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Tuberoinfundibular Peptide of 39 Residues: A New Mediator of Cardiac Function via Nitric Oxide Production in the Rat Heart

Institute of Physiology (G.R., P.E., Y.A., K.D.S.) and Institute of Anatomy (W.K.), Justus-Liebig-University, D-35392 Giessen, Germany

Address all correspondence and requests for reprints to: Dr. Günter Ross, Institute of Physiology, University of Giessen, Aulweg 129, D-35392 Giessen, Germany. E-mail: guenter.ross{at}physiologie.med.uni-giessen.de.

Tuberoinfundibular peptide (TIP39) was initially identified as a neurotransmitter and agonist of the PTH2 receptor, which is expressed in the cardiovascular system. This study documents for the first time the cardiac expression and function of TIP39.

Expression was analyzed via RT-PCR. Function was characterized on Langendorff-perfused rat hearts as left ventricular developed pressure (LVDP) and on isolated cells via a cell edge detection system. cGMP levels were detected with RIA. Tuberoinfundibular peptide (TIP39) mRNA was found to be constitutively expressed in coronary endothelium cells, isolated cardiomyocytes, ventricles, atria, and aorta. At first we investigated the vasodilatory properties of TIP39 (100 nM) in the presence of L-nitro-arginine (L-NA, 100 µM). Surprisingly, TIP39 had no vasodilatory effect but decreased LVDP by 35 ± 7%. In the absence of L-NA, addition of TIP39 decreased LVDP by 8 ± 2%. The PTH2 receptor antagonist Trp²³-Tyr³⁶-PTHrP (1–36, 100 nM) abolished this TIP39 effect in the presence of L-NA. The experiments with isolated cardiomyocytes provided similar results. TIP39 (10 nM) lowered the contraction amplitude by 6 ± 3%. In the presence of L-NA (100 µmol/liter), TIP39 lowered the amplitude by 34 ± 6%. cGMP concentration in cardiomyocytes was stimulated by TIP39 (10 nM) in the same range as by the nitric oxide (NO) donor SNAP (100 µM). In the presence of L-NA, this increase was abolished. These results suggest that an inhibition of endogenous NO production unmasks a profound negative inotropic effect of TIP39 that is mediated by an activation of the PTH2 receptor. The results obtained with isolated cardiomyocytes suggest that myocyte-derived NO, rather than vascular NO, is responsible for this effect. cGMP seems to be the downstream signal of produced NO.

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