Role of ET-1 receptor binding and [Ca<sup>2+</sup>]<sub>i</sub> in contraction of  coronary arteries from DOCA-salt hypertensive rats

Giulumian, Ararat D.; Molero, Mariela M.; Reddy, Vikram; Pollock, Jennifer S.; Pollock, David M.; Fuchs, Leslie C.

doi:10.1152/ajpheart.00627.2001

Cited by 10 publications

(15 citation statements)

References 32 publications

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“…24 16,24 -26 In contrast, the contractile response to ET-1 is significantly diminished in the DOCA-salt hypertensive rat compared with the normotensive rat. 27,28 Furthermore, the lower density of ET-A receptor on vascular smooth muscle has been reported in DOCA-salt hypertensive rats. 27 In addition, the increment of [Ca 2ϩ ] i induced by ET-1 also decreased in vascular smooth muscle from DOCA-salt hypertensive rats.…”

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“…27 In addition, the increment of [Ca 2ϩ ] i induced by ET-1 also decreased in vascular smooth muscle from DOCA-salt hypertensive rats. 28,29 Although the changes in the receptor number and intracellular Ca 2ϩ levels have been reported, the clear reason for this diminution in response to ET-1 in DOCA-salt hypertensive rats has not been elucidated.In the present study, because the MAPK pathway is an important mediator of vascular contraction, we hypothesized that this pathway regulates the diminished contractile response to ET-1 during DOCA-salt hypertension. To test this hypothesis, we examined the roles of MAPK isoforms and the decreased responsiveness to ET-1 in contraction between sham-operated and DOCA-salt hypertensive rats.…”

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“…The results from mechanical study are consistent with earlier studies. 24,27,28 To determine whether MAPK influences receptor agonistinduced responses, the activity of MAPK was measured using phosphorylated MAPK antibodies in aortic smooth muscles from sham-operated and DOCA-salt hypertensive rats. In the quiescent state without any stimulant, the phosphorylation of ERK1/2 was significantly greater in DOCA-salt hypertensive rat (182.0Ϯ19.3% of sham-operated rats, nϭ5).…”

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p38 Mitogen-Activated Protein Kinase Contributes to the Diminished Aortic Contraction by Endothelin-1 in DOCA-Salt Hypertensive Rats

et al. 2004

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Abstract-We investigated whether the diminished contractile responsiveness to endothelin-1 (ET-1) is associated with the altered activation of mitogen-activated protein kinase (MAPK) in aortic smooth muscles from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. ET-1 dose-dependently increased contractions in aortic smooth muscle strips, and the contractions were significantly attenuated in tissues from DOCA-salt hypertensive rats compared with those from sham-operated rats. The phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was elevated by ET-1, with the magnitude and time-course being similar between strips. Although ET-1 also increased the phosphorylation of p38 MAPK in both strips, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. 5-Hydroxytryptamine (5-HT) increased vascular contraction and phosphorylation of both MAPK isoforms; these were greater in DOCA-salt hypertensive rats than in sham-operated rats. ET-1 also increased the phosphorylation of caldesmon, an actin-binding protein, in sham-operated and DOCA-salt hypertensive rats. However, the increment was markedly lower in the strips from DOCA-salt hypertensive rats compared with sham-operated controls. The phosphorylation of MAPK isoforms and caldesmon elevated by ET-1 was inhibited by PD098059, an inhibitor of ERK1/2 kinase, and SB203580, an inhibitor of p38 MAPK, respectively. These results suggest that ET-1 and 5-HT induce contraction by activating the MAPK pathway in rat aortic smooth muscle and that the diminished responsiveness to ET-1 in the DOCA-salt hypertensive rat may be, in part, mediated by the decrease of caldesmon phosphorylation after the decreased activation of p38 MAPK. 3,4 Previous reports have shown that ET-1 induces a sustained contraction, which results from the increase of [Ca 2ϩ ] i in isolated vascular smooth muscle. 5,6 In addition to the [Ca 2ϩ ] i -MLC kinase pathway, a number of intracellular signal molecules, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphatidylinositol 3 kinase (PI3K), and Rho kinase, play important roles in the regulation of smooth muscle contraction. 4,7-10 ET-1 can also stimulate these kinases.MAPK is a family of serine/threonine-specific protein kinase, consisting of three isoforms: extracellular signalregulated kinase (ERK) 1/2, p38 MAPK, and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). 11,12 MAPK plays a central role in intracellular signal transduction initiated by extracellular stimuli, including growth factors, neurotransmitters, and hormones. 13,14 ERK1/2 is activated by receptor agonists, including angiotensin II and phenylephrine, which induce smooth muscle contraction. 15,16 ET-1 also increases the activity of ERK1/2 in vascular smooth muscle. [17][18][19] There is accumulating evidence that the MAPK pathway is closely linked to modulating the intensity of contraction in vascular smooth muscle. 15,20 -23 Moreover, the inhibition of p...

