Influence of Venular Pairing on Resting Arteriolar Tone and NO Bioavailability in Hypercholesterolemia

Abstract

This study addresses the possible role of venular pairing in arteriolar constriction and nitric oxide (NO) bioavailability in hypercholesterolemia. Arteriolar tone was measured in small arterioles closely paired with venules in the mesentery of both normal cholesterol rats (NC; total cholesterol=78±1.7 mg/dL) and rats fed a high cholesterol diet for 2 weeks (HC; total cholesterol=170±14 mg/dL). Perivascular NO concentrations were measured using a NO-selective microelectrode. Paired arterioles in the HC group demonstrated enhanced arteriolar tone (8.6±0.9 % for HC vs 1.9±0.4 % for NC) and reduced NO concentrations (250±13 nM for HC vs 426±37 nM for NC), and these alterations were closely associated with increased leukocyte adhesion in paired venules. The injection of monoclonal antibodies for CD11/CD18 and P-selectin (given simultaneously) successfully attenuated venular leukocyte adherence and arteriolar tone in HC. The antibodies also increased NO (by 33%), to a value that still was significantly lower than that of the NC group. To determine whether thromboxane plays a role in the venule-mediated arteriolar constriction, ozagrel, a thromboxane synthase inhibitor, was administered to HC rats. The ozagrel treatment partially attenuated arteriolar tone by 45% without affecting NO levels or leukocyte adherence. These findings indicate that leukocyte and/or platelet adherence in closely paired venules of HC rats contributes to arteriolar constriction via both NO- and thromboxane-dependent mechanisms. Supported by JDRF 1-2003-159.