In vitro studies on responses to pentoxifylline and aminophylline of rat mesenteric resistance vessels.
Pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine) is a metylxanthine derivative used in the treatment of peripheral arterial disease. In isolated rat mesenteric resistance vessels mounted on an isometric myograph and precontracted with noradrenaline (5 microM), pentoxifylline (0.1 microM-10 mM) and aminophylline (0.1 microM-10 mM) evoked concentration-dependent relaxations. The resistance vessels were more sensitive to pentoxifylline, i.e., the concentration of the agonist evoking 50% relaxation (EC50 value) was 105 +/- 15 microM for pentoxifylline vs. 200 +/- 20 microM for aminophylline (P < 0.01). The vasorelaxant response to pentoxifylline was attenuated by mechanical removal of the endothelium, or by inhibition of the endothelial production of nitric oxide with NG-nitro-L-arginine. Inhibition of cyclooxygenase metabolism with indomethacin did not influence the response to pentoxifylline significantly, but was associated with an increased sensitivity to aminophylline. Furthermore, the vasorelaxation of resistance vessels elicited by pentoxifylline was diminished after incubation with tetraethylammonium, a nonselective K+ channel blocker, and pertussis toxin, an inhibitor of certain G-proteins. In contrast, the vasorelaxation elicited by aminophylline was generally enhanced by these experimental manipulations. The results indicate that the vasorelaxant properties of pentoxifylline and aminophylline in resistance vessels are mediated primarily at the level of the vascular smooth muscle cell, but that the mechanisms of the two agonists partly differ. Endothelial-derived factors (e.g., nitric oxide) contribute to the response to pentoxifylline, and may, through other mechanisms, attenuate the vasorelaxation elicited by aminophylline.
Hansen
P R
PR
Department of Medicine B2142, Rigshospitalet, University of Copenhagen, Denmark.
D000628:Aminophylline / Q000494:pharmacology*; D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010431:Pentoxifylline / Q000494:pharmacology*; D037342:Pertussis Toxin; D015221:Potassium Channels / Q000187:drug effects; D011453:Prostaglandins / Q000502:physiology; D051381:Rats; D011921:Rats, Inbred WKY; D013152:Splanchnic Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D015221:Potassium Channels; D011453:Prostaglandins; D010566:Virulence Factors, Bordetella; D000628:Aminophylline; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D010431:Pentoxifylline