5-HT are specific receptors mediating a wide variety of central and peripheral effects. For two of the main 5-HT receptor classes, the 5-HT2 and 5-HT3 receptors, selective antagonists are available, but this is not the case for the heterogeneous population of 5-HT1 receptors. In addition, the drugs with antagonistic properties at the 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT1D receptors block other 5-HT receptors or even entirely different receptors (e.g., beta-adrenoceptors); as a rule, they do not discriminate between the four 5-HT receptor subtypes. Identification and characterization of these subtypes is further complicated by the fact that, with the exception of drugs activating 5-HT1A receptors, e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and urapidil; no subtype-selective agonists are available. Hence, the pharmacological characterization of a 5-HT1 receptor must be based on experiments with several putative 5-HT receptor agonists and antagonists with an overlapping profile of affinities for the various 5-HT1 receptor subclasses. The 5-HT1A receptor is the best-defined subclass and has already been cloned. It has been identified on cell bodies of 5-HT neurons in the raphe nuclei, and it mediates inhibition of cell firing.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1990
PMID:Identification and classification of 5-HT1 receptor subtypes. 170 82

The effects of serotonin (5-hydroxytryptamine; 5-HT) on the cardiovascular system are complex. These effects, consisting of bradycardia or tachycardia, hypotension or hypertension, and vasodilation or vasoconstriction are mediated by three main sets of receptors called 5-HT1-like, 5-HT2, and 5-HT3. In addition, recent findings suggest the participation of a putative 5-HT4 receptor. Though selective 5-HT1A receptor agonists can lower heart rate (and arterial blood pressure), 5-HT usually lowers heart rate by eliciting an initial short-lasting hypotension due to bradycardia (von Bezold-Jarisch-like reflex) via 5-HT3 receptors located on sensory vagal nerve endings in the heart. Once this bradycardia reflex is suppressed--for example, during deep anesthesia, vagotomy, or spinal section--5-HT can increase heart rate in different species by a variety of mechanisms. Myocardial 5-HT1-like, 5-HT2, and 5-HT4 receptors appear to be involved in the cat, rat, and pig, respectively. 5-HT-induced tachycardia in the dog and rabbit is due mainly to release of catecholamines and involves 5-HT2 receptors on the adrenal medulla and 5-HT3 receptors on postganglionic cardiac sympathetic nerve fibers. Recently, 5-HT3 receptors also have been implicated in the 5-HT-induced tachycardia in the conscious dog. The blood pressure response to 5-HT is usually triphasic and consists of a von Bezold-Jarisch-like reflex, a middle pressor phase, and a longer-lasting hypotension. The pressor response is a consequence of vasoconstriction mediated via 5-HT2 receptors; however, vasoconstriction in the dog saphenous vein and cephalic arteries and arteriovenous anastomoses is due to stimulation of 5-HT1-like receptors. The depressor response exclusively involves 5-HT1-like receptors located at four different sites: (a) central nervous system (decrease in sympathetic and increase in vagal nervous activity), (b) sympathetic nerve terminals (reduction of transmitter release), (c) vascular smooth muscle (vasodilatation), and (d) vascular endothelium (release of a relaxant factor, probably nitric oxide). Arteriolar dilatation, together with the constriction of arteriovenous anastomoses, leads to an increase in nutrient (tissue; capillary) blood flow. The 5-HT1-like receptors are heterogeneous in nature; however, apart from the resemblance of the central nervous system 5-HT1-like receptor causing hypotension and bradycardia to the 5-HT1A binding subtype, the relationship of the other 5-HT1-like receptors to 5-HT1 binding subtypes is still debatable.(ABSTRACT TRUNCATED AT 400 WORDS)
J Cardiovasc Pharmacol 1990
PMID:Cardiovascular effects of serotonin agonists and antagonists. 170 84

