Serotonin and melatonin inhibit phytohemagglutinin- (PHA) induced interferon-gamma (IFN-gamma) production by lymphocytes. In this paper, it is shown that IFN-gamma-increased tryptophan uptake by lymphocytes and macrophages led to an enhanced production of serotonin. When IFN-gamma and serotonin were added together to a lymphocyte culture, N-acetyl serotonin and melatonin production was increased, whereas the path to 5-hydroxy-indoleacetic acid remained unchanged. Therefore, the stimulated IFN-gamma production of serotonin and melatonin by lymphocytes and macrophages and the inhibition of IFN-gamma synthesis by these indoleamines suggest a hypothesis for an immunoregulatory circuit.

Since the discovery of the angiotensins a link was sought in vain between these polypeptides and the physiological mechanism that regulates the systemic blood pressure (1). This search, however, was rich in surprises as soon as the amazing diversity of pharmacological actions of angiotensin II was established. Besides being the most powerful vasopressor molecule known, the polypeptide is the hormone for aldosterone release (2) and has several effects on the autonomic nervous system: (a) it inhibits the uptake of catecholamines by sympathetic nerve endings (3); (b) it has a direct action on cholinergic ganglionic cells (4); (c) it accelerates the rate of biosynthesis of norepinephrine (5); and (d) it acts directly or indirectly on central sympathetic structures inducing a prolonged increase in blood pressure and heart rate (6). Even if this versatility shattered the early ideas concerning the function of the polypeptide, the classical scheme that accounted for angiotensin I production was not challenged until very recently. The liberation of the polypeptide was supposed to be restricted to the plasma, where a circulating alpha-2 globulin synthetized by the liver, angiotensinogen, is split by a proteolytic enzyme, renin, synthesized by the granular cells of the juxtaglomerular apparatus of the kidney. This proteolytic step releases a 10-residue long polypeptide from angiotensinogen, denominated angiotensin I, which is itself the substrate for a specific, Cl-activated carboxipeptidase, the converting enzyme, giving rise to the octapeptide angiotensin II. This scheme was first questioned after the finding that isolated rat renal glomeruli, devoid of plasma contamination and incubated in a simple salt medium, were able to secrete angiotensin I in great amounts (7-8). The release of the polypeptide was suppressed with protein-synthesis inhibitors. I The tissue synthesis of angiotensin I was strongly supported by the finding of a polypeptide in several tissues of the rat and the dog with pharmacological and

Abstract-Local thyrotropin-releasing hormone (TRH) may be involved in cardiac pathophysiology, but its role in left ventricular hypertrophy (LVH) is still unknown. We studied whether local TRH is involved in LVH of spontaneously hypertensive rats (SHR) by investigating TRH expression and its long-term inhibition by interference RNA (TRH-iRNA) during LVH development at 2 stages (prehypertrophy and hypertrophy). SHR and their control rats (WKY) were compared. Cardiac hypertrophy was expressed as heart/total body weight (HW/BW) ratio. TRH content (radioimmuno assay), preproTRH, TRH receptor type I, brain natriuretic peptide (BNP), and collagen mRNA expressions (real-time polymerase chain reaction) were measured. For long-term inhibition of TRH, TRH-iRNA was injected into the left ventricle (LV) wall for 8 weeks. Hearts were processed for morphometric studies and immunohistochemical analysis using antibodies against ␣-smooth muscle actin and collagen type III. LV preproTRHmRNA abundance was similar in both strains at 7 weeks of age. At the hypertrophic stage (18 weeks old), however, there was a 15-fold increase in SHR versus WKY, consistent with a significant increase in tripeptide levels and the expression of its receptor. Specific LV-TRH inhibition at the prehypertensive stage with TRH-iRNA, which decreased Ͼ50% preproTRH expression and tripeptide levels, prevented LVH development as shown by the normal HW/BW ratio observed in TRH-iRNA-treated SHR. In addition, TRH-iRNA impeded the increase in BNP and type III collagen expressions and prevented the increase in cardiomyocyte diameter evident in mismatch iRNA-treated adult SHR. These results show for the first time that the cardiac TRH system is involved in the development of LVH in SHR. (Hypertension. 2011;57:103-109.) • Online Data SupplementKey Words: TRH Ⅲ cardiac hypertrophy Ⅲ rat Ⅲ SHR Ⅲ interference RNA T hyrotropin-releasing hormone (TRH), a small neuropeptide (p-Glu-His-Pro-NH2) initially identified in the hypothalamus, is amply distributed in the central nervous system 1 and in other extraneural tissues 2 and has been shown to have central and peripheral biological effects independent of thyroid hormone production. 3 TRH also acts on the cardiovascular system of rodents. 4,5 Many groups have identified preproTRH-mRNA by Northern blot analysis and RNAse protection assay in rat cardiac tissues and have referred the presence of specific type I TRH receptors (TRH-R1) in ventricles, establishing that a TRH system is present in the rat heart. 6 -8 In contrast to the hypothalamic TRH system, cardiac preproTRH-mRNA may be augmented by glucocorticoids and by testosterone but may not be regulated by T 3 . 8 In addition, Hasegawa et al 9 reported for the first time an inotropic effect of TRH on the guinea pig myocardium, implying that this effect could be mediated by an increase in a slow inward Ca 2ϩ current. Furthermore, Socci et al 7 found similar results and reported that TRH modulates cardiac contractility of isolated rat hearts as an autocrine factor in a conce...

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