Induction of PDE5 and de-sensitization to endogenous NO signaling in a systemic resistance artery under altered blood flow.
In the classical pathway, the opposing activities of guanylyl cyclases (GC) and phosphodiesterases (PDE), and the effect of the cGMP-dependent protein kinase (cGK) on its targets, determine the biological responses to NO signaling. Here we tested the hypothesis that vascular dysfunction may be due to altered expression and activity of these effectors of NO signaling. Every other set of rat second order mesenteric resistance arteries (MA) were ligated, resulting in chronic low flow (LF) in the upstream MA1 and high flow (HF) in the adjacent MA1 without tissue ischemia. eNOS and iNOS were up-regulated in HF and LF MA1, respectively, in the sub-acute phase (four days) of vascular remodeling. The Day4 HF/LF MA1s were under increased control of NO as indicated by reduced sensitivity to the vasoconstrictor phenylephrine and its normalization with the NOS antagonist L-NAME. PDE5 mRNA and protein were also significantly up-regulated in the HF/LF MA1 with no change in sGC or PKG1, an effect that was dependent upon NO synthesis. The PDE5 inhibitor Sildenafil was several-fold more powerful in relaxing the HF/LF MA1s, and pre-treatment with Sildenafil uncovered an increased responsiveness of HF/LF MA1s to the NO donor DEA/NO. We conclude that induction of PDE5 de-sensitizes this systemic resistance artery to sustained NO signaling under chronic HF/LF. Treatment with PDE5 antagonists, in contrast to NO donors, may more specifically and effectively increase blood flow to chronically hypo-perfused tissues.
Department of Medicine (Cardiology), Case Western Reserve School of Medicine, 4-533 Wolstein Research Bldg., 2103 Cornell Rd., Cleveland, OH 44106, USA.
Haiying
H
Zhang
Praveen
P
Pakeerappa
Hyon Jae
HJ
Lee
Steven A
SA
Fisher
D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D006834:Hydrazines; D020030:Nitric Oxide Donors; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester