cGMP-kinase mediates cGMP- and cAMP-induced Ca2+ desensitization of skinned rat artery

Eur J Pharmacol. 1997 Mar 26;323(1):75-82. doi: 10.1016/s0014-2999(97)00028-9.

Abstract

(Rp)-8-Bromo-guanosine 3',5'-cyclic monophosphorothioate (Rp-8-Br-cGMPS) inhibited competitively both isozymes of type I alpha and I beta cGMP-dependent protein kinase (cGMP-kinase) purified from porcine aorta with apparent Ki values (microM) of 3.7 for I alpha and 1.8 for I beta. The compound also inhibited bovine heart type II cAMP-dependent protein kinase (cAMP-kinase), but with a Ki of 25 microM. Thus, it is a selective inhibitor of cGMP-kinase. In alpha-toxin-skinned smooth muscle preparations from rat mesenteric artery, 8-Br-cGMP (10(-7) M) and 8-Br-cAMP (10(-6) M) produced a rightward shift of the concentration-contraction curves for Ca2+, denoting a decrease in Ca2+ sensitivity of the contractile elements. The shift by 8-Br-cAMP as well as by 8-Br-cGMP was completely reversed by Rp-8-Br-cGMPS, while a selective inhibitor of activation of cAMP-kinase, (Rp)-adenosine-3',5'-cyclic monophosphorothioate (Rp-cAMPS), was without effects on the shift produced by these two compounds. These findings indicate the pivotal role that the activation of cGMP-kinase plays in the production of a decrease in Ca2+ sensitivity of contractile elements.

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Analysis of Variance
  • Animals
  • Aorta / drug effects
  • Aorta / enzymology
  • Calcium / metabolism
  • Cattle
  • Cyclic AMP / pharmacology
  • Cyclic AMP-Dependent Protein Kinase Type II
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / pharmacology
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors*
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Heart / drug effects
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / enzymology
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / enzymology
  • Myocardium / enzymology
  • Rats
  • Rats, Wistar
  • Swine
  • Thionucleotides / pharmacology*
  • Type C Phospholipases / toxicity

Substances

  • Isoenzymes
  • Thionucleotides
  • 8-bromoguanosino-3',5'-cyclic monophosphorothioate
  • 8-Bromo Cyclic Adenosine Monophosphate
  • 8-bromocyclic GMP
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinase Type II
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Type C Phospholipases
  • Cyclic GMP
  • Calcium