PMID- 22783192
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121002
LR  - 20231105
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 3
DP  - 2012
TI  - Comparison of soluble guanylate cyclase stimulators and activators in models of 
      cardiovascular disease associated with oxidative stress.
PG  - 128
LID - 10.3389/fphar.2012.00128 [doi]
LID - 128
AB  - Soluble guanylate cyclase (sGC), the primary mediator of nitric oxide (NO) 
      bioactivity, exists as reduced (NO-sensitive) and oxidized (NO-insensitive) 
      forms. We tested the hypothesis that the cardiovascular protective effects of 
      NO-insensitive sGC activation would be potentiated under conditions of oxidative 
      stress compared to those of NO-sensitive sGC stimulation. The cardiovascular 
      effects of the NO-insensitive sGC activator GSK2181236A [a low, non-depressor 
      dose, and a high dose which lowered mean arterial pressure (MAP) by 5-10 mmHg] 
      and those of equi-efficacious doses of the NO-sensitive sGC stimulator BAY 
      60-4552 were assessed in (1) Sprague Dawley rats during coronary artery 
      ischemia/reperfusion (I/R) and (2) spontaneously hypertensive stroke prone rats 
      (SHR-SP) on a high salt/fat diet (HSFD). In I/R, neither compound reduced infarct 
      size 24 h after reperfusion. In SHR-SP, HSFD increased MAP, urine output, 
      microalbuminuria, and mortality, caused left ventricular hypertrophy with 
      preserved ejection fraction, and impaired endothelium-dependent vasorelaxation. 
      The low dose of BAY 60-4552, but not that of GSK2181236A, decreased urine output, 
      and improved survival. Conversely, the low dose of GSK2181236A, but not that of 
      BAY 60-4552, attenuated the development of cardiac hypertrophy. The high doses of 
      both compounds similarly attenuated cardiac hypertrophy and improved survival. In 
      addition to these effects, the high dose of BAY 60-4552 reduced urine output and 
      microalbuminuria and attenuated the increase in MAP to a greater extent than did 
      GSK2181236A. Neither compound improved endothelium-dependent vasorelaxation. In 
      SHR-SP isolated aorta, the vasodilatory responses to the NO-dependent compounds 
      carbachol and sodium nitroprusside were attenuated by HSFD. In contrast, the 
      vasodilatory responses to both GSK2181236A and BAY 60-4552 were unaltered by 
      HSFD, indicating that reduced NO-bioavailability and not changes in the oxidative 
      state of sGC is responsible for the vascular dysfunction. In summary, GSK2181236A 
      and BAY 60-4552 provide partial benefit against hypertension-induced end-organ 
      damage. The differential beneficial effects observed between these compounds 
      could reflect tissue-specific changes in the oxidative state of sGC and might 
      help direct the clinical development of these novel classes of therapeutic 
      agents.
FAU - Costell, Melissa H
AU  - Costell MH
AD  - Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular 
      Therapy Area Unit, GlaxoSmithKline King of Prussia, PA, USA.
FAU - Ancellin, Nicolas
AU  - Ancellin N
FAU - Bernard, Roberta E
AU  - Bernard RE
FAU - Zhao, Shufang
AU  - Zhao S
FAU - Upson, John J
AU  - Upson JJ
FAU - Morgan, Lisa A
AU  - Morgan LA
FAU - Maniscalco, Kristeen
AU  - Maniscalco K
FAU - Olzinski, Alan R
AU  - Olzinski AR
FAU - Ballard, Victoria L T
AU  - Ballard VL
FAU - Herry, Kenny
AU  - Herry K
FAU - Grondin, Pascal
AU  - Grondin P
FAU - Dodic, Nerina
AU  - Dodic N
FAU - Mirguet, Olivier
AU  - Mirguet O
FAU - Bouillot, Anne
AU  - Bouillot A
FAU - Gellibert, Francoise
AU  - Gellibert F
FAU - Coatney, Robert W
AU  - Coatney RW
FAU - Lepore, John J
AU  - Lepore JJ
FAU - Jucker, Beat M
AU  - Jucker BM
FAU - Jolivette, Larry J
AU  - Jolivette LJ
FAU - Willette, Robert N
AU  - Willette RN
FAU - Schnackenberg, Christine G
AU  - Schnackenberg CG
FAU - Behm, David J
AU  - Behm DJ
LA  - eng
PT  - Journal Article
DEP - 20120705
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC3389674
OTO - NOTNLM
OT  - BAY 60-4552
OT  - GSK2181236A
OT  - SHR-SP
OT  - VASP
OT  - cGMP
OT  - soluble guanylate cyclase
EDAT- 2012/07/12 06:00
MHDA- 2012/07/12 06:01
PMCR- 2012/07/05
CRDT- 2012/07/12 06:00
PHST- 2012/04/27 00:00 [received]
PHST- 2012/06/18 00:00 [accepted]
PHST- 2012/07/12 06:00 [entrez]
PHST- 2012/07/12 06:00 [pubmed]
PHST- 2012/07/12 06:01 [medline]
PHST- 2012/07/05 00:00 [pmc-release]
AID - 10.3389/fphar.2012.00128 [doi]
PST - epublish
SO  - Front Pharmacol. 2012 Jul 5;3:128. doi: 10.3389/fphar.2012.00128. eCollection 
      2012.