In vitro and in vivo assessment of cellular permeability and pharmacodynamics of S-nitrosylated captopril, a nitric oxide donor.
1. The present studies were aimed at testing the hypothesis that S-nitrosylated captopril (CapNO), a novel crystalline nitric oxide (NO) donor, readily permeates both in vitro and in vivo endothelial monolayers, resulting in its pharmacodynamic effects. 2. CapNO and Captopril (Cap) were added to apical side of endothelial monolayers formed on microporous membranes, and the permeated drugs were collected from basolateral side and detected by a HPLC method. The permeability coefficient (P(app); cm sec(-1)) of CapNO across the endothelial monolayers was 6.0 x 10(-5), higher than that of Cap (3.13 x 10(-5)), indicating the enhancement effect of the attached NO group in CapNO on cellular permeability. The P(app) of CapNO and Cap across Caco-2 cells were 3.15 x 10(-5) and 1.53 x 10(-5), respectively. The low P(app) of CapNO to Caco-2 cells may be attributed to the high membrane resistance of Caco-2 cells. 3. A bolus injection of CapNO to epicardial coronary artery of chronically-instrumented awake dogs caused significant increases in coronary blood flow and coronary diameters dose-dependently without significant changes in aortic pressure. In contrast, the equimolar doses of Cap did not produce haemodynamic responses. 4. Intravenous CapNO caused an instant increase in the regional cerebral blood flow determined by H(2)-clearance, whereas the equimolar doses of Cap did not enhance the cerebral blood flow. 5. These results conclude that the NO group, an active component of CapNO, enhances both in vitro and in vivo endothelial permeability to the entire compound, resulting in instant increases in blood flow and vascular diameters. In contrast, the equimolar Cap does not have the instant vascular effects.
Jia
L
L
Institute For Drug Development, 14960 Omicron Dr. San Antonio, Texas, TX 78245-3217, USA. Ljia@saci.org
Wong
H
H
D000818:Animals; D001011:Aorta / Q000502:physiology; D001692:Biological Transport; D001794:Blood Pressure; D018938:Caco-2 Cells; D002216:Captopril / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D007231:Infant, Newborn; D007275:Injections, Intravenous; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D004364:Pharmaceutical Preparations / Q000737:chemistry; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D013687:Telencephalon / Q000098:blood supply; D014471:Umbilical Veins / Q000166:cytology
D020030:Nitric Oxide Donors; D004364:Pharmaceutical Preparations; C060039:S-nitrosocaptopril; D002216:Captopril