Modulations of shear stress-induced contractile responses and agonist-induced vasodilation in hypercholesterolemic rats

We used mesenteric arterial beds from normal rats and beef tallow-fed rats (hypercholesterolemic model) to study the interaction between the effects of viscosity-induced shear stress and agonists mesenteric vasoreactivity. Mesenteric arterial beds were perfused under constant-flow conditions (5 ml/min) via a peristaltic pump using warm oxygenated modified Krebs–Henseleit solution containing either 4% BSA to increase viscosity or 300 μM -arginine, a NO synthase substrate. Whether beds were perfused with BSA alone or -arginine alone as pretreatment, the methoxamine-induced contractile responses were similar to those in normal beds. However, methoxamine-induced contractile responses were significantly reduced following pretreatment with -arginine plus BSA. These reduced responses underwent significant recovery when either tyrphostin A23 (30 μM, a tyrosine kinase inhibitor) or wortmannin (300 nM, a PI3K inhibitor) was present. The dose–response curve for methoxamine was shifted to the right and the maximum contractile response was reduced in mesenteric arterial beds from beef tallow-fed rats, but the modulation of this response induced by -arginine plus BSA was preserved. In beef tallow-fed rats, the ACh-induced endothelium-dependent vasodilation was attenuated in both thoracic aortic strips and mesenteric arterial beds. These results suggest that in hypercholesterolemic rats, agonist-induced endothelial function is impaired, while shear stress-induced responses (tyrosine kinase- and PI3K-mediated NO production) are preserved. These abnormal vascular responses may contribute to hypertension in beef tallow-fed hypercholesterolemic model rats.