Differential biotransformation of the enantiomers of isoidide dinitrate in isolated rat aorta.
Previous studies have demonstrated that the D-enantiomer of isoidide dinitrate (IIDN) is 10-fold more potent than the L-enantiomer for relaxation and cyclic GMP accumulation in isolated rat aorta. To test whether preferential biotransformation of D-IIDN to a species that activates guanylate cyclase is the basis for this observed enantioselectivity, paired segments of rat aorta were exposed to D- and L-IIDN and the tissue accumulation of the parent compound and the formation of their respective metabolites (D- and L-isoidide mononitrate, IIMN) were determined. The extent of relaxation of rat aorta following exposure to 2 microM D-IIDN was greater than that by L-IIDN over a 5-minute time course, and this was associated with a higher rate of D-IIDN biotransformation to D-IIMN at all time points. In addition, the rate of D-IIDN biotransformation was greater than that of L-IIDN at most IIDN concentrations tested. By contrast, the amount of D- and L-IIDN in the tissue was the same at all time points and concentrations tested, indicating that selective uptake of D-IIDN into blood vessels did not occur. When tissues were made tolerant to organic nitrate-induced relaxation by treatment with a high concentration of glyceryl trinitrate, the biotransformation of both D- and L-IIDN was attenuated. This suggests that mechanism-based biotransformation may be affected during tolerance development. Furthermore, the association of preferential D-IIDN biotransformation with its greater potency for vasodilation and cyclic GMP accumulation suggests than an enantioselective site for biotransformation is an important component of organic nitrate-induced vasodilation.
Stewart
D H
DH
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Hayward
L D
LD
Bennett
B M
BM
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001711:Biotransformation; D002849:Chromatography, Gas; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013402:Sugar Alcohols / Q000493:pharmacokinetics* / Q000494:pharmacology
D013402:Sugar Alcohols; C002589:isoidide dinitrate