Relaxation Induced by Atrial Natriuretic Peptide Is Impaired in Carotid but Not Renal Arteries from Spontaneously Hypertensive Rats Due to Reduced BK&lt;sub&gt;Ca&lt;/sub&gt; Channel Activity

Pflugers Arch - Eur J Physiol

Ando

et al. 2016

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Serotonin (5-hydroxytryptamine, 5-HT) is an important endogenous substance that regulates the vascular tone, and the abnormal signaling of 5-HT has been observed in the arteries under several pathophysiological conditions such as diabetes and hypertension. However, signaling pathways of 5-HT-mediated vasocontraction in hypertension remain unclear. Therefore, we tested the hypothesis that 5-HT-mediated contraction and contributions of various kinases such as mitogen-activated protein kinases (MAPKs), phosphoinositide 3-kinase (PI3K), Rho kinase (ROCK), and 3-phosphoinositide-dependent kinase 1 (PDK1) to the contraction would be altered in the carotid arteries obtained from spontaneously hypertensive rats (SHR) compared to control Wistar Kyoto (WKY) rats. In the carotid arteries from SHR (vs. those from WKY), (1) the 5-HT-mediated contraction was increased, whereas the norepinephrine-mediated contraction was not; (2) 5-HT-mediated contractions were partly inhibited by each kinase (extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK, c-Jun N-terminal kinase (JNK), PI3K, ROCK, and PDK1) inhibitor; and (3) 5-HT-stimulated phosphorylation of ERK1/2, p38 MAPK, JNK, myosin phosphatase target subunit 1 (MYPT1), and PDK1 was increased. The expression of ROCK2 but not ROCK1 was increased in the carotid arteries from SHR compared to WKY. The expression of 5-HT2A receptor, a major receptor of 5-HT-mediated contraction in rat carotid artery, was similar in carotid arteries between the two groups. These results suggest that 5-HT-mediated contraction was utilized multiple signaling pathways such as ERK1/2, p38 MAPK, JNK, PI3K, ROCK, and PDK1. Although 5-HT-mediated contraction was increased in the carotid arteries obtained from SHR, further studies are necessary to clarify how each kinase may integrate in the vascular smooth muscles under hypertension.

Section: Introductionmentioning

confidence: 99%

Multiple activation mechanisms of serotonin-mediated contraction in the carotid arteries obtained from spontaneously hypertensive rats

Watanabe

Pflugers Arch - Eur J Physiol

Ando

et al. 2016

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“…Following incubation under these three conditions at 37°C for 23 ± 1 h, vascular function was assessed by our previously-established organ bath technique. [26][27][28]30,32,[36][37][38] Subsequently, the rings were mounted into the organ bath system. After stabilization, the rings were exposed to an 80 mM high-K + solution and washed with modified Krebs-Henseleit solution [KHS; comprising (in mM) 118.0 NaCl, 4.7 KCl, 25.0 NaHCO 3 , 1.8 CaCl 2 , 1.2 NaH 2 PO 4 , 1.2 MgSO 4 , and 11.0 glucose].…”

Section: Methodsmentioning

confidence: 99%

Effect of Equol on Vasocontractions in Rat Carotid Arteries Treated with High Insulin

Biological & Pharmaceutical Bulletin

Takayanagi

Kobayashi

et al. 2019

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Previous research has indicated that high insulin affects vascular function. Equol is an active metabolite of daidzein, an isoflavone produced from soy by intestinal microbial flora, with beneficial effects on the vascular system. This study investigated whether equol was beneficial for vascular function under high insulin conditions. Using organ culture techniques, rat carotid arteries were treated for 23 1 h with a vehicle, high insulin (100 nM), or equol (100 µM) plus high insulin (100 nM). Vascular isometric forces were measured by the organ bath technique. In each endothelium-intact ring, the contractions induced by high-K , noradrenaline, or by serotonin (5-HT) were similar for the vehicle, insulin, and equol insulin treatments. Contractions induced by a selective 5-HT 2A receptor agonist (TCB2) increased with insulin treatment (vs. vehicle), but less so with equol insulin. Under basal conditions, a selective 5-HT 2B receptor agonist (BW723C86) did not induce contraction; following precontraction by a thromboxane analog, it induced contraction but not relaxation. These responses were similar across the three treatments. Acetylcholine-induced relaxations were also similar for the three treatments. In the endothelium-denuded preparations, 5-HT-induced contraction was augmented with insulin treatment (vs. vehicle) but less so by equol insulin treatment. These differences in 5-HT-induced contractions were eliminated by iberiotoxin, a large-conductance calcium-activated K channel (BK Ca) inhibitor. These results suggest that equol exerts a preventive effect on the enhancement of 5-HT-induced contraction by high insulin (possibly mediated by the 5-HT 2A receptor), and that these effects may be attributed to the activation of BK Ca channels in vascular smooth muscle.

