Phosphodiesterase 5 attenuates the vasodilatory response in renovascular hypertension

PLoS One. 2013 Nov 15;8(11):e80674. doi: 10.1371/journal.pone.0080674. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure
  • Cyclic GMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
  • Disease Models, Animal
  • Hypertension, Renovascular / enzymology
  • Hypertension, Renovascular / genetics
  • Hypertension, Renovascular / metabolism*
  • Kidney / blood supply
  • Kidney / metabolism
  • Mice
  • Mice, Knockout
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Phosphodiesterase 5 Inhibitors / pharmacology
  • Piperazines / pharmacology
  • Purines / pharmacology
  • Sildenafil Citrate
  • Sulfones / pharmacology
  • Vasodilation* / genetics
  • Vasodilator Agents / pharmacology

Substances

  • Phosphodiesterase 5 Inhibitors
  • Piperazines
  • Purines
  • Sulfones
  • Vasodilator Agents
  • Nitric Oxide
  • Sildenafil Citrate
  • Nitric Oxide Synthase Type III
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Cyclic GMP

Grant support

This work was supported by a FoRUM grant of the Ruhr-University, Bochum. Johannes Stegbauer was supported by a Grant of the German Society of Hypertension and the Heinrich-Heine-University Duesseldorf. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.