Inhibition of rho-kinase by hydroxyfasudil prevents vasopressin-induced myocardial ischemia in Donryu rats by attenuating coronary vasoconstriction.
BACKGROUND
Inhibition of rho-kinase has been shown to attenuate vasopressin (AVP)-induced myocardial ischemia measured as S-wave depression in Donryu rats. This has been attributed to a direct inhibitory effect on AVP-induced coronary vasoconstriction. However, since AVP also increased mean arterial blood pressure (MAP) which was attenuated by the rho-kinase inhibitors used, the prevention of myocardial ischemia could have been due to effects on afterload.


RESULTS
The purpose of this study was to determine if rho-kinase inhibition prevents S-wave depression independent of the effects on blood pressure. In anesthetized Donryu rats (200-340 g), infusion of AVP (0.1 IU/kg) resulted in a sustained increase in MAP (DeltaMAP=46+/-7 mm Hg) and a transient S-wave depression (-90+/-20 microV). Infusion of phenylephrine titrated to achieve a comparable pressor response (DeltaMAP=52+/-2 mm Hg) resulted in a significantly smaller S-wave depression (-30+/-20 microV). Pretreatment with the rho-kinase inhibitor, hydroxyfasudil (3 mg/kg), decreased MAP by -28+/-2 mm Hg and significantly attenuated AVP-induced S-wave depression (-10+/-10 microV) compared to AVP. When rats were pretreated with phenylephrine titrated to maintain MAP, hydroxyfasudil still significantly attenuated AVP-induced S-wave depression (-14+/-12 microV). Hydralazine (1 mg/kg), which lowered MAP by -36+/-5 mm Hg, had no significant effect on AVP-induced S-wave depression (-105+/-32 microV).


CONCLUSIONS
These data indicate that inhibition of rho-kinase with hydroxyfasudil attenuates AVP-induced myocardial ischemia independent of changes in MAP and are consistent with an inhibitory effect on coronary vasoconstriction.
Vincelette
Jon
J
Berlex Biosciences, Richmond, CA 94804, USA.
Pagila
Rene
R
Kawai
Kohichi
K
Ishii
Masaaki
M
Horimizu
Yuko
Y
Vergona
Ronald
R
Sullivan
Mark E
ME
Morser
John
J
Dole
William P
WP
Wang
Yi-Xin
YX
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin; D001794:Blood Pressure / Q000187:drug effects; D004562:Electrocardiography; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D017202:Myocardial Ischemia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D014665:Vasodilator Agents; C431085:hydroxyfasudil; D001127:Arginine Vasopressin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases