Functions of 5-HT2A receptor and its antagonists in the cardiovascular system

Nagatomo, Takafumi; Rashid, Mamunur; Muntasir, Habib Abul; Komiyama, Tomoyoshi

doi:10.1016/j.pharmthera.2004.08.005

Cited by 164 publications

(136 citation statements)

References 196 publications

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“…In the periphery, serotonin induces platelet aggregation, and in the presence of endothelial damage induces vasoconstriction and hyperplasia of smooth muscle cells of arteries, conditions that can lead to the formation of thrombi (45,46). The effects of serotonin on platelets are mediated by 5-HT 2A receptors (47), and the reuptake of circulating serotonin in platelets is mediated through its specific transporter (5-HTT). Many studies have shown that in depressed patients there is an increase in the platelet binding sites for 5-HT 2A and a reduction in the amount of carrier, indicating that depressed patients are particularly vulnerable to aggregating platelets and vasoconstriction associated with CAD (33).…”

Section: Discussionmentioning

confidence: 99%

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

et al. 2009

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Abstract. Cardiovascular disease (CVD) and depression are two of the most common human health problems. Patients with depression have an increased risk of developing cardiovascular disease and mortality after experiencing a cardiac event. Both diseases are complex disorders that are influenced by genetic and environmental factors. Brain-derived neurotrophic factor (BDNF) plays a critical role in regulating both vascular development and response to injury, and promotes survival, differentiation, and maintenance of neurons in the peripheral and nervous system. Evidence suggests that BDNF can enhance serotoninergic transmission. Serotonin modulates different brain functions and is known to regulate sleep, appetite, pain and inflammation. The aims of the present casecontrol study were to investigate the possible role of BDNF Val66Met, 5-HTTLPR and -1438 G/A polymorphisms in the development of coronary artery disease (CAD) in patients with and without depression. Regarding BDNF, our data suggest an involvement of the AA genotype in the pathogenesis of CAD in females and in the predisposition to CAD associated with depression. Furthermore, it could be argued that the GG genotype is protective against CAD in the female population and against CAD associated with depression. In our CAD population we also observed a significant increase in the L/L genotype and a decrease in the S/L genotype with respect to the controls. A higher frequency of the L allele, responsible for enhancing the efficiency of transcription, was found in CAD patients. These findings may be responsible for the increased capacity of platelet serotonin uptake previously observed in patients with CAD. Although no differences were found for genotype and allelic frequencies of the -1438 G/A polymorphism between the CAD patients and controls, we cannot exclude the possible role of this receptor in coronary artery disease.

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Section: Discussionmentioning

confidence: 99%

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

et al. 2009

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“…[18][19][20][21] A recent study 22 of a novel selective 5-HT 2A receptor antagonist (AT-1015) did not show any evidence of efficacy in the treatment of intermittent claudication. In the present study on sarpogrelate (MCI-9042), which exhibits a selective antagonistic effect on 5-HT 2A receptors, and has a chemical structure different from ketanserin and AT-1015, 5,6 there was a marked training/placebo effect on ACD which persisted up to 16 weeks, despite the 6-week placebo run-in period. The extent and variability in the placebo response has always been a major difficulty in evaluating drugs in intermittent claudication.…”

Section: Discussionmentioning

confidence: 75%

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

Norgren

Jawień

Mátyás³

et al. 2006

Vasc Med

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This was a multinational, multicentre, double-blind Phase II study in Europe to evaluate the efficacy and safety of two dose regimens (200 mg bid and 200 mg tid) of sarpogrelate (MCI-9042, 5-HT2A receptor antagonist) compared to placebo in patients with stable, moderately severe intermittent claudication. Following a single-blind placebo run-in period of 6 weeks, 364 (309 male and 55 female) patients (59.2 ± 8.4 years, mean SD) were randomized to receive sarpogrelate 200 mg bid, 200 mg tid or placebo for 24 weeks with a follow-up of 8 weeks. The primary objective was the increase of absolute claudication distance (ACD) at the end of treatment (week 24) compared to placebo. Analysis of covariance (ANCOVA) was performed on the log-transformed percentage of baseline ACD: loge (ACD/baseline). A responder analysis (defined as a 50% improvement in ACD) was also performed. There was a marked training/placebo effect on the ACD which persisted up to 16 weeks. At 24 weeks the primary objective did not reach statistical significance (200 mg bid vs placebo, p = 0.225; 200 mg tid vs placebo, p = 0.580). In the responder analysis, 200 mg bid showed a statistically significant difference vs placebo ( p = 0.035). In the exploratory analysis with completers (patients completing all treadmill tests), there was a statistical difference in ACD/baseline change for 200 mg bid ( p = 0.035) and in the responder analysis for 200 mg tid ( p = 0.044) at 24 weeks compared to placebo. Both treatments showed a carry-over effect for ACD during the 8-week follow-up (weeks 28-32). The treatment was well tolerated and no clinically significant safety concerns were reported. In conclusion, the study results confirm that sarpogrelate is well tolerated and although the primary endpoint failed to reach statistical significance, the responder analysis showed an increased absolute walking distance, which makes a further trial warranted, including a larger population, and possibly also a longer treatment period.

