Acute hypertension after nitric oxide synthase inhibition is mediated primarily by increased endothelin vasoconstriction

Banting, J. D.; Friberg, Peter; Adams, Michael

doi:10.1097/00004872-199608000-00007

Cited by 49 publications

(49 citation statements)

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“…However, an alternative explanation could be that a tonic release of endothelins occurs without demonstrable vasoconstriction because of antagonistic release of NO or other endogenous vasodilator mediators [16][17][18][19]. The current data suggest that this is the case for the systemic but not the pulmonary circulation, since inhibition of NO synthesis did not affect pulmonary vascular resistance but was associated with a bosentan-reversible increase in systemic vascular resistance [17].…”

Section: Pulmonary and Systemic Vascular Tone During Hyperoxia And Nomentioning

confidence: 54%

“…In anesthetised rats, mixed endothelin A and endothelin B receptor antagonism and selective endothelin A receptor antagonism did not affect Psa when given alone, but decreased it after NO synthase inhibition [16,17]. Blockade of NO synthase also increased the plasma levels of endothelin-1 [17].…”

Section: -Effects Of Bosentan Aftermentioning

confidence: 90%

“…However, some investigators have been unable to demonstrate pulmonary or systemic vascular effects of these compounds in vivo [7][8][9][10][11][12][13][14][15][16][17]. The failure to show a vasoconstrictor effect of endogenous endothelins appears related, at least in part, to the release of nitric oxide (NO) by the endothelium, which either counteracts the effect and/or inhibits the synthesis of endothelins [16][17][18][19].…”

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confidence: 99%

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Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction

Hubloue¹,

Biarent²,

Kafi³

et al. 2003

Eur Respir J

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The effects of endothelin receptor blockade on the pulmonary circulation have been reported variably, possibly in relation to a more or less important associated release of endogenous nitric oxide (NO). The aim of this study was to test whether endothelin antagonism would inhibit hypoxic pulmonary vasoconstriction, and if it would not, then would it do so after NO synthase inhibition.Hypoxic pulmonary vasoconstriction (HPV) was evaluated in anesthetised dogs by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow.Bosentan, an endothelin A and B receptor antagonist, did not affect baseline Ppa, Ppao or systemic arterial pressure (Psa) and did not alter HPV (n=8). The NO synthase inhibitor N G -nitro-L-arginine (L-NA) did not affect baseline Ppa and Ppao, but increased Psa and enhanced HPV (n=12). The addition of bosentan in these dogs did not affect baseline Ppa or Ppao, but decreased Psa and inhibited HPV. Exhaled NO was decreased by L-NA and by bosentan and abolished by L-NAzbosentan (n=9).The authors conclude that endogenous nitric oxide is released by, and opposes the vasoconstricting effects of, endothelins in vivo, reducing systemic blood pressure and limiting hypoxic pulmonary vasoconstriction.

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Section: Pulmonary and Systemic Vascular Tone During Hyperoxia And Nomentioning

confidence: 54%

Section: -Effects Of Bosentan Aftermentioning

confidence: 90%

mentioning

confidence: 99%

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Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction

Hubloue¹,

Biarent²,

Kafi³

et al. 2003

Eur Respir J

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“…ET has previously been shown to induce exaggerated vasoconstriction and cause renal damage in L-NAME-treated rodents (2,4,20) and has no affinity to the AT 1a R. Due to these reasons, the vascular response to ET was used as a measure of renal microvascular function.…”

Section: Resultsmentioning

confidence: 99%

Losartan increases NO release in afferent arterioles during regression ofl-NAME-induced renal damage