“…The systolic blood pressure (SBP) of 13-or 14-week-old rats was measured, as previously described. 22,25) In brief, SBP was measured employing the tail-cuff method using a blood pressure analyzer (BP-98A; Softron, Tokyo, Japan) after the rat had been in a constant-temperature box at 37°C for at least 5 min. Surgical procedures were performed under anesthetic cover of isoflurane as previously described.…”

Section: 18)mentioning

confidence: 99%

“…22,25,[32][33][34] Functional Studies Vascular isometric force was essentially recorded as described in our previous studies. 13,17,22,25,26,28,[32][33][34] Concentration-response curves to ATP (10 for 20 min prior to PE application. To investigate the effect of endothelium on relaxations, we analyzed concentrationresponse curves in the presence/absence of endothelium of superior mesenteric arteries from Wistar rat at 17 weeks of age.…”

Section: 18)mentioning

confidence: 99%

“…An important and contributory element in sustained hypertension is an increase in vascular tone, potentially resulting from concurrently reduced relaxation and augmented contraction induced by various endogenous ligands. [19][20][21][22][23][24][25][26] Hypertension-associated vascular dysfunction is partly regulated by endothelium-derived factors. [21][22][23][24] There is a fine balance between endothelium-derived relaxing and contracting factors, a disturbance of this balance can contribute to changes in blood pressure.…”

mentioning

confidence: 99%

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A Comparative Study of Vasorelaxant Effects of ATP, ADP, and Adenosine on the Superior Mesenteric Artery of SHR

Watanabe

Biological & Pharmaceutical Bulletin

Ando

et al. 2016

Self Cite

We investigated superior mesenteric arteries from spontaneously hypertensive rats (SHR) to determine the relaxation responses induced by ATP, ADP, and adenosine and the relationship between the relaxant effects of these compounds and nitric oxide (NO) or cyclooxygenase (COX)-derived prostanoids. In rat superior mesenteric artery, relaxation induced by ATP and ADP but not by adenosine was completely eliminated by endothelial denudation. In the superior mesenteric arteries isolated from SHR [vs. age-matched control Wistar Kyoto rats (WKY)], a) ATP-and ADP-induced relaxations were weaker, whereas adenosine-induced relaxation was similar in both groups, b) ATP-and ADP-induced relaxations were substantially and partly reduced by N G -nitro-L-arginine [a NO synthase (NOS) inhibitor], respectively, c) indomethacin, an inhibitor of COX, increased ATP-and ADP-induced relaxations, d) ADP-induced relaxation was weaker under combined inhibition by NOS and COX, and e) adenosine-induced relaxation was not altered by treatment with these inhibitors. These data indicate that levels of responsiveness to these nucleotides/adenosine vary in the superior mesenteric arteries from SHR and WKY and are differentially modulated by NO and COX-derived prostanoids.Key words adenosine; ADP; ATP; relaxation; spontaneously hypertensive rat Extracellular nucleotides and their metabolites including ATP, ADP, and adenosine play pivotal roles in (patho)-physiological processes, including immune responses, inflammation, cardiac fibrosis, atherosclerosis, hypertension, and diabetes.1-10) They also exert a variety of effects on the vasculature, such as platelet activation and alteration in smooth muscle contraction and relaxation, by activating plasmalemmal receptors (e.g., purinoceptors). 1,2,8,11,12) Purinoceptors are classified into two subtypes, namely P1 and P2, based on their pharmacological properties and molecular cloning characteristics.11,12) Adenosine and its phosphates ATP and ADP are endogenous ligands for P1 and P2 receptors, respectively. Several studies have suggested that the expression and signaling responses of these receptors is altered under disease conditions. 4,11,[13][14][15][16][17] Moreover, these receptors can mediate a variety of responses to several nucleotides, resulting in the existence of multiple receptors with overlapping ligand preferences. 11,18)Therefore, it is difficult to understand the effect of nucleotides on vascular function under pathophysiological conditions. Hypertension is a leading risk factor for cardiovascularassociated morbidity and mortality. An important and contributory element in sustained hypertension is an increase in vascular tone, potentially resulting from concurrently reduced relaxation and augmented contraction induced by various endogenous ligands. [19][20][21][22][23][24][25][26] Hypertension-associated vascular dysfunction is partly regulated by endothelium-derived factors. [21][22][23][24] There is a fine balance between endothelium-derived relaxing and contracting factors, a disturba...