Flavonoid-induced gastroprotection in rats: role of blood flow and leukocyte adherence.

To elucidate the mechanisms of flavonoid-induced protection against nonsteroidal anti-inflammatory drug (indomethacin)-induced acute gastric damage, the effects of 5-methoxyflavone and 5-methoxyflavanone on the gastric vasculature were compared both in vivo (using laser Doppler flowmetry in anesthetized rats) and in vitro on rat superior mesenteric arteries. The effects of the compounds on indomethacin-induced leukocyte adherence to mesenteric venules were investigated by intravital videomicroscopy. Oral 5-methoxyflavone reduced indomethacin-induced macroscopic damage by 38 to 99% (ED50 = 5.5 mg/kg). Damage was not significantly reduced by 5-methoxyflavanone. Light microscopy studies also demonstrated a reduction in damage severity. 5-Methoxyflavone, but not 5-methoxyflavanone, increased the gastric conductance significantly. The effects on isolated mesenteric arteries correlated with the effects on in vivo conductance. Finally, indomethacin-induced leukocyte adherence was inhibited to a greater extent by 5-methoxyflavone than by 5-methoxyflavanone. In conclusion, the flavonoid 5-methoxyflavone provides gastroprotection against nonsteroidal anti-inflammatory drug-induced gastric damage. A structurally similar compound, 5-methoxyflavanone, demonstrated minimal gastroprotective activity, suggesting that the double bond of 5-methoxyflavone is required for biological activity. The finding that 5-methoxyflavone (but not 5-methoxyflavanone) significantly increased gastric vascular perfusion and reduced leukocyte adherence to mesenteric venules suggests that these mechanisms may contribute to the flavonoid's gastroprotective activity.

Synthesis and biological evaluation of substituted flavones as gastroprotective agents.

Flavone (1) was found to protect against ethanol-induced gastric damage in rats; however, it is known that certain compounds in the flavone class, including flavone itself, are inducers of hepatic drug metabolizing enzymes. With the hope of identifying gastroprotective flavones that have minimal effects on drug metabolizing enzymes, we have synthesized and evaluated selected flavone analogs. Gastroprotective potency in the ethanol model was retained by methoxy substitution in the 5-position (4) and by methoxy (12) or methyl (14) substitution in the 7-position. A number of substituted analogs of the potent molecule 5-methoxyflavone (4) were also synthesized, and in many cases, these substitutions provided gastroprotective molecules. In order to assess liver enzyme induction potential, two of the gastroprotective flavones, 7-methoxyflavone (12) and 5-methoxy-4'-fluoroflavone (26), were examined for their effect on liver microsomal cytochrome P450 and 7-ethoxyresorufin O-dealkylase (CYP1A) activity. These two compounds caused minimal changes in the cytochrome P450 concentration and were considerably less potent than beta-naphthoflavone as inducers of CYP1A enzyme activity. Furthermore, following oral administration to rats, 5-methoxy-4'-fluoroflavone (26) was found to protect against indomethacin-induced gastric damage. These results indicate that, through appropriate substitution, flavones can be obtained that are gastroprotective but have minimal effects on drug-metabolizing enzymes.

Identification and characterization of B2 bradykinin receptors in sheep nasal turbinate membranes.

Because bradykinin (BK) has been implicated as a mediator of upper respiratory tract symptomatology, specific 3H-BK binding was investigated in membrane homogenates prepared from sheep nasal turbinate tissue in order to identify and characterize the BK receptor subtype(s) present. 3H-BK saturation and Scatchard analyses revealed a single, high affinity, saturable site (KD of 0.098 nM) with a density of 0.44 pmol/g wet weight tissue. Competition experiments using B1 and B2 receptor agents revealed a B2-BK receptor pharmacology; the B2 agents BK, Lys-BK, NPC-567, [D-Phe7]-BK and [Thi,5,8 D-Phe7]-BK displayed nM affinity while the B1 agents [des-Arg9]-BK and [Leu,8 des-Arg9]-BK competed in the uM range. The absolute and rank order of affinities in this tissue paralleled that found in the guinea pig ileum. No specific binding was found using the putative B1 receptor radioligand 3H-[des-Arg9]-BK. Specific B2-BK receptor binding was not effected by the addition of non-hydrolyzable guanine or adenine nucleotides. These data confirm the presence of B2-BK receptors in this tissue and provide support for a role of BK in nasal function.