Effect of H-8, an isoquinolinesulfonamide inhibitor of cyclic nucleotide-dependent protein kinase, on cAMP- and cGMP-mediated vasorelaxation.
We theorized that H-8, N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide, an inhibitor of cyclic nucleotide-dependent protein kinases, might be a useful probe to assess cyclic nucleotide-dependent relaxation of blood vessels. However, working in the rat caudal artery and aorta, we found that neither cyclic AMP- nor cyclic GMP-mediated relaxations were diminished by even large doses of H-8. For example, in the caudal artery, relaxation of a phenylephrine contraction by 8-bromo-cGMP (10(-5) M) was unaffected by H-8: control, 33 +/- 6.2%; 10 microM H-8, 41 +/- 12%; 30 microM H-8, 30 +/- 16% (p NS). The amount of relaxation by 8-bromo-cAMP (3 x 10(-4) M) was actually increased by H-8: control, 29 +/- 7.6%; 10 microM H-8, 34 +/- 7.4%; 30 microM H-8, 80 +/- 14%. In the rat aorta, H-8 also failed to diminish relaxation induced by 8-bromo-cGMP, or by atriopeptin II or sodium nitroprusside. In both caudal artery and aorta, H-8 of itself caused a dose-dependent suppression of alpha-adrenergic contraction: for example, in the caudal artery, with 10 or 30 microM H-8, peak contraction to phenylephrine was reduced to 70 (SEM) +/- 12% or 52 +/- 7% of control, respectively. The results suggest that the protein kinase inhibitor H-8 is not a useful probe to study cyclic nucleotide-dependent relaxation.
Daugirdas
J T
JT
Department of Medicine, University of Illinois, Chicago School of Medicine.
Zhou
H L
HL
Tamulaitis
V V
VV
Nutting
C W
CW
Fiscus
R R
RR
D000818:Animals; D001011:Aorta / Q000502:physiology; D001158:Arteries / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D010656:Phenylephrine; C016276:8-bromocyclic GMP; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D006152:Cyclic GMP