The effects of acute and long-term administration of 5-HT1A agonists were studied in vivo in the rat brain. Unitary extracellular recordings were obtained from dorsal raphe 5-HT neurons and dorsal hippocampus pyramidal neurons. Gepirone and 8-OH-DPAT, two 5-HT1A agonists, when administered intravenously or applied by microiontophoresis, dose-dependently decreased the firing rate of these 5-HT neurons. Gepirone acted as a full agonist at the somatodendritic 5-HT autoreceptor, which is of the 5-HT1A subtype. Microiontophoretic application of gepirone also decreased the firing activity of postsynaptic hippocampus pyramidal neurons. At these postsynaptic 5-HT1A receptors, however, gepirone acted as a partial agonist. A 2-day treatment with gepirone markedly reduced the firing rate of 5-HT neurons; this was followed by a partial recovery after 7 days of treatment and a complete one after 14 days of treatment. This adaptation of 5-HT neurons was attributable to a desensitization of their somatodendritic 5-HT autoreceptors. The 14-day treatment with gepirone did not induce a desensitization of 5-HT1A receptors on postsynaptic pyramidal neurons. It is concluded that the sustained administration of a 5-HT1A agonist results in an enhanced tonic activation of postsynaptic 5-HT1A receptors in the forebrain. It can be presumed that the recovery of the firing activity of 5-HT neurons restores a normal release of endogenous 5-HT, upon which the agonistic action of the 5-HT1A agonist on normosensitive postsynaptic 5-HT receptors is superimposed.
J Cardiovasc Pharmacol 1990
PMID:Electrophysiological investigation of the adaptive response of the 5-HT system to the administration of 5-HT1A receptor agonists. 170 86

The purpose of our study was to test the hypothesis that drugs that activate the 5-HT1A receptor lower arterial pressure by interacting with 5-HT1A receptors located in the ventrolateral medulla. For this purpose, cats were anesthetized with alpha-chloralose while arterial pressure, heart rate, and several indices of respiratory activity were being monitored during either topical application or microinjection of 5-HT1A receptor agonist and antagonist drugs in the region of the intermediate area of the ventrolateral medulla. Topical application of drugs that activate 5-HT1A receptors (e.g., 8-OH-DPAT and urapidil) produced decreases in arterial pressure, heart rate, and tidal volume but an increase in respiratory rate. These effects were prevented by prior topical application of the 5-HT1A antagonist drug, spiperone. Intravenous administration of 5-HT1A receptor agonist drugs produced similar cardiorespiratory effects, and these effects were counteracted by topical application of spiperone to the intermediate area of the ventrolateral medulla. Microinjection of 8-OH-DPAT into two sites associated with the intermediate area, namely the subretrofacial nucleus and the bicuculline-sensitive hypotensive site, also resulted in decreases in arterial pressure (-40 +/- 10 mm Hg, n = 5; and -21 +/- 4 mm Hg, n = 3, respectively). These data indicate that hypotension produced by drugs that activate 5-HT1A receptors occurs, at least in part, from an action in the ventrolateral medulla, presumably in the subretrofacial nucleus and/or the bicuculline-sensitive hypotensive site.
J Cardiovasc Pharmacol 1990
PMID:Ventrolateral medulla: an important site of action for the hypotensive effect of drugs that activate serotonin-1A receptors. 170 87

An attempt to determine the central site of the sympathoinhibitory effects of 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, has been made in normotensive anesthetized dogs. Intravenous and central (cisterna magna, vertebral artery) administration of 8-OH-DPAT induced dose-dependent decreases in blood pressure and sympathetic (splanchnic and renal) nerve activity in intact and baroreceptor denervated dogs. In contrast, 8-OH-DPAT was ineffective when injected into the nucleus tractus solitarii or into the raphe nuclei. Administration of 8-OH-DPAT into the ventrolateral pressor area (VLPA) decreased blood pressure and renal sympathetic nerve activity. The sympathoinhibitory effects of 8-OH-DPAT injected into the vertebral artery (v.a.) were antagonized by methiothepin and (+/-)pindolol injected into the v.a. Likewise, the effects of 8-OH-DPAT administered into the VLPA were antagonized by methiothepin injected into the same site. Depletion of central catecholamines and 5-HT content did not change the sympathoinhibitory effects of 8-OH-DPAT. These results suggested that 8-OH-DPAT has a direct effect on 5-HT1A receptors located in the VLPA in dogs.
J Cardiovasc Pharmacol 1990
PMID:Hypotensive effects of 5-HT1A receptor agonists on the ventrolateral medullary pressor area in dogs. 170 88

