Osteopontin expression in platelet-derived growth factor-stimulated vascular smooth muscle cells and carotid artery after balloon angioplasty.

Osteopontin (OPN), an arginine-glycine-aspartate (RGD)-containing adhesive glycoprotein, is constitutively expressed in rat aorta and carotid arteries and is markedly elevated in response to vascular injury. OPN is chemotactic for vascular smooth muscle cells (SMCs), suggesting a role in vascular remodeling. However, the mechanism for the regulation of OPN expression is poorly understood. In the present study, the effect of platelet-derived growth factor (PDGF) on OPN mRNA expression was investigated in cultured rat aortic SMCs (RASMCs). When RASMCs were stimulated with 1 nmol/L PDGF, a 2.4-fold increase in OPN mRNA expression was observed at 3 hours (P < .05) that peaked at 14 hours with a 6.7-fold increase (P < .001). This induction was blocked by a monoclonal anti PDGF antibody. Further studies revealed that OPN mRNA expression was induced by PDGF-AB or PDGF-BB but not by PDGF-AA, indicating that only the beta-type PDGF receptor mediates this response. Compared with basic fibroblast growth factor, epidermal growth factor, transforming growth factor-beta, and interleukin-1 beta, PDGF was the most potent factor studied to induce OPN mRNA expression in RASMCs. Immunohistochemical studies demonstrated the elevation of OPN protein in PDGF-stimulated RASMCs. The temporal expression of OPN mRNA after rat carotid artery balloon angioplasty as assessed by both reverse transcription-polymerase chain reaction and Northern blot analysis revealed a 1.5-fold increase at 6 hours (P < .01) that peaked at 1 and 3 days with a 3.1-fold increase (P < .001). Immunohistochemical studies of carotid artery after angioplasty localized OPN expression in the medical SMCs at 1 day, ie. at a time of significant platelet adherence to the injured vessel, and thereafter to the intimal lesion during neointimal formation. These data suggest that OPN expression in vascular SMCs is regulated by PDGF through the beta-type PDGF receptor in vitro, and possibly in vivo in situations that involve PDGF released from platelets or other cellular sources, such as blood vessels after angioplasty injury.

Selective inhibition of endothelium-dependent relaxation by gold-containing compounds.

Gold-containing compounds inhibited endothelium-dependent relaxation mediated by acetylcholine and the calcium ionophore A23187 in isolated rabbit thoracic aortic rings. Auranofin was the most potent gold-containing compound studied, producing approximately 40% inhibition of vascular relaxation at a concentration of 1 microM. Concentration-response curves to vascular relaxation produced by sodium nitroprusside were significantly shifted 5-fold to the left in the presence of auranofin. However, concentration-response curves to vascular relaxation produced by nitric oxide or isoproterenol were unaffected by auranofin. A series of other gold-containing compounds also inhibited endothelium-dependent relaxation with varying degrees of potency, but none approaching that observed with auranofin. These findings reveal that certain gold-containing compounds are potent and selective inhibitors of endothelium-dependent relaxation.

Coronary vascular activity of the novel inotropic pro-drug ibopamine and the de-esterified active form epinine.

The effects of the novel inotropic pro-drug, ibopamine, and the de-esterified active form, epinine (N-methyldopamine), were investigated in isolated canine circumflex coronary arteries in vitro. Both ibopamine and epinine produced concentration-dependent contractions of isolated canine coronary arteries, with epinine being approximately 7-fold more potent than ibopamine. The coronary vasoconstrictor response produced by ibopamine was inhibited completely by the irreversible alpha-adrenoceptor antagonist, phenoxybenzamine, whereas the response produced by epinine was transformed into relaxation which was inhibited by the beta-adrenoceptor antagonist, propranolol. The results indicate that ibopamine has the capacity to produce coronary arterial vasoconstriction, but that this activity may be partially offset by the beta-adrenoceptor-mediated activity of the active form, epinine.