Locally synthesized angiotensin modulates pineal melatonin generation.
We aimed to study the mechanisms and the significance of the influence exerted by the renin-angiotensin system (RAS) on the pineal melatonin production. Pineal melatonin and other indoles were determined by HPLC with electrochemical detection after angiotensin AT1-receptor blockade with Losartan in vivo or in cultured glands. N-acetyltransferase (NAT) activity was radiometricaly measured. To test the in vivo relevance of the local RAS, pineal melatonin and its indole precursors were determined in transgenic rats with inhibited production of angiotensinogen exclusively in astrocytes, TGR(ASrAOGEN). Tryptophan hydroxylase (TPH) and NAT mRNA levels were determined by real-time RT-PCR. Pineal melatonin content was significantly decreased by AT1-receptor blockade in vivo, in cultured glands and in TGR(ASrAOGEN) (35%, 32.4% and 17.5% from control, respectively). Losartan produced a significant decrease of pineal 5-hydroxytryptophan, serotonin, 5-hydroxyindole acetic acid and N-acetylserotonin in pineal cultures. Also, the pineal content of the precursor indoles in TGR(ASrAOGEN) rats was significantly lowered. The reduction of 5-hydroxytryptophan levels by 33-75% in both in vivo and in vitro studies suggests a decreased activity of TPH. Moreover, the TPH mRNA levels in TGR(ASrAOGEN) rats were significantly lower than control rats. On the other hand, NAT activity was unaffected by Losartan in pineal culture and its expression was not significantly different from control in TGR(ASrAOGEN) rats. Our results demonstrate that a local pineal RAS exerts a tonic modulation of indole synthesis by influencing the activity of TPH via AT1-receptors.
Baltatu
Ovidiu
O
Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany. baltatu@mdc-berlin.de
Afeche
Solange Castro
SC
José dos Santos
Sabrina Heloisa
SH
Campos
Luciana Aparecida
LA
Barbosa
Roseli
R
Michelini
Lisete C
LC
Bader
Michael
M
Cipolla-Neto
José
J
D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000235:genetics; D000809:Angiotensins / Q000096:biosynthesis*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008550:Melatonin / Q000096:biosynthesis*; D010870:Pineal Gland / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D014365:Tryptophan Hydroxylase; D001191:Arylamine N-Acetyltransferase; D008550:Melatonin; D019808:Losartan