The effects of urapidil, of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and of the alpha 2-adrenoceptor agonist clonidine on the in vivo rate of synthesis of 5-hydroxytryptamine (5-HT) were determined in rat brain cortex and hypothalamus. Urapidil (10 mg/kg), 8-OH-DPAT (0.3 mg/kg) or clonidine (0.3 mg/kg; all drugs i.p.) caused significant reductions in 5-HT synthesis rate. Pretreatment with the selective 5-HT1A receptor antagonist spiroxatrine (SPX; 1 mg/kg s.c.) or the nonselective 5-HT1 receptor antagonist metitepine (1 mg/kg i.p.) abolished the effects of urapidil and 8-OH-DPAT, but not of clonidine. The effects of urapidil and 8-OH-DPAT on mean arterial blood pressure (MAP) and heart rate (HR) of pentobarbital-anesthetized, normotensive rats were measured following stereotaxic microinjection into the B1/B3 cell region of the ventral medulla. The mean percentage decreases induced by urapidil (3 micrograms) and 8-OH-DPAT (0.2 micrograms) amounted to (MAP/HR) -13%/-6% and -19%/-25%, respectively. The following pretreatments markedly attenuated or prevented the effects of intramedullary injections of urapidil or 8-OH-DPAT: (a) SPX (1 mg/kg s.c., 60 min): (b) intracisternal injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 0.2 mg; 7-10 days); (c) bilateral injection of 5,7-DHT at the cervical level of the spinal cord (each side 5 micrograms; 7-10 days). The present results are compatible with an action of urapidil as agonist at central 5-HT1A receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol 1990
PMID:Influence of urapidil and 8-OH-DPAT on brain 5-HT turnover and blood pressure in rats. 170 89

Activity in central sympathetic pathways can be modified by stimulating central alpha 2-adrenoceptors, e.g., with clonidine, or, more recently, by stimulating central 5-hydroxytryptamine (5-HT1A) receptors. Stimulation of 5-HT1A receptors causes central sympathoinhibition and an increase in cardiac vagal drive, which results in a profound fall in blood pressure. However, the central sympathoinhibition observed with 5-HT1A agonists such as 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] is not uniform for all regional sympathetic outflows, renal outflow being the most sensitive. The classical centrally acting antihypertensive drugs, the alpha 2-adrenoceptor agonists, also cause differential sympathoinhibition, but cardiac rather than renal nerve activity is the most sensitive. Now, if a 5-HT1A agonist is combined with an alpha 1-adrenoceptor antagonist, e.g., urapidil, then uniform central sympathoinhibition is observed. 5-HT1A agonists also differ from alpha 2-adrenoceptor agonists in that they increase central vagal drive. Further, 5-HT-containing boutons have been shown to make synaptic contact with cardiac vagal motoneurons (CVMs), and there is also a high density of 5-HT1A binding in the brain nuclei containing these CVMs. This suggests that there is an excitatory 5-HT-containing pathway that innervates CVMs and involves the activation of 5-HT1A receptors. In this respect, cardiopulmonary afferent fiber activation of CVMs is blocked by central administration of 5-HT1A receptor antagonists. In conclusion, 5-HT1A receptors are important in the patterning of sympathetic outflow by central cardiovascular pathways and are involved in the central control of parasympathetic outflow, at least to the heart.
J Cardiovasc Pharmacol 1990
PMID:Influence of 5-HT1A receptor agonists on sympathetic and parasympathetic nerve activity. 170 90

