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 microM L-arginine, a NO synthase substrate. Whether beds were perfused with BSA alone or L-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 L-arginine plus BSA. These reduced responses underwent significant recovery when either tyrphostin A23 (30 microM, 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 L-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.
Matsumoto
Takayuki
T
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Sato
Atsushi
A
Suenaga
Hiroshi
H
Kobayashi
Tsuneo
T
Kamata
Katsuo
K
D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology; D001809:Blood Viscosity / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D006937:Hypercholesterolemia / Q000150:complications / Q000503:physiopathology*; D006973:Hypertension / Q000150:complications / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000503:physiopathology; D008729:Methoxamine / Q000494:pharmacology*; D017942:Nitric Acid / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D020032:Tyrphostins / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D000077191:Wortmannin
D000316:Adrenergic alpha-Agonists; D000730:Androstadienes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020032:Tyrphostins; D014665:Vasodilator Agents; D017942:Nitric Acid; D011505:Protein-Tyrosine Kinases; D008729:Methoxamine; D000109:Acetylcholine; C060641:tyrphostin A23; D000077191:Wortmannin