CARDIOVASCULAR PROTECTIVE EFFECTS OF UROGUANYLIN IN DAHL-IWAI SALTS SENSITIVE RATS
Y. Momose , S. Yamamura, F. Okabe
Toho Univeristy, Funabashi, Chiba, Japan
Uroguanylin is a small cysteine-rich peptide that activates membrane-bound receptor guanylate cyclases in the intestine, kidney and epithelia. This peptide increases in plasma and urine during congestive heart failure. To elucidate the link of cardiovascular action between levels of whole body and cell, we investigated the effects of uroguanylin on systemic circulation and body weight as well as membrane currents using Dahl-Iwai salt sensitive rats. Treatment with uroguanylin (0.1 ug/kg ip/day) for eight weeks in Dahl-Iwai salt sensitive rats significantly reduced both body weight and arterial blood pressure during initial three to five weeks, thereafter followed by marginal changes in both parameters. These effects are mainly due to the diuretic action of uroguanylin. The hypotensive effect of uroguanylin was accompanied by a small negative chronotropic action. The treatment with uroguanylin attenuated heart failure developed in the salt sensitive rats. Uroguanylin also diminished the plasma level of BNP in rats. We further studied the cellular action of uroguanylin on contractile response and membrane currents of cardiac myocytes and vascular smooth muscle cells. The presence of uroguanylin 10-8 M slightly increased the contractile response as well as the L-type Ca2+ current in single cardiac myocytes. On the other hand, uroguanylin activated an inwardly rectifying potassium current in a single vascular smooth muscle cell. Our results suggest that uroguanylin prevents congestive heart failure in Dahl-Iwai salt sensitive rats with coordinate actions of increased cardiac contractility and decreased arterial tone. Thus, uroguanylin could be useful as a therapeutic agent in congestive heart failure.