Urapidil and three derivatives with hypotensive properties (5-acetyl-, 5-formyl-, 5-methylurapidil) bind selectively to 5-HT receptors of the 5-HT1A subtype and to alpha 1-adrenoceptors labeled by [3H]8-OH-DPAT and [3H]prazosin, respectively. Binding to these receptors is likely to contribute to their hypotensive action. 5-Methylurapidil, the most potent of these drugs, was used in its 3H-labeled form as a radioligand. After blockade of alpha 1-adrenoceptors by prazosin, [3H]5-methylurapidil binds with nanomolar affinity to a binding site that is similar to the (5-HT1A) site labeled by [3H]8-OH-DPAT. No binding to other 5-HT1 and 5-HT2 receptors was observed. 5-HT uptake inhibitors did not inhibit [3H]5-methylurapidil binding. [3H]5-methylurapidil binding is sensitive to GTP and is modulated by divalent cations. Our results show that urapidil derivatives bind to the 5-HT1A recognition site and that [3H]5-methylurapidil is a valuable tool for the investigation of this receptor subtype.
J Cardiovasc Pharmacol 1990
PMID:Urapidil analogues are potent ligands of the 5-HT1A receptor. 170 91

This study investigated the effects of (-)-pindolol, a putative 5-HT1A receptor antagonist, upon the central hypotensive action of the antihypertensive drug urapidil and of the purported 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in cats. Chloralose/urethane-anesthetized cats were thoracotomized and artificially ventilated. Blood pressure was monitored in the iliac artery, and the drugs were injected into the vertebral artery. Urapidil (1-300 nmol/kg) or 8-OH-DPAT (0.01-1 nmol/kg) dose-dependently reduced blood pressure. (-)-Pindolol (30 and 100 nmol/kg) shifted the dose-response curves of both drugs significantly and in a similar manner to the right. Doses of urapidil of 30 nmol/kg or higher also reduced the elevation of blood pressure following the intravenous injection of the alpha 1-adrenoceptor agonist cirazoline whereas 8-OH-DPAT was ineffective. Yet, the hypotensive response to the directly acting vasodilator nitroglycerin remained unchanged after urapidil. The results support the hypothesis that the centrally mediated component of the antihypertensive action of urapidil is due to stimulation of 5-HT1A receptors in the brainstem. Peripheral alpha 1-adrenoceptor blockade comes into play with higher doses of the drug administered via the vertebral artery.
J Cardiovasc Pharmacol 1990
PMID:Involvement of 5-HT1A receptors in blood pressure reduction by 8-OH-DPAT and urapidil in cats. 170 92

The systemic and regional hemodynamic effects of the selective 5-HT1A receptor agonist flesinoxan (3-300 micrograms/kg, i.v., in cumulative doses) were investigated in normotensive anesthetized and pithed rats using a pulsed Doppler system and were compared to those of the alpha 2-adrenoceptor agonist clonidine. In anesthetized rats, flesinoxan and clonidine induced dose-dependent decreases in blood pressure and heart rate. Total peripheral resistance and hindquarters vascular resistance dose-dependently decreased after flesinoxan administration whereas cardiac output remained unchanged. Clonidine dose-dependently decreased cardiac output and did not change total peripheral resistance. These results indicate that the decrease in blood pressure induced by flesinoxan is due to a reduction in total peripheral and hindquarters vascular resistance. In contrast, clonidine decreased blood pressure by reducing cardiac output. In the pithed rat, the systemic and regional hemodynamic effects of flesinoxan were abolished whereas those of clonidine were reversed. These results provide evidence for the participation of the central nervous system in the systemic and regional hemodynamic effects of flesinoxan. However, direct administration into the central nervous system remains to be performed in order to strengthen this conclusion.
J Cardiovasc Pharmacol 1991 Oct
PMID:Implication of the central nervous system in the systemic and regional hemodynamics of two centrally acting hypotensive drugs, flesinoxan and clonidine, in the rat. 172 39


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