A pure tone evokes propagating activities in a strip of the primary auditory cortex (AI), an isofrequency strip (IS). A fundamental issue concerns the roles that thalamocortical input and intracortical connectivity play in generating the activities. Here we addressed this issue in guinea pigs using in vivo and in vitro real-time optical imaging techniques. As reported previously, tone-evoked activity propagated dorsoventrally along a strip (an IS) in AI. We found that an electrical pulse applied focally within the strip, triggered activity propagation with a spatiotemporal pattern highly similar to tone-evoked activation. The propagation velocity of electrically evoked activity was significantly slower than that of tone-evoked activity, but was comparable to the velocity of lateral activity propagation in cortical slices, suggesting that the electrically evoked activity propagation in vivo is mediated by intracortical circuits. To test this notion, we lesioned the auditory thalamus chemically; in such animals, electrically evoked activity in AI was not affected, although tone-evoked activity was abolished. Further, in slices of the AI, the extent of electrically evoked activity propagation in layer II/III was significantly larger in coronal slices than in horizontal slices. Together, our results suggest that intracortical connectivity in AI enables a focally evoked activity to propagate throughout an IS.

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Focusing on the disposition of cyclosporin A (CsA) in the liver and intestine, effects of gentamicin-induced acute renal failure (ARF) on the decreased oral bioavailability of CsA were evaluated in rats. The area under the CsA concentration-time curve (AUC) in ARF rats after oral administration (5 mg/kg) significantly decreased by 43% as compared to the control, while the apparent oral clearance significantly increased by 76% of the control. The portal AUC of CsA in ARF rats with bile flow decreased by 67% as compared to the control rats. Without bile flow, the portal AUC of CsA in control rats decreased by 50% as compared to those with bile flow, whereas ARF rats without bile flow showed no notable change as compared to those with bile flow. The AUC of CsA mono-oxidative metabolite via CYP3A (M-OH) in ARF rats after oral or intravenous administration increased significantly by 84% or 241%, respectively, while there was no difference in the portal M-OH between control and ARF rats, suggesting that the elimination of M-OH was prolonged because of nephrotoxicity. Although the exsorption clearance of CsA from the blood circulation to the intestine after intravenous administration to ARF rats decreased significantly as compared to the control; and basolateral-to-apical transport of CsA through Caco-2 monolayers was significantly retarded in the presence of uremic toxins, there was no significant change in the total body clearance of CsA between ARF and control rats. Moreover, there were no effects of uremic toxins on the protein binding of CsA in plasma. These observations suggest that hepatic or intestinal CYP3A and P-glycoproteine (P-gp) are not likely to be concerned with lowering the oral bioavailability of CsA, and that bile function under the ARF condition induced by gentamicin is responsible for a marked decrease in the fraction absorbed of CsA in the small intestine.

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