Helle

Iversen

Chatziantoniou

2010

American Journal of Physiology-Renal Physiology

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Inhibition of nitric oxide synthesis (NOS) induces hypertension and heavy proteinuria. Renal structure and function have shown striking improvement after interventions targeting ANG II or endothelin (ET) receptors in rats recovering after long-term NOS inhibition. To search for mechanisms underlying losartan-assisted regression of renal disease in rodents, we measured NO release and contractility to ET in afferent arterioles (AAs) from Sprague-Dawley rats recovering for 2 wk after 4 wk of N G -nitro-L-arginine methyl ester treatment. Losartan administration during the recovery period decreased blood pressure (113 Ϯ 4 vs. 146 Ϯ 5 mmHg, P Ͻ 0.01), reduced protein/creatinine ratio more (proteinuria decrease: ⌬1,836 Ϯ 214 vs. ⌬1,024 Ϯ 180 mg/mmol, P Ͻ 0.01), and normalized microvascular hypertrophy (AA media/lumen ratio: 1.74 Ϯ 0.05 vs. 2.09 Ϯ 0.08, P Ͻ 0.05) compared with no treatment. In diaminofluorescein-FM-loaded AAs from losartan-treated animals, NO release (% of baseline) was increased compared with untreated animals after stimulation with 10 Ϫ7 M ACh (118 Ϯ 4 vs. 90 Ϯ 7%, t ϭ 560 s, P Ͻ 0.001) and 10 Ϫ9 M ET (123 Ϯ 4 vs. 101 Ϯ 5%, t ϭ 560 s, P Ͻ 0.001). There was also a blunted contractile response to 10 Ϫ7 M ET in AAs from losartan-treated animals compared with untreated animals (⌬4.01 Ϯ 2.9 vs. ⌬14.6 Ϯ 1.7 m, P Ͻ 0.01), which disappeared after acute NOS inhibition (⌬10.7 Ϯ 3.7 vs. ⌬12.5 Ϯ 2.9 m, not significant). Contractile dose responses to ET (10 Ϫ9 , 10 Ϫ8 , 10 Ϫ7 M) were enhanced by NOS inhibition and blunted by exogenous NO (10 Ϫ2 mM S-nitroso-N-acetyl-penicillamine) in losartan-treated but not in untreated vessels. Reducing blood pressure similar to losartan with hydralazine did not improve AA hypertrophy, ET-induced contractility, ET-induced NO release, and NO sensitivity. In conclusion, blockade of the local action of ANG II improved endothelial function in AAs, a mechanism that is likely to contribute to the beneficial effects of AT 1aR antagonism during the recovery of renal function after long-term NOS inhibition in rats.endothelin; nitric oxide; endothelial dysfunction; angiotensin II; vascular remodeling DETERIORATION OF RENAL FUNCTION is a result of several mechanisms, such as disturbances of renal blood flow (RBF), endothelial dysfunction, inflammation, fibrosis, or increased deposition of extracellular matrix. At present, few therapeutic tools are available to halt these processes, and the final result is often chronic renal failure. The only available treatments for these patients are dialysis or renal transplantation, costly replacement therapies that are available only for a limited portion of the world's population. An important challenge in modern medicine is therefore the development of intervention strategies that may halt or reverse the development of chronic renal failure.Drugs that are able to suppress the renin-angiotensin system have shown remarkable results in reversal of chronic renal disease in rodents (1, 3). In contrast, large-scale human trials showed less effect of AT 1a...

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“…14 Thus, we applied the concept that a key adaptive response that occurs after NOS blockade is the dramatic up-regulation of the vasoconstrictor actions of endothelin. 15 To test the applicability of this concept in the penis we administered intravenously an ET receptor antagonist to rats prior to the L-NAME treatment. 16 The prior pharmacological blockade of ET receptor activation fully prevented any decrease in the apomorphine-induced erection responses that normally occurs following acute NOS blockade.…”

Section: Penile Control Systemsmentioning

confidence: 99%

Vascular control mechanisms in penile erection: phylogeny and the inevitability of multiple and overlapping systems

Adams

et al. 1997

Int J Impot Res

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A co-ordinated series of vascular events underlie the generation of a penile erection. The control and regulation of this simple event is, in fact, a complex of interactions occurring at multiple levels. Many of these individual pathways and responses have been studied extensively. The understanding of the necessity for the integration between the individual pathways into a complex of series and parallel coupled mechanisms provides a rationale for the development of a framework of multiple and overlapping systems. This paper sets out some of the principles of integrated and balanced control of vasodilation and vasoconstriction in the penis. In addition, the role of growth induction and regression and the importance of time as a factor in studying penile structure and function is discussed.

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Acute hypertension after nitric oxide synthase inhibition is mediated primarily by increased endothelin vasoconstriction

Cited by 49 publications

References 0 publications

Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction

Endogenous endothelins and nitric oxide in hypoxic pulmonary vasoconstriction

Losartan increases NO release in afferent arterioles during regression ofl-NAME-induced renal damage

Vascular control mechanisms in penile erection: phylogeny and the inevitability of multiple and overlapping systems

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