Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension

Banes, Amy K.; Watts, Stephanie W.

doi:10.1161/hy02t2.102793

Cited by 41 publications

(32 citation statements)

References 29 publications

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“…3c). Previous studies showed that the 5-HT 2B receptor was up-regulated in DOCA-salt rats (Watts et al, 1996;Banes and Watts, 2002;Watts, 2002) because we observed that the 5-HT 2B receptor antagonist LY272015 reduced 5-HT-induced contraction in aorta from and blood pressure (Watts and Fink, 1999) in DOCA rats but not SHAM rats. We expected to observe that 5-HT 2B receptors played a role in (ϩ)-norfenfluramine-induced contraction in vessels from DOCA-salt rats.…”

Section: Discussionsupporting

confidence: 42%

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The 5-Hydroxytryptamine_2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

Fink

Watts

2007

J Pharmacol Exp Ther

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The highly effective anorexigen (ϩ)-fenfluramine was widely used to control body weight until the association with primary pulmonary hypertension and valvular heart disease. (ϩ)-Norfenfluramine is the major hepatic metabolite of (ϩ)-fenfluramine and is primarily responsible for the anorexic effect as well as side effects. We reported that (ϩ)-norfenfluramine causes vasoconstriction and a blood pressure increase in rats with normal blood pressure via the 5-hydroxytryptamine (5-HT) 2A receptor. With the knowledge that (ϩ)-norfenfluramine also has affinity for 5-HT 2B receptors and that arterial 5-HT 2B receptor expression is up-regulated in deoxycorticosterone acetate (DOCA)-salt hypertension, we tested the hypothesis that (ϩ)-norfenfluramine-induced vasoconstriction and pressor effects are potentiated in DOCA-salt hypertensive rats in a 5-HT 2 receptor-dependent manner. Contractions of arteries were measured using an isolated tissue bath system or myograph. Mean arterial blood pressure was measured in chronically instrumented conscious rats. Effects of (ϩ)-norfenfluramine in stimulating arterial contraction (leftward shift versus SHAM, aorta, 5.13-fold; renal artery, 1.95-fold; mesenteric resistance artery, 1.77-fold) and raising blood pressure were significantly enhanced in hypertension. In arteries from both normotensive and hypertensive rats, (ϩ)-norfenfluramine-induced contraction in aorta was inhibited by 5-HT 2A receptor antagonists, ketanserin and LY53857 (4-isopropyl-7-methyl-9-(2-hydroxy-1-meth ylpropoxycarbonyl) 4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline), but not by the 5-HT 2B receptor antagonist, LY272015 [6-chloro-5-methyl-N-(5-quinolinyl)-2,3-dihydro-1H-indole-1-carboxamide]. Ketanserin (3 mg/kg) reduced (ϩ)-norfenfluramine-induced pressor response in both SHAM and DOCA rats. Our results demonstrate that (ϩ)-norfenfluramineinduced arterial contraction and blood pressure increases are potentiated in DOCA-salt hypertensive rats. However, it is the 5-HT 2A receptor and not the 5-HT 2B receptor that participates in these effects.The highly effective anorexigen (ϩ)-fenfluramine (Redux) was taken off the market in 1997 because of the incidence of pulmonary hypertension (Abenhaim et al., 1996) and aortic valvular disease (Connolly et al., 1997). The anorexic effect of (ϩ)-fenfluramine is due to activation of 5-hydroxytryptamine (5-HT) 2C receptor (Smith et al., 2006), whereas the 5-HT 2B receptor plays an important role in the pathogenesis of (ϩ)-fenfluramine-induced pulmonary hypertension (Launay et al., 2002) and aortic valvular disease (Fitzgerald et al., 2000).Radioligand binding experiments show that (ϩ)-fenfluramine has low affinity for the 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors, but the hepatic deethylated metabolite of (ϩ)-fenfluramine, (ϩ)-norfenfluramine, has high affinity at the 5-HT 2B receptor (K i ϭ 11.2 nM), 5-HT 2C receptor (K i ϭ 324 nM) and a lesser affinity at the 5-HT 2A receptor (K i ϭ 1516 nM) (Rothman et al., 2000). Consistent with binding results, two studies s...

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Section: Discussionsupporting

confidence: 42%

“…The up-regulated expression and function of 5-HT 2B receptors (Watts et al, 1996;Banes and Watts, 2002) in aorta from DOCA-salt rats has been reported. However, without the use of a specific 5-HT 2A receptor agonist, it has been difficult to prove this receptor is still present and functional in arteries of hypertensive animals.…”

Section: Discussionmentioning

confidence: 97%

The 5-Hydroxytryptamine_2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

Fink

Watts

2007

J Pharmacol Exp Ther

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“…Among these genes, Serotonin 1B receptor was expressed at a higher level in testosterone-treated than control females. Serotonin 1B receptor expression is upregulated by mineralcorticoids in the aorta of rats (Banes and Watts, 2002); thus, expression of this serotonin receptor may be mediated indirectly by testosterone treatment through changes in other signaling molecules. Serotonin 1B receptor has a range of effects on both behavior and physiology (Donaldson et al, 2013), though its role in skeletal muscle tissue is unclear.…”

Section: Effect Of Testosterone Treatment In Femalesmentioning

confidence: 99%

Potential for sexual conflict assessed via testosterone-mediated transcriptional changes in liver and muscle of a songbird

