In the aquatic environment, diet is an important route of exposure for the common contaminant and procarcinogen benzo(a)pyrene (BaP). Dietary organisms var'yin their BaP content and in contaminated areas often contain other xenobiotics including cytochrome P4501A inducers.This study eamined the effect of dose and previous dietary exposure to the inducer 3-naphthoflavone (BNF) upon the intestinal metabolism of BaP and the sptemic bioavailability of BaP-derived products in catfish. BaP was administered at 2 and 20 pM into in situ-isolated perflsed intestines of control and BNF-pretreated catfish. The intestine formed an array of metabolites in all treatments including potentially hazardous metabolites such as BaP-7,8 and 9,10 dihydrodiols and 6-methy-BaP. BNF treatment disproportionally increased the contribution of BaP-7,8 and 9,10 dihydrodiols relative to the contributions of other metabolites. A greater percentage of metabolites was evident as conjugates in 2 pM controls, whereas a greater percentage of unconjugated metabolites was evident for 20 pM controls and BNF treatments of both dosages. BNF pretreatment and the higher 20 pM BaP dose resulted in greater bioavailabilit4 with 2.6-5.5-fold and 3.0-6.3-fold s in temically avhlable BaP products, respectively.Metabolites represented 10.2-23.1% of the increased bioavilability with BNF treatment, saggesting that mechanisms, in addition to induced metabolism, may be operative. These results indicate that intestnal bioavailability, level of biotransformation, and the metabolic profile of BaP-derived products entering the bloed from the intestine may be altered by dose and dietary BNF pretreatment.

A B S T R A C T To determine if electrical stimulation ofautonomic nerves could excite nonadrenergic inhibitory motor pathways in the guinea pig respiratory system in vivo, we studied the effects of electrical stimulation of the cervical vagi and sympathetic nerve trunks on pressure changes (Pp) within an isolated, fluid-filled cervical tracheal segment which reflected changes in trachealis muscle tone. We preserved the innervation and circulation of the segment as evidenced by a rise in Pp with vagus nerve stimulation and a fall in Pp with intravenous isoproterenol.In five atropine-treated animals, stimulation of the cut vagi or sympathetic nerve trunks resulted in a mean fall in P, of 7.9 and 8.2 cm H2O, respectively. Treatment with propranolol attenuated the response to sympathetic stimulation but not vagal stimulation. To determine if these relaxation responses were mediated by an adrenergic or nonadrenergic mechanism, we studied an additional five animals that had been treated with 6-hydroxydopamine to destroy adrenergic nerve endings. In 6-hydroxydopamine, atropine, and propranolol-treated animals, sympathetic nerve stimulation decreased Pp only 0.65 cm H20, confirm-ing the elimination of adrenergic nerve influences, whereas vagus nerve stimulation decreased Pp 17.7 cm H20.After sectioning the recurrent laryngeal nerves, the mean decrease in Pp during vagus nerve stimulation was only 3.2 cm H20. These findings demonstrate the This work was presented in part at

The predominant airway site and mechanism underlying ozone (O3)-induced respiratory hyperresponsiveness was examined in anesthetized guinea pigs and in vitro tissue preparations. Animals exposed to 1.0 or 1.2 ppm O3 (1 h) demonstrated an enhanced airway response to subcutaneous histamine compared with air-exposed animals. The anatomic site of hyperresponsiveness most likely did not involve the parenchyma, since quasi-static deflationary pulmonary compliance was decreased to a similar extent by histamine in air- and O3-preexposed animals. In contrast, the conducting airways were probably involved as changes in pulmonary resistance elicited by subcutaneous histamine were greater in O3- than in air-exposed animals. Neither atropine nor vagotomy abolished this enhanced responsiveness induced by O3. Although vagal interruption did not alter responsiveness, O3-exposed animals demonstrated greater respiratory responses to efferent electrical stimulation of the vagi than air-exposed animals. This suggests the site of hyperresponsiveness may be located distal to the site of efferent stimulation, possibly in the smooth muscle itself or in its microenvironment.

In the aquatic environment, diet is an important route of exposure for the common contaminant and procarcinogen benzo(a)pyrene (BaP). Dietary organisms vary in their BaP content and in contaminated areas often contain other xenobiotics including cytochrome P4501A inducers. This study examined the effect of dose and previous dietary exposure to the inducer ss-naphthoflavone (BNF) upon the intestinal metabolism of BaP and the systemic bioavailability of BaP-derived products in catfish. BaP was administered at 2 and 20 microM into in situ-isolated perfused intestines of control and BNF-pretreated catfish. The intestine formed an array of metabolites in all treatments including potentially hazardous metabolites such as BaP-7,8 and 9,10 dihydrodiols and 6-methyl-BaP. BNF treatment disproportionally increased the contribution of BaP-7,8 and 9,10 dihydrodiols relative to the contributions of other metabolites. A greater percentage of metabolites was evident as conjugates in 2 microM controls, whereas a greater percentage of unconjugated metabolites was evident for 20 microM controls and BNF treatments of both dosages. BNF pretreatment and the higher 20 microM BaP dosage resulted in greater bioavailability, with 2.6-5.5-fold and 3.0-6. 3-fold increases in systemically available BaP products, respectively. Metabolites represented 10.2-23.1% of the increased bioavailability with BNF treatment, suggesting that mechanisms, in addition to induced metabolism, may be operative. These results indicate that intestinal bioavailability, level of biotransformation, and the metabolic profile of BaP-derived products entering the blood from the intestine may be altered by dose and dietary BNF pretreatment.ImagesFigure 1Figure 2Figure 3Figure 4

1. The role of endothelium in modulating equine colonic vessel responses to histamine (HST), 5-hydroxytryptamine (5-HT), bradykinin (BK) and acetylcholine (ACh) was evaluated in vitro. 2. Segments of mesenteric arteries and veins were collected from the left ventral colon of six adult horses destined for euthanasia for reasons unrelated to cardiovascular or gastrointestinal systems. Vessels were gently cleansed and cut into 4 mm wide rings. 3. Three vessel conditions namely endothelium intact, endothelium removed and N omega-nitro-L-arginine methyl ester (L-NAME)-treated were used for both arterial and venous rings. Each ring was placed in an organ bath with oxygenated Tyrode's solution. One side of the ring was fixed to the floor of the bath and the other side to a force-displacement transducer interfaced with a polygraph. 4. An initial tension of 2 g was applied to rings which were allowed to equilibrate for 45 min. The bath solution was gently replaced every 15 min and tension was readjusted to 2 g each time except following the last wash. 5. Rings were precontracted with a single EC25 dose of noradrenaline and after the response plateaued, cumulative concentration (10(-12)-10(-4) M) response curves were determined for each agent on separate rings. The relaxation from the precontracted level to the baseline was considered as 100% relaxation. Maximal relaxation and maximal contractions were statistically analyzed. 6. All agents induced a relaxation response initially, followed by a contractile phase as the concentrations increased in both arteries and veins, thus, making a biphasic concentration-response curve. In arteries, relaxation produced by ACh was significantly greater than 5-HT. Endothelium removal and L-NAME treatment significantly reduced relaxation in arteries. Only endothelium removal produced a significant reduction of relaxation in veins. 7. In both arteries and veins, HST and 5-HT produced significantly greater contraction than ACh or BK. No significant change in contraction was observed in arteries either by endothelium removal or L-NAME treatment, however, contraction was significantly reduced in veins by endothelium removal. 8. These findings suggest that the endothelium plays a major role in modulating equine colonic arterial relaxation via nitric oxide and venous contraction via endothelium-derived contractile mediators, probably endothelin and/or arachidonates.