AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats.
Insulin-like growth factor-I (IGF-I) is an important cardioprotective substance. We previously reported that sensory neuron stimulation increases IGF-I production by releasing calcitonin gene-related peptide (CGRP) in spontaneously hypertensive rats (SHRs). Because angiotensin II (Ang II) inhibits sensory neuron activation by interacting with Ang II type 1 (AT(1)) receptors, it is possible that AT(1) receptor blockers (ARBs) increase IGF-I production in SHRs. We examined this possibility in the current study, using the ARBs olmesartan, valsartan, losartan, and telmisartan. Plasma, renal, and cardiac levels of CGRP and IGF-I in SHRs were significantly lower than those in normotensive Wistar Kyoto rats (WKYs) (P < 0.01), which increased to levels found in WKYs after the administration of ARBs. These ARB-induced increases in SHRs were completely reversed by pretreatment with capsazepine (CPZ), which is a specific vanilloid receptor-1 (VR-1) antagonist. The mean arterial blood pressure (MABP) was decreased after administration of ARBs in SHRs, and those decreases were reversed by pretreatment with CPZ. The administration of nifedipine decreased MABP but did not increase CGRP or IGF-I levels in SHRs. Baseline CGRP release and cellular cyclic adenosine 3',5'-monophosphate (cAMP) levels in dorsal root ganglion neurons (DRG) isolated from SHRs were significantly lower than those in DRG isolated from WKYs (P < 0.01). Although ARBs reversed decreases in CGRP release and cAMP levels in the presence of Ang II in DRG isolated from WKYs, they increased CGRP release and cAMP levels in the absence of Ang II in DRG isolated from SHRs. Cellular levels of Ang II were not detected in DRG isolated from WKYs or SHRs, but messenger RNA (mRNA) levels for angiotensin-converting enzyme in DRG were significantly higher in SHRs than in WKYs (P < 0.01). The expression of AT(1) receptors in DRG was not different between WKYs and SHRs. Thus, it is likely that decreases in CGRP release and cAMP levels in DRG isolated from SHRs are mainly caused by AT(1) receptor activation by Ang II through an autocrine mechanism. These observations suggest that ARBs might increase CGRP release from sensory neurons by sensitizing VR-1 activation through increases in cAMP levels, which thereby increased the production of IGF-I in SHRs. These activities of ARBs might at least partly explain their therapeutic effects in areas such as improving insulin resistance in patients with diabetes and hypertension.
Harada
Naoaki
N
Department of Translational Medical Science Research, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Shimozawa
Nobuhiko
N
Okajima
Kenji
K
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D014665:Vasodilator Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D007093:Imidazoles; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D014665:Vasodilator Agents; D007334:Insulin-Like Growth Factor I; D000068756:Valsartan; C437965:olmesartan; D007703:Peptidyl-Dipeptidase A; D014633:Valine; D009543:Nifedipine; D015740:Calcitonin Gene-Related Peptide; D019808:Losartan; C071423:capsazepine; D002211:Capsaicin; D000077333:Telmisartan