Closed chest permanent atrioventricular block in dogs

Ten mongrel dogs underwent transcutaneous His bundle ablation by means of pulsed synchronized electrical shocks delivered between an electrode catheter adjacent to the His bundle and a metal plate behind the dog's back. Detailed histologic studies were performed 3 months after induction of stable complete atrioventricular (AV) block in nine dogs. The ventricular response ranged from 35 to 51 beats/min (bpm). Graded increases in overdrive ventricular pacing resulted in graded increases in pacemaker suppression up to a paced cycle length of 450 msec. All dogs showed extensive damage to the approaches to the AV node, the AV node, and the penetrating portion of the common bundle. This technique resulted in complete AV block with typical features of an infranodal pacemaker and correlated with the histologic findings of severe damage to the AV junction. The minimal myocardial damage suggests that this technique may be applicable for control of drug refractory supraventricular arrhythmias in humans.     

Enhanced liver DNA synthesis in partially hepatectomized rats pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver DNA synthesis was studied in rats after a $\text{1}\text{3}$ hepatectomy. The rats were maintained on a controlled feeding schedule and were treated with 5 μg/kg of TCDD or acetone/corn oil (control). Five days after treatment a $\text{1}\text{3}$ hepatectomy was performed and at designated times thereafter liver DNA synthesis was measured by [³H]thymidine incorporation into DNA. The main finding was that liver DNA synthesis was increased 8- to 10-fold by TCDD over that which was observed in control rats. This increase occurred after a latency period that was appropriate for the regenerative liver DNA synthesis response. Other experiments showed that increased incorporation of thymidine in TCDD-treated rats could be blocked by hydroxyurea, an inhibitor of semiconservative DNA synthesis, and that the increased incorporation was secondary to increased DNA synthesis and not increased thymidine kinase activity. Thus, hepatocytes in TCDD-treated rats respond in a quantitatively different manner than control rats to the same proliferative signal, $\text{1}\text{3}$ hepatectomy. Liver DNA synthesis in nonhepatectomized TCDD-treated rats tended to be greater than control, but the difference was not statistically significant.     

The relationship between the binding of 2-n-alkylbenzimidazoles to rat hepatic microsomal cytochrome P-450 and the inhibition of monooxygenation

The binding of a homologous series of 2-n-alkylbenzimidazoles to rat hepatic microsomal cytochrome P-450 has been examined. Type I, Type RI and mixed Type I/RI spectra were observed with control, phenobarbitone or 20-methylcholanthrene-induced microsomal preparations. In general short chain (C₁-C₄) substituted compounds elicited Type RI spectra, whereas C₅-C₉ substituted benidazoles gave rise to Type RI/I or Type I spectra. The type of binding spectrum observed was dependent upon the substrate concentration, the source of microsomes and the length of the substituent alkyl chain. As the lipophilic character of the substituent was increased a corresponding increase in Type I nature was noted. However, an optimal chain length of C₇-C₈ carbon atoms was observed for Type I binding; compounds with longer side chains showed a decreased affinity for the Type I site. The apparent spectral binding constants (f_s values) for the Type I site (but not the Type RI site) were closely associated with the K_i and I₅₀ values for the inhibition of cytochrome P-450-dependent monooxygenation. From their inhibition properties it seems that even the short chain (C₁-C₄) substituted benzimidazoles also bind to the Type I site and thus compete for the substrate binding site of cytochrome P-450.