The role of NO-cGMP pathway and potassium channels on the relaxation induced by clonidine in the rat mesenteric arterial bed

Pimentel, Adriana M.; Costa, Cristiane Aguiar da; Carvalho, Lenize Costa Reis Marins de; Brandão, Ricardo; Rangel, B.; Tano, T.; Moura, Roberto Soares de; Resende, Ângela Castro

doi:10.1016/j.vph.2006.12.003

Cited by 14 publications

(9 citation statements)

References 28 publications

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“…Clonidine has also been reported to stimulate peripheral α 2 receptors and induce vasodilatation through the activation of α 2 receptors in endothelial cells. This effect can be blocked by l ‐NAME, an inhibitor of NOS, suggesting that NO pathway may be involved in this process . The “rescue” effect of clonidine and methyldopa on eNOS mRNA expression in the presence of TNF‐α shown in our in vitro model also suggests the involvement of endothelial α 2 receptors and the NO pathway in the action of methyldopa and clonidine.…”

Section: Discussionsupporting

confidence: 57%

Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor‐α inhibited endothelial nitric oxide synthase expression in endothelial‐trophoblast cellular networks

Bobek

Makris

et al. 2017

Clin Exp Pharma Physio

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Medications used to control hypertension in pregnancy also improve trophoblast and endothelial cellular interaction in vitro. Tumour necrosis factor-α (TNF-α) inhibits trophoblast and endothelial cellular interactions and simultaneously decreases endothelial nitric oxide synthase (eNOS) expression. This study investigated whether antihypertensive medications improved these cellular interactions by modulating eNOS and inducible nitric oxide synthase (iNOS) expression. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose TNF-α (0.5 ng/mL) or TNF-α plus soluble fms-like tyrosine kinase-1 (sFlt-1) (100 ng/mL). The endothelial cells were cultured on Matrigel. After endothelial cellular networks appeared, trophoblast derived HTR-8/SVneo cells were co-cultured in the presence of clinically relevant doses of methyldopa, labetalol, hydralazine or clonidine for 24 hours. Cells were retrieved from the Matrigel to extract mRNA and eNOS and iNOS expression were examined by quantitative PCR. Methyldopa, labetalol, hydralazine and clonidine reversed the inhibitory effect of TNF-α on eNOS mRNA expression. After pre-incubating endothelial cells with TNF-α and sFlt-1, all the medications except methyldopa lost their effect on eNOS mRNA expression. In the absence of TNF-α, antihypertensive medications did not change eNOS expression. The mRNA expression of iNOS was not affected by TNF-α or any medications. This study shows that selected antihypertensive medications used in the treatment of hypertension in pregnancy increase eNOS expression in vitro when induced by the inflammatory TNF-α. The anti-angiogenic molecule sFlt-1 may antagonise the potential benefit of these medications by interfering with the NOS pathway.

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Section: Discussionsupporting

confidence: 57%

Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor‐α inhibited endothelial nitric oxide synthase expression in endothelial‐trophoblast cellular networks

Bobek

Makris

et al. 2017

Clin Exp Pharma Physio

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“…Our data show that S100A1 KO mice have greater peripheral vasoconstrictive responses than WT mice to xylazine injection, which could possibly be attributed to an increased response of VSMCs to the agonist and/or a reduced endothelium-dependent vasodilatation, given that ␣ 2 -ARs are also functionally expressed on the vascular endothelium and produce vasorelaxation upon activation (2,30,39). Previous studies (31,45) have suggested that endothelial ␣ 2 -ARs may be involved in the antihypertensive action of clonidine (31,45). On the other hand, we believe that central autonomic dysregulation could not have explain the effects of xylazine in our KO mice given that components of the central effect were not different between the two groups, as seen by Fig.…”

Section: Discussionmentioning

confidence: 49%

Lack of S100A1 in mice confers a gender-dependent hypertensive phenotype and increased mortality after myocardial infarction

