title: The selective Rho-kinase inhibitor azaindole-1 has long-lasting erectile activity in the rat.
abstract: OBJECTIVE
  To investigate the effects of the selective Rho-associated protein kinase (ROCK) inhibitor azaindole-1 on erectile function under physiologic and pathophysiologic conditions in the rat.
  
  
  METHODS
  The effect of intracavernosal (i.c.) injections of azaindole-1 on change in intracavernous pressure (ICP), ICP/mean arterial pressure (MAP), area under the curve (AUC), and response duration were investigated in the anesthetized rat under control conditions and when nonadrenergic noncholinergic neurotransmission and cholinergic function or soluble guanylyl cyclase (sGC) were inhibited or after cavernosal nerve crush injury.
  
  
  RESULTS
  The i.c. injections of azaindole-1 produced dose-related increases in ICP/MAP and AUC that were long-lasting at the highest doses studied compared with the prototypical ROCK inhibitor fasudil. Erectile responses were not altered by 7-nitroindazole and atropine in doses that reduced the response to cavernosal nerve stimulation by 86%, indicating that they were independent of NO release by cavernosal nerves or activation of muscarinic receptors in the corpora cavernosa. Erectile responses to azaindole-1 were not altered by the sGC inhibitor ODQ in a dose that attenuated responses to the NO donor sodium nitroprusside, indicating that they were independent of an action on sGC. The erectile response to i.c. injections of azaindole-1 or Y-27632, which was reported to be NO/cyclic guanosine monophosphate-dependent, was not attenuated after cavernosal nerve crush injury.
  
  
  CONCLUSIONS
  The present studies indicate that azaindole-1 has long-lasting erectile activity that is independent of NO release, muscarinic receptor, or sGC activation or the integrity of the cavernosal nerves.
authors: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699, USA.
authors: George F
authors: GF
authors: Lasker
authors: Edward A
authors: EA
authors: Pankey
authors: Alexander V
authors: AV
authors: Allain
authors: Subramanyam N
authors: SN
authors: Murthy
authors: Johannes-Peter
authors: JP
authors: Stasch
authors: Philip J
authors: PJ
authors: Kadowitz
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001285:Atropine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003959:Diamines / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology*; D010413:Penis / Q000294:innervation; D059348:Peripheral Nerve Injuries / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: C526226:(6-chloro-N4-(3,5-difluoro-4-((3-methyl-1H-pyrrolo(2,3-b)pyridin-4-yl)oxy)-phenyl)pyrimidine-2,4-diamine); C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000577:Amides; D003959:Diamines; D004791:Enzyme Inhibitors; D007191:Indazoles; D018727:Muscarinic Antagonists; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011810:Quinoxalines; D011976:Receptors, Muscarinic; C108830:Y 27632; D009569:Nitric Oxide; D001285:Atropine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D006162:Guanylate Cyclase; C049347:fasudil; C080122:7-nitroindazole
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