Response to Thyrotropin-Releasing Hormone Precursor Gene Knocking Down Impedes Melanocortin-Induced Hypertension in Rats
We appreciate the interest of Landa et al1 in our recent study in which we showed that chronic pharmacological blockade of the central nervous system melanocortin 3 and 4 receptors (MC3/4-R) caused a greater reduction in blood pressure (BP) in spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto control rats.2 Our observations suggest that the endogenous tonic activity of these receptors contributes to the maintenance of the elevated BP in the SHR.
Landa et al1 suggest that we should consider inhibition of the hypothalamic thyrotropin-releasing hormone (TRH) system as a potential mechanism by which blockade of MC3/4-R caused a greater reduction in BP in SHRs. This hypothesis is based on the observations that leptin receptor and MC3/4-R activation in the hypothalamus inhibit TRH production and release,3 on previous studies demonstrating increased TRH levels in SHRs compared to Wistar-Kyoto rats, and on their finding that inhibition of the TRH system using antisense or small-interfering RNA markedly lowers BP in SHRs but not in Wistar-Kyoto rats.4 They also showed that the acute pressor responses to leptin were blocked by previous inhibition of TRH with antisense or small-interfering RNA against the TRH precursor gene.5 In their letter to the editors, Landa et al1 show that blockade of prepro-TRH gene expression in Wistar-Kyoto rats, with the antisense technique used in previous studies, prevented the acute pressor responses to α-melanocyte-stimulating hormone agonist, an agonist of the MC3/4-R.1
We agree that reduced TRH release by blockade of the hypothalamic melanocortin/MC3/4-R pathway is a potential mechanism for the cardiovascular responses to block central nervous system MC3/4-R. However, the importance of the TRH system in mediating the long-term cardiovascular effects of activation or blockade of the MC3/4-R is, in our opinion, still unclear. Additional studies are needed to fully determine the role of the interaction between the central nervous system melanocortin pathway and the TRH system in regulating autonomic function and BP. For example, although Landa et al1 showed that intracerebroventricular (ICV) injection of the prepro-TRH antisense blocked the pressor responses to ICV α-melanocyte-stimulating hormone agonist infusion; only 24-hour and 48-hour postinjection BP data are shown, and no control group receiving the prepro-TRH antisense followed by ICV vehicle infusion was studied to demonstrate the specificity of the BP response to ICV prepro-TRH antisense injection. Also, additional experiments where the TRH system is blocked before chronic ICV infusion of the MC3/4-R antagonist, SHU-9119, are required to directly test the role of the TRH system in mediating the long-term cardiovascular actions of the MC3/4-R in the maintenance of elevated BP in the SHR.
Sources of Funding
The authors’ research was supported by a National Heart, Lung and Blood Institute grant PO1HL-51971 and by a Scientist Development Grant from the American Heart Association to A.A.d.S.
Landa MS, Garcia SI, Schuman ML, Alvarez AL, Finkielman S, Pirola CJ. Thyrotropin-releasing hormone precursor gene knocking down impedes melanocortin-induced hypertension in rats. Hypertension. 2008; 52: e8.
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.
Garcia SI, Alvarez AL, Porto PI, Garfunkel VM, Finkielman S, Pirola CJ. Antisense inhibition of thyrotropin-releasing hormone reduces blood pressure in spontaneously hypertensive rats. Hypertension. 2001; 37: 365–370.
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.