5-Hydroxytryptamine2B Receptor Function Is Enhanced in the Nω-Nitro-l-arginine Hypertensive Rat

Russell, Amber; Banes, Amy K.; Berlin, Hilary; Fink, Gregory D.; Watts, Stephanie W.

doi:10.1124/jpet.102.037390

Cited by 51 publications

(36 citation statements)

References 19 publications

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“…Thus, such data do suggest that mineralocorticoids, independent of an increase in blood pressure, can modulate 5-HT 2B receptor function. Enhanced contraction to the 5-HT 2B receptor agonist BW723C86 has also been seen in arteries from the N w -nitro-L-arginine hypertensive rat model 14 as well as in the spontaneously hypertensive rat model of hypertension. 15 Interestingly, in the spontaneously hypertensive rat model 16 and the N w -nitro-L-arginine methyl ester model 17 of hypertension, treatment with the mineralocorticoid receptor antagonist spironolactone reduces blood pressure.…”

Section: Discussionmentioning

confidence: 84%

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

Banes

Watts

2002

Hypertension

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Abstract-Previous studies have established a role for 5-hydroxytryptamine (5-HT) 2B and 5-HT 1B receptors in mediating enhanced contraction to serotonin (5-HT) in arteries from hypertensive deoxycorticosterone acetate (DOCA)-salt rats.To determine whether the observed increase in responsiveness was due to upregulation of 5-HT receptors, we used Western analysis to measure 5-HT 1B and 5-HT 2B receptor protein density. In endothelium-denuded aortas from hypertensive DOCA-salt rats (mean systolic blood pressure 192Ϯ6 mm Hg), 5-HT 1B and 5-HT 2B receptor proteins were upregulated Ϸ2-fold compared with the response in the aortas of sham-operated control rats (mean systolic blood pressure 119Ϯ2 mm Hg). Contraction to 5-HT 2B receptor agonists was also enhanced in arteries from Wistar-Furth rats given DOCA and salt. This strain is relatively resistant to the hypertensive effects of DOCA and salt treatment. A common factor between the model of DOCA-salt hypertension and the DOCA-salt-treated Wistar-Furth rats is the presence of mineralocorticoids. Therefore, we tested the hypothesis that mineralocorticoids can upregulate 5-HT 1B and 5-HT 2B receptors. Aortas from normal Sprague-Dawley rats were incubated with aldosterone (100 nmol/L) for 8, 12, 24, and 48 hours. The expression of 5-HT 2B and 5-HT 1B receptor proteins was significantly increased (Ϸ2-fold over vehicle treatment) by 8 hours. 5-HT 2B and 5-HT 1B receptors were upregulated by aldosterone in a concentration-dependent manner, and incubation with spironolactone (10 mol/L) blocked this upregulation. These data support the conclusion that the increased expression of 5-HT 1B and 5-HT 2B receptors observed in arteries from DOCA-salt rats may be partially due to mineralocorticoids acting via the mineralocorticoid receptor to modulate gene expression. Recently, in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, 5-HT 2B and 5-HT 1B receptors have been implicated as mediators of 5-HT contractile hyperresponsiveness. 3-6 5-HT 2B and 5-HT 1B receptors do not appear to be involved in mediating contraction to 5-HT under conditions of normal blood pressure. The 5-HT 2B receptor has also been implicated as a mediator of 5-HT-induced contraction in the mesenteric arteries of Wistar and Wistar-Furth rats, which undergo the DOCA-salt protocol. 7 Interestingly, the WistarFurth rat is relatively resistant to the hypertensive effects of mineralocorticoids. 8 -10 This is important to note because although the Wistar-Furth DOCA-salt-treated rats do not obtain the same magnitude of change in blood pressure as do the Wistar DOCA-salt-treated rats, arteries from both of these rats show an increase in response to the 5-HT 2B receptor agonist BW723C86. 7 These previous studies, from the Wistar-Furth as well as the Sprague-Dawley DOCA-salttreated rats, have demonstrated a functional upregulation of the 5-HT 2B receptors. However, none of these studies has addressed the issue of changes in the levels of 5-HT receptor proteins. We speculated that the change in contractility to ...

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Section: Discussionmentioning

confidence: 84%

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

Banes

Watts

2002

Hypertension

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“…Hyper-reactivity occurs in arteries and in veins in hypertension, in a number of different vascular beds and differently sized vessels (Cummings et al, 1986;Thompson and Webb, 1987;Huzoor-Akbar et al, 1989;Dohi and Lü scher, 1991;Webb et al, 1992;Moreno et al, 1996). In several models of experimental hypertension, up-regulation of 5-HT 2B receptors in the smooth muscle is one mechanism by which 5-HT becomes hyper-reactive (Watts et al, 1995(Watts et al, , 1996Watts, 1997;Watts and Fink, 1999;Watts, 2002, 2003;Russell et al, 2002). Mineralocorticoids can directly stimulate expression of the 5-HT 2B receptor Watts, 2002, 2003) such that an up-regulated receptor enables a more sensitive contraction.…”

Section: Change In Pathological Conditionsmentioning

confidence: 99%

Serotonin and Blood Pressure Regulation

Watts

Morrison

Davis

et al. 2012

Pharmacological Reviews

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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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5-Hydroxytryptamine2B Receptor Function Is Enhanced in the Nω-Nitro-l-arginine Hypertensive Rat

Cited by 51 publications

References 19 publications

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

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

Serotonin and Blood Pressure Regulation

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

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