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Intravenous Delivery of PTH/PTHrP Type 1 Receptor cDNA to Rats Decreases Heart Rate, Blood Pressure, Renal Tone, Renin Angiotensin System, and Stress-Induced Cardiovascular Responses

Samuel Fritsch^*, Veronique Lindner^*,, Sandra Welsch^*, Thierry Massfelder^*, Michele Grima, Sylvie Rothhut^*, Mariette Barthelmebs^* and Jean-Jacques Helwig^*

*Renovascular Pharmacology and Physiology (INSERM), University Louis Pasteur School of Medicine, Strasbourg, France; University Louis Pasteur Hospital Institute of Pathology, Strasbourg, France; and Institute of Pharmacology, University Louis Pasteur Medical School, Strasbourg, France

Correspondence to Dr. Jean-Jacques Helwig, Pharmacologie & Physiologie Rénovasculaires (INSERM-ULP 0015), 11 rue Humann, Bâtiment 4, 1er étage, F67085 Strasbourg Cedex, France. Phone: 333-90-24-34-54; Fax: 333-90-24-34-59; E-mail: jean-jacques.helwig{at}pharmaco-ulp.u-strasbg.fr

While parathyroid hormone type 1 receptor (PTH1R)-mediated vasodilatory, cardiac stimulatory, and renin-activating effects of exogenous PTH/PTH-related protein (PTHrP) are acknowledged, interactions of endogenous PTHrP with these systems remain unclear, mainly because the unavailability of viable PTHrP/PTH1R knockout mice. Transgenic mice overexpressing PTH1R in smooth muscle strongly have supported the PTHrP/PTH1R system as a cardiovascular system (CVS) regulator, but the consequences on renovascular (RVS) and renin-angiotensin systems (RAS) have not been explored in these studies. The aim was to develop a model in which one could study the consequences on CVS, RVS, and RAS of generalized PTH1R overexpression. Systemic PTH1R cDNA plasmid delivery was used in adult rats, a system that is amenable to studies in isolated perfused kidneys and that minimizes development-induced compensatory mechanisms. Intravenous administration of hPTH1R or green fluorescence protein–tagged hPTH1R in pcDNA3 resulted 3 wk later, in generalized expression of hPTH1R (mRNA and protein), especially in vessels, liver, heart, kidney, and central nervous system, where it is expressed physiologically. As expected, PTH1R overexpression decreased BP and renal tone. Unexpected, however, PTH1R overexpression decreased heart rate. These studies also revealed that endogenous PTHrP actually inhibits renin release and that hPTH1R overexpression tends to increase that effect. Striking, liver production and circulatory level of angiotensinogen and hence plasma renin activity were markedly reduced. Thus, abrupt PTH1R overexpression in adult rats profoundly alters the CVS, RVS, and RAS, strongly supporting the PTH/PTHrP/PTH1R system as crucial for heart and vascular tone regulation. In addition, these results revealed that PTH1R-mediated mechanisms might have protective effects against cardiovascular stress–induced responses, including stimulations in heart rate and RAS.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673