Published online before print June 16, 2008, doi: 10.1161/HYPERTENSIONAHA.108.114686
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(Hypertension. 2008;52:e8.)
© 2008 American Heart Association, Inc.
Letters to the Editor |
Thyrotropin-Releasing Hormone Precursor Gene Knocking Down Impedes Melanocortin-Induced Hypertension in Rats
Molecular Cardiology, Instituto de Investigaciones Médicas A. Lanari, Universidad de Buenos Aires, IDIM-CONICET, Buenos Aires, Argentina
Recently, da Silva et al1 reported that endogenous melanocortin may cause elevation of arterial blood pressure (ABP) in spontaneously hypertensive rats. We invite authors to consider that the hypothalamic thyrotropin-releasing hormone (TRH) system may be involved, because spontaneously hypertensive rats show an hyperactivity of this system,2 and intracerebroventricular (ICV) injections of a prepro-TRH antisense oligonucleotide (AS) decreases both elevated TRH content and ABP independent of thyroid status.3
Leptin effects include increases in sympathetic activity and inhibition of the starvation-induced suppression of thyroid hormones apparently by upregulating prepro-TRH gene expression. Then, leptin can increase the MC4R ligand (
-melanocyte-stimulating hormone) production to regulate TRH expression.4 Furthermore, we have shown that ICV leptin injections induce a pressor effect that is avoided by prepro-TRH AS pretreatment.5 Hence, we proposed that melanocortin activity may raise ABP through TRH activation, and we report here that, in Wistar rats, the MCR4 agonist (-melanocyte-stimulating hormone agonist [MTII])–induced elevation of ABP can be blocked by 24-hour ICV pretreatment with prepro-TRH AS.
Wistar rats were implanted with a guided canula into the III ventricle for MTII, AS, or saline infusion (V) as described elsewhere.5 Carotid artery was cannulated for mean ABP measurements. We measured body weight and food consumption in basal condition and 24 hours after ICV injection in awake animals with (ICV 1) vehicle (V), AS (150 µg), and oligonucleotide with the inverted AS sequence (150 µg) as a control. After another 24 hours we performed a second injection (ICV 2) with V or MTII (0.6 nmol). Animals were then euthanized and the hypothalamus was removed to measure TRH (radioimmunoassay).
As expected, MTII induces a decrease in food consumption and body weight. MTII also produced increases of mean ABP and hypothalamic TRH in rats treated with MTII, whereas AS pretreatment prevented both increases. MTII action was not reversed by the AS inverted sequence (Table).
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In conclusion, we show that the melanocortin 3 and 4 agonist induced hypertension only in the presence of an intact hypothalamic TRH system; thus, we propose that an activation of the axis leptin-melanocortin-TRH might explain increases of ABP in this genetic model of hypertension.
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Acknowledgments |
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Sources of Funding
These studies were supported by grants from the Agencia Nacional De Investigaciones Cientificas y Técnicas (ANPCyT): PICT-03-13862 and PICT-05-25920.
Disclosures
None.
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Footnotes |
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M.S.L. and S.I.G. contributed equally to this work.
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References |
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 Top References |
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1. da Silva AA, do Carmo JM, Kanyicska B, Dubinion J, Brandon E, Hall JE. Endogenous melanocortin system activity contributes to the elevated arterial pressure in spontaneously hypertensive rats. Hypertension. 2008; 51: 884–890.
2. Garcia SI, Dabsys SM, Martinez VN, Delorenzi A, Santajuliana D, Nahmod VE, Finkielman S, Pirola CJ. Thyrotropin-releasing hormone hyperactivity in the preoptic area of spontaneously hypertensive rats. Hypertension. 1995; 6: 1105–1110.
3. Garcia SI, Alvarez AL, Porto PI, Garfunkel VM, Finkielman S, Pirola CJ. Antisense inhibition of thyrotropin-releasing hormone reduces arterial blood pressure in spontaneously hypertensive rats. Hypertension. 2001; 2: 365–370.
4. Perello M, Stuart RC, Nillni EA. The role of intracerebroventricular administration of leptin in the stimulation of prothyrotropin releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology. 2006; 147: 3296–3306.
5. Garcia SI, Landa MS, Porto PI, Alvarez AL, Schuman M, Finkielman S, Pirola CJ. Thyrotropin-releasing hormone decreases leptin and mediates the leptin-induced pressor effect. Hypertension. 2002; 39: 491–495.
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  A. A. da Silva, J. M. do Carmo, B. Kanyicska, J. Dubinion, E. Brandon, and J. E. Hall Response to Thyrotropin-Releasing Hormone Precursor Gene Knocking Down Impedes Melanocortin-Induced Hypertension in Rats Hypertension, August 1, 2008; 52(2): e9 - e9. [Full Text] [PDF]
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