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AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats.
Transl Res. 2009 Sep; 154(3):142-52.TR

Abstract

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.

Authors+Show Affiliations

Department of Translational Medical Science Research, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19665690

Citation

Harada, Naoaki, et al. "AT(1) Receptor Blockers Increase Insulin-like Growth factor-I Production By Stimulating Sensory Neurons in Spontaneously Hypertensive Rats." Translational Research : the Journal of Laboratory and Clinical Medicine, vol. 154, no. 3, 2009, pp. 142-52.
Harada N, Shimozawa N, Okajima K. AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. Transl Res. 2009;154(3):142-52.
Harada, N., Shimozawa, N., & Okajima, K. (2009). AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. Translational Research : the Journal of Laboratory and Clinical Medicine, 154(3), 142-52. https://doi.org/10.1016/j.trsl.2009.06.004
Harada N, Shimozawa N, Okajima K. AT(1) Receptor Blockers Increase Insulin-like Growth factor-I Production By Stimulating Sensory Neurons in Spontaneously Hypertensive Rats. Transl Res. 2009;154(3):142-52. PubMed PMID: 19665690.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AT(1) receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats. AU - Harada,Naoaki, AU - Shimozawa,Nobuhiko, AU - Okajima,Kenji, Y1 - 2009/07/07/ PY - 2009/01/23/received PY - 2009/06/02/revised PY - 2009/06/12/accepted PY - 2009/8/12/entrez PY - 2009/8/12/pubmed PY - 2009/9/26/medline SP - 142 EP - 52 JF - Translational research : the journal of laboratory and clinical medicine JO - Transl Res VL - 154 IS - 3 N2 - 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. SN - 1931-5244 UR - https://www.unboundmedicine.com/medline/citation/19665690/AT_1__receptor_blockers_increase_insulin_like_growth_factor_I_production_by_stimulating_sensory_neurons_in_spontaneously_hypertensive_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1931-5244(09)00180-7 DB - PRIME DP - Unbound Medicine ER -