cAMP signal transduction, a potential compensatory pathway for coronary endothelial NO production after heart failure

This study investigated whether cAMP signal transduction regulates coronary microvascular NO production after heart failure (HF), a state in which endothelial NO synthase (eNOS) is downregulated.

Myocardial microvessels were isolated. Nitrite, the hydration product of NO, from these vessels was quantified by using the Griess reaction. Forskolin (10(-4) mol/L), 8-bromo-cAMP (10(-2) mol/L), isoproterenol (10(-4) mol/L), or adrenomedullin (10(-6) mol/L) significantly increased nitrite release by 78+/-8, 84+/-14, 71+/-11, and 73+/-15 pmol/mg, respectively, from isolated microvessels from normal canine hearts (P<0.05 versus control). Bradykinin (10(-5) mol/L) and acetylcholine (10(-5) mol/L) increased nitrite release by 83+/-13 and 72+/-6 pmol/mg, respectively (P<0.05 versus control). However, NO production induced by bradykinin and acetylcholine was markedly reduced after HF (46+/-7 and 39+/-7 pmol/mg, respectively; P<0.05 versus normal), reflecting eNOS downregulation (55% in eNOS protein). Surprisingly, NO production in response to forskolin, 8-bromo-cAMP, isoproterenol, and adrenomedullin not only was preserved but also was substantially enhanced in these microvessels after HF (121+/-14, 124+/-21, 107+/-18, and 122+/-16 pmol/mg, respectively; P<0.05 versus normal group) and was associated with an upregulation of protein kinase B (220% increase in protein kinase B protein). All these responses were in an NO synthase or a protein kinase A inhibitor-blockable manner.

Our data indicate that cAMP signal transduction may be an important potential compensatory pathway to increase myocardial microvascular NO production after HF when eNOS is downregulated.