Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:4.6.1.2 (
guanylate cyclase
)
8,497
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Ramelteon
is a Melatonin 1 (MT1)-and Melatonin 2 (MT2)-receptor agonist conferring cardioprotection by pharmacologic preconditioning. While activation of mitochondrial calcium-sensitive potassium (mK
Ca
)-channels is involved in this protective mechanism, the specific upstream signaling pathway of
Ramelteon
-induced cardioprotection is unknown. In the present study, we (1) investigated whether
Ramelteon
-induced cardioprotection involves activation of protein kinase G (PKG) and/or protein kinase B (Akt) and (2) determined the precise sequence of PKG and Akt in the signal transduction pathway of
Ramelteon
-induced preconditioning. Hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia, hearts were perfused with
Ramelteon
(Ram) with or without the PKG or Akt inhibitor KT5823 and MK2206, respectively (KT5823 + Ram, KT5823, MK2206 + Ram, MK2206). To determine the precise signaling sequence, subsequent experiments were conducted with the
guanylate cyclase
activator BAY60-2770 and the mK
Ca
-channel activator NS1619. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining.
Ramelteon
-induced infarct size reduction was completely blocked by KT5823 (
p
= 0.0012) and MK2206 (
p
= 0.0005). MK2206 with
Ramelteon
combined with BAY60-2770 reduced infarct size significantly (
p
= 0.0014) indicating that PKG activation takes place after Akt.
Ramelteon
and KT5823 (
p
= 0.0063) or MK2206 (
p
= 0.006) respectively combined with NS1619 also significantly reduced infarct size, indicating that PKG and Akt are located upstream of mK
Ca
-channels. This study shows for the first time that
Ramelteon
-induced preconditioning (1) involves activation of PKG and Akt; (2) PKG is located downstream of Akt and (3) both enzymes are located upstream of mK
Ca
-channels in the signal transduction pathway.
...
PMID:Activation of PKG and Akt Is Required for Cardioprotection by Ramelteon-Induced Preconditioning and Is Located Upstream of mKCa-Channels. 3227 6
