Sperm from naturally mated mice were observed and videotaped moving within mouse oviducts. The typical pattern of sperm progress involved intermittently breaking free and swimming a short distance, then reattaching to the epithelium. The proportion of sperm that swam freely (were not attached to the epithelium) was calculated and analyzed for effects of oviductal region, ovulation status, and sperm location relative to the lumen. A significantly higher proportion of sperm were free in the ampulla than in the isthmus (26.3% +/- 0.8% vs. 11.8% +/- 1.0%; p less than 0.0001) and in post-ovulatory than pre-ovulatory (16.2% +/- 2.0% vs. 10.6% +/- 1.6%; p less than 0.05) oviducts. Flagellar curvature ratio values showed that free sperm (0.716 +/- 0.024) had more sharply curved tails than stuck sperm (0.782 +/- 0.013). While this difference is significant (p = 0.01), the effect of attachment status interacted significantly (p less than 0.05) with the oviductal region such that there was a greater difference in the isthmus than in the ampulla. Only sperm using the more curved tail beats of hyperactivation were seen to break free from the epithelium and to progress along the oviduct. These results indicate that hyperactivation plays a role in moving sperm out of the isthmic reservoir and to the site of fertilization.
The lower isthmus of the mammalian oviduct appears to serve as a reservoir for sperm that are retained by adherence to the epithelium. By inhibiting sperm binding within excised hamster oviducts and making use of carbohydrate probes, we have characterized the adherence of sperm in the reservoir and established a potential biochemical mechanism for the adherence and release of sperm. Fetuin and its terminal sugar, N-acetylneuraminic acid, interfered with the adherence of sperm to the oviductal epithelium. Labeled fetuin bound to the acrosomal region of fresh epididymal sperm, but not hyperactivated sperm, which have previously been reported to release from epithelial binding. Western blots labeled with fetuin and sialic acid-recognizing lectins identified proteins at several molecular masses that are candidates for the sperm surface component involved in adherence. Labeling of some of these candidates was reduced in samples from hyperactivated sperm. These results indicate that a sialylated oligosaccharide similar to that found on fetuin may be recognized by a sperm surface component and mediate binding to the oviductal epithelium. Release may be accomplished by loss or modification of the component during capacitation or hyperactivation.
Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for potentiation to occur. The importance of dose timing has not been evaluated for adrenergic potentiation of methylphenidate hepatotoxicity, but it is clear that this interaction is based on yet a third mechanism. While only three hepatotoxicants of the group I type have been examined in detail, the diversity of receptor types and mechanisms involved suggest that this phenomenon may be relevant for a wide variety of hepatotoxic drugs and chemicals. This interaction is also of interest because factors or events that lead to increased adrenergic stimulation are common in everyday life. Most over-the-counter cold and allergy preparations contain sympathomimetic drugs, and many prescription drugs produce adrenergic effects as either an extension of the intended therapeutic effect or as a side effect. Stress and some disease states can also lead to significant increases in peripheral adrenergic activity, creating the potential for increased susceptibility to hepatic injury from exposure to certain drugs or chemicals. Cocaine and bromobenzene represent group II, che...
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