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p38 Mitogen-Activated Protein Kinase Contributes to the Diminished Aortic Contraction by Endothelin-1 in DOCA-Salt Hypertensive Rats

et al. 2004

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“…Therefore, as shown for the kidney, several specific ET responses apparently exist in the heart (Nambi et al, 2001) which represent not only a prohypertrophic stimulus for cardiomyocytes but also stimulate fibroblasts (Tsuruda et al, 2002) and vascular smooth muscle cells (VSMC; Giulumian et al, 2002), as indicated by earlier studies using ET-receptor blockers (Amann et al, 2000;Nabokov et al, 1999).…”

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Gene expression profiling on global cDNA arrays gives hints concerning potential signal transduction pathways involved in cardiac fibrosis of renal failure

Amann

Ridinger²,

Rutenberg³

et al. 2003

Comp Funct Genom

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Cardiac remodelling with interstitial fibrosis in renal failure, which so far is only poorly understood on the molecular level, was investigated in the rat model by a global gene expression profiling analysis. Sprague-Dawley rats were subjected to subtotal nephrectomy (SNX) or sham operation (sham) and followed for 2 and 12 weeks, respectively. Heart-specific gene expression profiling, with RZPD Rat Unigene-1 cDNA arrays containing about 27 000 gene and EST sequences revealed substantial changes in gene expression in SNX compared to sham animals. Motor protein genes, growth and differentiation markers, and extracellular matrix genes were upregulated in SNX rats. Obviously, not only genes involved in cardiomyocyte hypertrophy, but also genes involved in the expansion of non-vascular interstitial tissue are activated very early in animals with renal failure. Together with earlier findings in the SNX model, the present data suggest the hypothesis that the local renin-angiotensin system (RAS) may be activated by at least two pathways: (a) via second messengers and Gproteins (short-term signalling); and (b) via motor proteins, actins and integrins (longterm signalling). The study documents that complex hybridization analysis yields reproducible and promising results of patterns of gene activation pointing to signalling pathways involved in cardiac remodelling in renal failure. The complete array data are available via http://www.rzpd.de/cgi-bin/services/exp/viewExpressionData.pl.cgi

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Endothelin‐1‐induced venous contraction is maintained in DOCA‐salt hypertension; studies with receptor agonists

Watts

Fink

Northcott

et al. 2002

British J Pharmacology

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1 Deoxycorticosterone acetate (DOCA) salt hypertension is associated with an endothelin-1 (ET-1)-dependent increase in arterial resistance and mean circulatory ®lling pressure. Contraction of endothelium-intact arteries and veins from sham and DOCA-salt hypertensive rats to agonists of the ET A (ET-1 (1 ± 31) ) and ET B receptor (sarafotoxin 6c; S6c) was investigated in tissue baths as was expression of mRNA for ET-1 and mRNA and protein for the ET A and ET B receptor. 2 ET-1 (1 ± 31) contracted aorta and vena cava from sham rats with a 30 fold lower potency than ET-1. Contraction was not altered by the ET B receptor antagonist BQ788 (100 nM) but was abolished by the ET A receptor antagonist ABT-627 (30 nM). 3 In DOCA-salt thoracic aorta, maximum contraction to ET-1 and ET-1 (1 ± 31) was reduced (36.6+6.3 and 13.3+4.4% of sham response, respectively); aorta did not contract to S6c. 4 In vena cava from DOCA-salt rats, contraction to ET-1 and ET-1 (1 ± 31) was not reduced compared to sham contraction; vena cava from sham and DOCA-salt rats contracted to S6c with a similar potency. 5 Real time RT ± PCR revealed that prepro ET-1 mRNA was increased 6.6+3.3 fold and 8.7+3.9 fold greater in DOCA-salt aorta and vena cava, respectively, compared to sham. Vena cava expressed a higher content of ET A and ET B receptor mRNA than aorta (P50.05), but no dierences were observed between sham and DOCA-salt tissues. ET A and ET B receptor protein was identi®ed in all tissues. Immunoreactive ET A receptor, observed as a 65, 30 and 28 kDa bands, was expressed 400% greater in DOCA-salt aorta compared to sham, but was not altered in vena cava. Immunoreactive ET B receptor, observed as 120, 45 and 30 kDa bands, tended to be higher in vena cava compared to aorta, but was not dierent in sham and DOCA-salt vena cava. 6 These results suggest that ET A receptor function is impaired in aorta but not vena cava of DOCA-salt rats. The ET B receptor was present in the aorta but, unlike in veins, does not mediate contraction directly. A sustained response to ET-1 in the venous circulation may contribute to the elevated blood pressure in the DOCA-salt model.

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Role of ET-1 receptor binding and [Ca²⁺]_i in contraction of coronary arteries from DOCA-salt hypertensive rats

Cited by 10 publications

References 32 publications

p38 Mitogen-Activated Protein Kinase Contributes to the Diminished Aortic Contraction by Endothelin-1 in DOCA-Salt Hypertensive Rats

p38 Mitogen-Activated Protein Kinase Contributes to the Diminished Aortic Contraction by Endothelin-1 in DOCA-Salt Hypertensive Rats

Gene expression profiling on global cDNA arrays gives hints concerning potential signal transduction pathways involved in cardiac fibrosis of renal failure

Endothelin‐1‐induced venous contraction is maintained in DOCA‐salt hypertension; studies with receptor agonists

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Role of ET-1 receptor binding and [Ca2+]i in contraction of coronary arteries from DOCA-salt hypertensive rats

Cited by 10 publications

References 32 publications

p38 Mitogen-Activated Protein Kinase Contributes to the Diminished Aortic Contraction by Endothelin-1 in DOCA-Salt Hypertensive Rats

p38 Mitogen-Activated Protein Kinase Contributes to the Diminished Aortic Contraction by Endothelin-1 in DOCA-Salt Hypertensive Rats

Gene expression profiling on global cDNA arrays gives hints concerning potential signal transduction pathways involved in cardiac fibrosis of renal failure

Endothelin‐1‐induced venous contraction is maintained in DOCA‐salt hypertension; studies with receptor agonists

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Role of ET-1 receptor binding and [Ca²⁺]_i in contraction of coronary arteries from DOCA-salt hypertensive rats