Peterson

Rosvall

Taylor

et al. 2013

Journal of Experimental Biology

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Males and females can be highly dimorphic in metabolism and physiology despite sharing nearly identical genomes, and both sexes respond phenotypically to elevated testosterone, a steroid hormone that alters gene expression. Only recently has it become possible to learn how a hormone such as testosterone affects global gene expression in non-model systems, and whether it affects the same genes in males and females. To investigate the transcriptional mechanisms by which testosterone exerts its metabolic and physiological effects on the periphery, we compared gene expression by sex and in response to experimentally elevated testosterone in a well-studied bird species, the dark-eyed junco (Junco hyemalis). We identified 291 genes in the liver and 658 in the pectoralis muscle that were differentially expressed between males and females. In addition, we identified 1727 genes that were differentially expressed between testosterone-treated and control individuals in at least one tissue and sex. Testosterone treatment altered the expression of only 128 genes in both males and females in the same tissue, and 847 genes were affected significantly differently by testosterone treatment in the two sexes. These substantial differences in transcriptional response to testosterone suggest that males and females may employ different pathways when responding to elevated testosterone, despite the fact that many phenotypic effects of experimentally elevated testosterone are similar in both sexes. In contrast, of the 121 genes that were affected by testosterone treatment in both sexes, 78% were regulated in the same direction (e.g. either higher or lower in testosteronetreated than control individuals) in both males and females. Thus, it appears that testosterone acts through both unique and shared transcriptional pathways in males and females, suggesting multiple mechanisms by which sexual conflict can be mediated.

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“…In the rat aorta, the 5-HT 2A receptor has been established as the sole mediator of 5-HT contraction. Though present, the 5-HT 2B receptor is not functional and the 5-HT 2C receptor has not been detected (2,32). Thus use of the 5-HT 2 receptor agonist ␣-methyl-5-HT and 5-HT 2A/2C receptor antagonist ketanserin allows us to draw connections between 5-HT 2A receptor acti-…”

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confidence: 99%

A new signaling paradigm for serotonin: use of Crk-associated substrate in arterial contraction

Ogden

Thompson

Hickner

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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A new signaling paradigm for serotonin: use of Crk-associated substrate in arterial contraction. Am J Physiol Heart Circ Physiol 291: H2857-H2863, 2006. First published July 21, 2006 doi:10.1152/ajpheart.00229.2006.-Crkassociated substrate (CAS), a 130-kDa adaptor protein, was discovered as a tyrosine kinase substrate of Src that was important to cellular motility and actin filament formation. As the tyrosine kinase Src is utilized by the 5-hydroxytryptamine (5-HT)2A receptor in arterial contraction, we tested the hypothesis that CAS was integral to 5-HT2A receptor-mediated vasoconstriction. Rat thoracic aorta was used as a model of the arterial 5-HT2A receptor. Western and immunohistochemistry analyses validated the presence of CAS in the aorta, and tissue bath experiments demonstrated reduction of contraction to 5-HT (13.5 Ϯ 5% control maximum) and the 5-HT2 receptor agonist ␣-methyl-5-HT (6 Ϯ 2% maximum) by latrunculin B (10 Ϫ6 mol/l), an actin disruptor. In aorta contracted with 5-HT (10 Ϫ5 mol/l), tyrosine phosphorylation (Tyr410) of CAS was significantly increased (ϳ225%), and both contraction and CAS phosphorylation were reduced by the 5-HT2A/2C receptor antagonist ketanserin (3 ϫ 10 Ϫ8 mol/l). Src is one candidate for 5-HT-stimulated CAS tyrosyl-phosphorylation as 5-HT promoted interaction of Src and CAS in coimmunoprecipitation experiments, and the Src tyrosine kinase inhibitor PP1 (10 Ϫ5 mol/l) abolished 5-HT-induced tyrosyl-phosphorylation of CAS and reduced 5-HT-and ␣-methyl-5-HT-induced contraction. Antisense oligodeoxynucleotides delivered to the aorta reduced CAS expression (33% control) and arterial contraction to ␣-methyl-5-HT (45% of control), independent of changes in myosin light chain phosphorylation. These data are the first to implicate CAS in the signal transduction of 5-HT. 5-hydroxytryptamine; antisense oligodeoxynucleotides; signal transduction; Src THE ACTIVATION of protein kinases in phosphorylation cascades is critical to signal transduction. This process is facilitated by adaptor proteins that contain Src homology 2 (SH2) and Src homology 3 (SH3) protein regions that allow for docking of other proteins and facilitation of protein-protein interactions. One such adapter protein is Crk-associated substrate or CAS (also known as p130 or p130 CAS). This 130-kDa protein has been recognized as a substrate for the tyrosine kinase Crk (23), and CAS is highly tyrosine phosphorylated in response to activation of Crk or Src (25,26). Docking of and tyrosylphosphorylation by these proteins, as well as other regulators, including focal adhesion kinase (FAK) and protein tyrosine phosphatase 1B (PTP1B), enables CAS to participate in important physiological events, including cell migration (14, 18, 27), mitosis (30), adhesion (42), and apoptosis (48).The involvement of CAS in contraction is logical because CAS is essential for actin filament reorganization (12, 38). CAS is a regulator of the actin-associated protein profilin (14), which is necessary for actin-filament polymerization in smooth muscl...

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Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension

Cited by 41 publications

References 29 publications

The 5-Hydroxytryptamine_2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

The 5-Hydroxytryptamine_2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

Potential for sexual conflict assessed via testosterone-mediated transcriptional changes in liver and muscle of a songbird

A new signaling paradigm for serotonin: use of Crk-associated substrate in arterial contraction

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Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension

Cited by 41 publications

References 29 publications

The 5-Hydroxytryptamine2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

The 5-Hydroxytryptamine2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

Potential for sexual conflict assessed via testosterone-mediated transcriptional changes in liver and muscle of a songbird

A new signaling paradigm for serotonin: use of Crk-associated substrate in arterial contraction

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The 5-Hydroxytryptamine_2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

The 5-Hydroxytryptamine_2A Receptor Is Involved in (+)-Norfenfluramine-Induced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension