title: Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil.
abstract: Phosphodiesterase type 5 (PDE5) inhibitors are used to treat erectile dysfunction, and growing evidence supports potential cardiovascular utility. Their efficacy declines with reduced nitric-oxide synthase (NOS) activity common to various diseases. We tested whether direct soluble guanylate cyclase (sGC) stimulation restores in vivo cardiovascular modulation by PDE5 inhibition despite acute or chronically suppressed NOS activity. Mice (C57/Bl6; n = 62) were studied by in vivo pressure-volume analysis to assess acute modulation by the PDE5 inhibitor sildenafil (SIL; 100 microg/kg/min) of the cardiac response to isoproterenol (ISO) with or without NOS inhibition [N(omega)-nitro-L-arginine methyl ester (L-NAME)] and cotreatment by the sGC stimulator 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-morpholinyl)pyrimidine-4,6-diamine (BAY 41-8543). SIL induced mild vasodilation but no basal cardiac effects and markedly blunted ISO-stimulated contractility. Acute BAY 41-8543 at a dose lacking cardiovascular effects did not alter ISO responses. However, after acute L-NAME, SIL ceased to influence cardiovascular function, but adding BAY 41-8543 fully restored SIL effects. After 1 week of L-NAME, neither SIL nor SIL + BAY 41-8543 acutely induced vasodilation or blunted ISO responses. However, sustained BAY 41-8543 despite concurrent NOS inhibition restored the cardiovascular efficacy of SIL. The disparity between acute and chronic NOS inhibition related to diffusion of PDE5 away from myocyte z-bands coupled with reduced protein kinase G activation. Both were restored by sustained sGC costimulation. Thus, PDE5 regulation of adrenergic reserve and systemic vasodilation depends upon NOS-induced cGMP/protein kinase G and can be enhanced by sustained low-level stimulation of sGC. This may prove beneficial for enhancing the efficacy of PDE5 inhibitors in conditions with chronically reduced NOS activity.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.forename: Manling
authors.initials: M
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Hsu
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000068677:Sildenafil Citrate; D000071756:Soluble Guanylyl Cyclase; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C450679:BAY 41-8543; D002316:Cardiotonic Agents; D009025:Morpholines; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester