Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.

NO/cGMP signaling plays an important role in vascular relaxation and regulation of blood pressure. The key enzyme in the cascade, the NO-stimulated cGMP-forming guanylyl cyclase exists in two enzymatically indistinguishable isoforms (NO-GC1, NO-GC2) with NO-GC1 being the major NO-GC in the vasculatu...

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Autores principales:	Johannes Stegbauer, Sebastian Friedrich, Sebastian A Potthoff, Kathrin Broekmans, Miriam M Cortese-Krott, Ivo Quack, Lars Christian Rump, Doris Koesling, Evanthia Mergia
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8cc1768db3ab46b3992aefaba8290028
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spelling	oai:doaj.org-article:8cc1768db3ab46b3992aefaba82900282021-11-18T08:46:15ZPhosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.1932-620310.1371/journal.pone.0080674https://doaj.org/article/8cc1768db3ab46b3992aefaba82900282013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24260450/?tool=EBIhttps://doaj.org/toc/1932-6203NO/cGMP signaling plays an important role in vascular relaxation and regulation of blood pressure. The key enzyme in the cascade, the NO-stimulated cGMP-forming guanylyl cyclase exists in two enzymatically indistinguishable isoforms (NO-GC1, NO-GC2) with NO-GC1 being the major NO-GC in the vasculature. Here, we studied the NO/cGMP pathway in renal resistance arteries of NO-GC1 KO mice and its role in renovascular hypertension induced by the 2-kidney-1-clip-operation (2K1C). In the NO-GC1 KOs, relaxation of renal vasculature as determined in isolated perfused kidneys was reduced in accordance with the marked reduction of cGMP-forming activity (80%). Noteworthy, increased eNOS-catalyzed NO formation was detected in kidneys of NO-GC1 KOs. Upon the 2K1C operation, NO-GC1 KO mice developed hypertension but the increase in blood pressures was not any higher than in WT. Conversely, operated WT mice showed a reduction of cGMP-dependent relaxation of renal vessels, which was not found in the NO-GC1 KOs. The reduced relaxation in operated WT mice was restored by sildenafil indicating that enhanced PDE5-catalyzed cGMP degradation most likely accounts for the attenuated vascular responsiveness. PDE5 activation depends on allosteric binding of cGMP. Because cGMP levels are lower, the 2K1C-induced vascular changes do not occur in the NO-GC1 KOs. In support of a higher PDE5 activity, sildenafil reduced blood pressure more efficiently in operated WT than NO-GC1 KO mice. All together our data suggest that within renovascular hypertension, cGMP-based PDE5 activation terminates NO/cGMP signaling thereby providing a new molecular basis for further pharmacological interventions.Johannes StegbauerSebastian FriedrichSebastian A PotthoffKathrin BroekmansMiriam M Cortese-KrottIvo QuackLars Christian RumpDoris KoeslingEvanthia MergiaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e80674 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Johannes Stegbauer Sebastian Friedrich Sebastian A Potthoff Kathrin Broekmans Miriam M Cortese-Krott Ivo Quack Lars Christian Rump Doris Koesling Evanthia Mergia Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
description	NO/cGMP signaling plays an important role in vascular relaxation and regulation of blood pressure. The key enzyme in the cascade, the NO-stimulated cGMP-forming guanylyl cyclase exists in two enzymatically indistinguishable isoforms (NO-GC1, NO-GC2) with NO-GC1 being the major NO-GC in the vasculature. Here, we studied the NO/cGMP pathway in renal resistance arteries of NO-GC1 KO mice and its role in renovascular hypertension induced by the 2-kidney-1-clip-operation (2K1C). In the NO-GC1 KOs, relaxation of renal vasculature as determined in isolated perfused kidneys was reduced in accordance with the marked reduction of cGMP-forming activity (80%). Noteworthy, increased eNOS-catalyzed NO formation was detected in kidneys of NO-GC1 KOs. Upon the 2K1C operation, NO-GC1 KO mice developed hypertension but the increase in blood pressures was not any higher than in WT. Conversely, operated WT mice showed a reduction of cGMP-dependent relaxation of renal vessels, which was not found in the NO-GC1 KOs. The reduced relaxation in operated WT mice was restored by sildenafil indicating that enhanced PDE5-catalyzed cGMP degradation most likely accounts for the attenuated vascular responsiveness. PDE5 activation depends on allosteric binding of cGMP. Because cGMP levels are lower, the 2K1C-induced vascular changes do not occur in the NO-GC1 KOs. In support of a higher PDE5 activity, sildenafil reduced blood pressure more efficiently in operated WT than NO-GC1 KO mice. All together our data suggest that within renovascular hypertension, cGMP-based PDE5 activation terminates NO/cGMP signaling thereby providing a new molecular basis for further pharmacological interventions.
format	article
author	Johannes Stegbauer Sebastian Friedrich Sebastian A Potthoff Kathrin Broekmans Miriam M Cortese-Krott Ivo Quack Lars Christian Rump Doris Koesling Evanthia Mergia
author_facet	Johannes Stegbauer Sebastian Friedrich Sebastian A Potthoff Kathrin Broekmans Miriam M Cortese-Krott Ivo Quack Lars Christian Rump Doris Koesling Evanthia Mergia
author_sort	Johannes Stegbauer
title	Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
title_short	Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
title_full	Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
title_fullStr	Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
title_full_unstemmed	Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
title_sort	phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/8cc1768db3ab46b3992aefaba8290028
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Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.

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