Thyrotropin-releasing hormone precursor gene knocking down impedes melanocortin-induced hypertension in rats.

LANDA MS; GARCIA SI; SCHUMAN ML; ALVAREZ AL; FINKIELMAN S; PIROLA CJ

HYPERTENSION

Año: 2008 vol. 52 p. 8 - 8

0194-911X

Recently, Da Silva et al.1reported that endogenous melanocortin may cause elevation of arterial blood pressure (ABP) in SHR. We invite authors to consider that hypothalamic TRH system may be involved since SHR show an hyperactivity of this system 2, and intracerebroventricular (icv) injections  of an preproTRH antisense oligonucleotide (AS) decreases both elevated TRH content and ABP independently of thyroid status3. Leptin effects include increases in sympathetic activity and inhibition of the starvation-induced suppresion of thyroid hormones apparently by up-regulating preproTRH gene expression. Then, leptin can increase the MC4R ligand (aMSH) production to regulate TRH expression4. Furthermore, we have shown that icv leptin injections induce a pressor effect that is avoided by preproTRH 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 (MTII)-induced elevation of ABP can be blocked by 24 hs icv pretreatment with preproTRH AS. Wistar rats were implanted with a guided canula  into the III ventricle for MTII, AS or saline infusion (V) as described elsewhere5. Carotid artery was canulated for mean ABP measurements. We measured body weight and food consumption in basal condition and 24 hours after icv in awake animals: icv1: V, AS (150ug), oligonucleotide with the AS inverted sequence (INV, 150ug) as a control. After another 24hours we performed a second inyection (icv 2) with V or  MTII (0.6nmol). Animals were then sacrificed and hypothalamus  removed to measure TRH (RIA). Results are expressed as mean ± SD, *p<0.05 vs 24 hours, †p<0.05 vs basal, ‡ p<0.05 vs vehicle and AS+MTII , n=4. icv 1 icv 2 ABP basal mmHg ABP 24h mmHg ABP 48h mmHg TRH pg/mg protein V V 109.7±3.3 107.3±6.3 109±3.6 1161.4±212 V MTII 105.1±2.0 106.5±2.8 113.8±7.3*† 1926.8±454.3‡ AS     MTII 105.7±3.2 102.4±2.4 93.9±3.4*† 1098.6±253 Inv     MTII 106.7±4.0 102.0±8.5 109.8±3.9* 1839.3±297‡     As expected, MTII induces a decrease in food consumption and body weight. MTII also produced increases of ABP and hypothalamic TRH in rats treated with MTII, whereas AS pretreatment prevented both increases. MTII action was not reversed by INV. In conclusion, we show that the MC3/4 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.