Desjardins

Pourdjabbar²,

Quan³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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S100A1 is a small Ca(2+)-binding protein expressed in the myocardium and blood vessels that is downregulated in the diseased heart and plays a role in the regulation of cardiac muscle Ca(2+) homeostasis and contractility. To understand its physiological role under basal conditions and after myocardial infarction (MI), we used a mouse strain with targeted deletion of the S100A1 gene [S100A1 knockout (KO) mice]. We compared 49 wild-type (WT) and 56 S100A1 KO mice (6-8 wk old) over 28 days after MI with sham-operated controls. We also examined the effect of S100A1 deficiency on vascular function of isolated blood vessels. S100A1 KO mice demonstrated worse survival compared with WT mice (21% vs. 69%, respectively, P < 0.001). Hemodynamic evaluation revealed a higher mean arterial pressure (MAP) in sham-operated KO animals compared with WT animals (99 +/- 4 vs. 77 +/- 3 mmHg, respectively, P < 0.001) that persisted in both groups after MI (86 +/- 2 vs. 66 +/- 4 mmHg, respectively, P < 0.001). Sham-operated male S100A1 KO mice had higher MAP than female KO mice (122 +/- 5 vs. 93 +/- 3 mmHg, respectively P < 0.05) and reduced survival after MI (4% vs. 27%, respectively, P < 0.05). In isolated aortas and mesenteric arteries, ACh-evoked vasodilatation in KO mice was significantly reduced compared with WT mice (P < 0.05). Nitric oxide production was reduced in endothelial cells isolated from KO mice. Thus, absence of S100A1 results in acute functional impairment and high mortality after MI associated with a gender-specific hypertensive phenotype. S100A1 appears to play a role in the endothelium-dependent regulation of blood pressure.

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“…The contribution of NO and EDHF to endotheliumdependent vasodilation varies according to the vessel studied (27). In the rat isolated MAB, muscarinic receptor-induced vasorelaxation has two components: one is L-NAME sensitive and the other is sensitive to K + -channel blockers, presumably mediated via NO and EDHF, respectively (28,29). In our experiments, the inhibitory effect of L-NOARG and high K + on the PRFinduced vasorelaxation was further enhanced when those inhibitors were perfused simultaneously.…”

Section: +mentioning

confidence: 99%

Mechanisms Underlying the Vasorelaxant Effect Induced by Proanthocyanidin-Rich Fraction From Croton celtidifolius in Rat Small Resistance Arteries

et al. 2008

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Abstract. Proanthocyanidins are condensed tannins present in fruits, vegetables, and flowers, consumed in the human diet. These compounds are believed to decrease coronary heart disease. The present study was designed to investigate the relaxing effects of a proanthocyanidin-rich fraction (PRF) obtained from Croton celtidifolius BAILL (Euphorbiaceae) barks in rat mesenteric arterial bed (MAB) and isolated mesenteric artery (MA). In the MAB pre-contracted with phenylephrine (Phe), PRF (0.1 -100 µg) induced a concentration-dependent relaxation of 73% (compared to the control). This effect was significantly reduced by the nitric oxide (NO) synthase inhibitor N ω -nitro-L-arginine (L-NOARG) or high K + solution and completely abolished in vessels perfused with KCl plus L-NOARG. However, the vasorelaxant effect was not altered by indomethacin, atropine, yohimbine, pyrilamine, or K + -channel blockers: BaCl 2 , glibenclamide, ouabain, and 4-aminopyridine. In isolated MA pre-contracted with Phe, PRF also induced a concentration-dependent relaxation (0.1 -30 µg/ mL), which was in turn inhibited by endothelial removal, guanylyl cyclase inhibitor 1H [1,2,3]oxadiazolo [4,3-alpha]quinoxalin, charybdotoxin (ChTx), and ChTx plus apamin. Moreover, the relaxant effect was not altered by HOE140 and apamin given alone. The present study demonstrates that the vasorelaxing effect of PRF is dependent upon the NO-cGMP pathway in combination with hyperpolarization due to activation of Ca 2+-dependent K + channels.

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The role of NO-cGMP pathway and potassium channels on the relaxation induced by clonidine in the rat mesenteric arterial bed

Cited by 14 publications

References 28 publications

Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor‐α inhibited endothelial nitric oxide synthase expression in endothelial‐trophoblast cellular networks

Antihypertensive methyldopa, labetalol, hydralazine, and clonidine reversed tumour necrosis factor‐α inhibited endothelial nitric oxide synthase expression in endothelial‐trophoblast cellular networks

Lack of S100A1 in mice confers a gender-dependent hypertensive phenotype and increased mortality after myocardial infarction

Mechanisms Underlying the Vasorelaxant Effect Induced by Proanthocyanidin-Rich Fraction From Croton celtidifolius in Rat Small Resistance Arteries

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