Vasoactive effects of endothelin‐1 in the mesentery and cremaster muscle of leptin deficient mice (674.11)

Leptin has been shown to up‐regulate endothelin‐1 production. We investigated the responses to endothelin‐1 (ET) in leptin deficient diabetic mice (db/db) in comparison to C57BL/6J (C57) genetic background mice in the absence or presence of endogenous NO (LNNA), and with blockade of the ETB receptor (PD142893, BQ788). The cremaster muscle of anesthetized (50 mg/kg Nembutal or 4% isoflurane) mice (n=33) was prepared for intravital microscopy. Arteriole(A)/venule(V) pairs were chosen for study. Baseline diameters in the cremaster (A/V, 30/35 um) were ~20‐30% larger than in db/dbs; in the mesentery (60/120 um) they were similar for the 2 strains. Vasodilatory tone (adenosine, 10‐4M) was not significantly different between strains, and was lower in mesentery vs. cremaster. Vasoconstrictor tone (Phenylephrine, 10‐4M) was decreased in db/db compared to C57 in the cremaster, but not mesentery. ET1 dose dependent constriction in the C57 or db/db cremaster (logM EC50: C57 ‐11.9±29.6 A, ‐11.7±2.8 V; db/db ‐11.7±4.4 A, ‐10.0 V) was suppressed by LNNA, and enhanced with ETB antagonism to a greater extent in the A vs. V. In the mesentery, baseline constriction to ET1 was diminished to a greater extent in the db/db vs C57 and was suppressed by LNNA and enhanced with ETB antagonism. Thus, the leptin deficient mouse exhibits a tissue specific loss of ET1 mediated constriction. Yet, the potential role for ETB mediated vasodilation appears similar for C57 and db/db in both tissues Grant Funding Source : NIH DK68401, The UWI