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“…Considering the pharmacodynamics, aripiprazole and clozapine might act together to antagonize the α 1 receptors, thereby increasing the risk of OH. Moreover, 5-hydroxytryptamine 2A (5-HT 2A ) antagonism could induce vasodilation 4 , and central 5-HT 1A stimulation could produce hypotension and bradycardia 5 . Being a 5-HT 2A antagonist and a 5-HT 1A partial agonist, aripiprazole may increase the risk of OH.…”

Section: Dear Editormentioning

confidence: 99%

Severe orthostatic hypotension after adding low-dose aripiprazole to clozapine

Lin

Liang

2017

Arch. Clin. Psychiatry (São Paulo)

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Lin YS et al. / Arch Clin Psychiatry. 2017;44(3):84 Dear Editor, Antipsychotics can cause orthostatic hypotension (OH) by blocking adrenergic receptors 1 . OH is easily under-recognized as it can be asymptomatic. In clinical practice, combination treatment of two or more antipsychotics is common; however, little attention has been paid to OH in this scenario. Here, we presented a patient who developed severe OH after adding aripiprazole 5 mg/d to clozapine 400 mg/d.A 33-year-old man with a 15-year history of schizophrenia presented because of severe auditory hallucination and persecutory delusion. After admission, the dose of clozapine was gradually increased to 400 mg/day, and the psychotic symptoms were improved. Over the following 4 weeks, the patient still exhibited negative symptoms, including alogia, avolition, asociality, and poor selfcare. Aripiprazole 5 mg/day was added, and the negative symptoms were improved. However, 2 weeks later, the patient fell down twice on a sudden rise from supine position. Physical and neurological examinations and the results of laboratory tests were negative. Notably, the lying-to-standing orthostatic test caused a remarkable change in blood pressure (BP). The patient showed 118/83 mmHg with pulse rate (PR) 90 beats per minute (bpm) in supine position and 70/36 mmHg with PR 122 bpm in standing position. Aripiprazole was discontinued, and the OH was relieved. After careful consideration of the risks and benefits, aripiprazole 5 mg/d was added again. However, OH recurred 2 weeks later. Therefore, aripiprazole was switched to escitalopram, and OH did not recur.OH is defined as a drop in BP (> 20/10 mmHg) within in 3 minutes of standing. The OH is associated with aripiprazole because of the temporal relationship between its occurrence and the commencement of aripiprazole, its resolution upon aripirazole discontinuation, and its recurrence with aripiprazole rechallenge. An animal study suggested that both clozapine and aripiprazole could block α 1 adrenoceptors, while the potential to cause OH is higher in clozapine 2 . There are few data addressing OH under the combination therapy of aripiprazole and clozapine. A review article reported no pharmacokinetic interaction between aripiprazole and clozapine 3 . Considering the pharmacodynamics, aripiprazole and clozapine might act together to antagonize the α 1 receptors, thereby increasing the risk of OH. Moreover, 5-hydroxytryptamine 2A (5-HT 2A ) antagonism could induce vasodilation 4 , and central 5-HT 1A stimulation could produce hypotension and bradycardia 5 . Being a 5-HT 2A antagonist and a 5-HT 1A partial agonist, aripiprazole may increase the risk of OH.In this case, the combination of aripiprazole and clozapine increased the risk of OH that was considered to be principally related to clozapine. However, the patient did not develop OH under high-dose clozapine treatment (400 mg/d). We suggest that the high-dose clozapine treatment have primed his vulnerability to OH. Therefore, even though the dose of add-on aripiprazole...

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Functions of 5-HT2A receptor and its antagonists in the cardiovascular system

Cited by 164 publications

References 196 publications

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

Coronary artery disease and depression: Possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms

Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study

Severe orthostatic hypotension after adding low-dose aripiprazole to clozapine

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