title: Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension.
abstract: 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.
authors.affiliation: Klinik für Nephrologie, Universitätsklinikum Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Friedrich
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Potthoff
authors.forename: Kathrin
authors.initials: K
authors.lastname: Broekmans
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Cortese-Krott
authors.forename: Ivo
authors.initials: I
authors.lastname: Quack
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Rump
authors.forename: Doris
authors.initials: D
authors.lastname: Koesling
authors.forename: Evanthia
authors.initials: E
authors.lastname: Mergia
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D006978:Hypertension, Renovascular / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014664:Vasodilation / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D052250:Nitric Oxide Synthase Type III; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP