SUMMARY The effect of adrenalectomy on the increase of the transmucosal potential difference (p.d.) of the colon of the rat induced by Na depletion, together with the action of aldosterone on the p.d. and on colonic Na+ and Cl− transport, and K+ and bicarbonate secretion have been investigated. Adrenalectomy increased the Na+ content in the stool, an effect reversed by treatment with aldosterone. When Na+-depleted rats were adrenalectomized and maintained on cortisone, the elevated p.d. fell to levels below those found in normal rats. Aldosterone given intravenously (i.v.) in physiological doses increased the p.d. in normal, adrenalectomized and Na+-depleted adrenalectomized rats after a latency period of 80–110 min., and the p.d. tended to rise further when injections were continued for several days. The p.d. gradient along the colon after treatment with aldosterone was similar to that of Na+-depleted rats, the highest p.d. being at the distal end of the descending colon. Cortisol intravenously increased the p.d. but the effect was small in comparison with that of aldosterone. Measurement of ionic fluxes in the descending colon of adrenalectomized rats showed that treatment with aldosterone produced an increase in Na+ and water absorption, and in K+ secretion, but had no effect on bicarbonate secretion. The effects of aldosterone on the transmucosal p.d. and ion transport were similar to those of Na+ depletion.

SUMMARY1. Using a preparation of rat colon mucosa mounted in vitro in small chambers, some factors which influence the electrical properties of the mucosa have been investigated.2. The mucosa behaved mainly as an ohmic resistance although a very brieftransient occurred on first passing current. At 32°C, the fresh preparation had a mean resistance of 108 Q/cm2 and a mean short circuit current (s.c.c.) of 143 /uA/cm2. Tissues taken from Na-depleted and adrenalectomized rats differed little from normal tissues in electrical resistance but those from Na-depleted rats had higher potential difference (p.d.) and s.c.c.3. Increase of temperature led to a rise of conductance of similar order to that found for ions in aqueous solution. S.c.c. also rose with increase of temperature but the effect was relatively greater consistent with its being dependent on metabolic processes.4. Anoxia or the addition of cyanide, iodoacetate or 2,4-dinitrophenol to the bath fluid caused considerable fall in the p.d. and s.c.c.5. Ouabain decreased the p.d. and s.c.c. when added to the serosal side but had no effect when on the luminal side.6. Aldosterone and acetazolamide had no effect.

SUMMARY1. A method for measurement of short-circuit current and for applying a voltage clamp to segments of rat colon in vivo is described.2. The mucosa behaved as an ohmic resistor of average resistance 154 Q/cm2 although brief transient effects were frequently observed. Tissue resistance was independent of considerable changes in ionic strength and composition of the luminal solution.3. The short-circuit current averaged 120,A/cm2 in normal rats. Aldosterone intravenously raised the p.d., short-circuit current rising proportionately and tissue resistance being unchanged. The effects of various modifications of the intraluminal solution in respect to composition, hydrostatic pressure and pH were examined. An increase in the osmolality of the luminal solution sufficient to abolish water absorption did not affect p.d. or short-circuit current.4. The short-circuit current measured with 150 mM-NaCl in the lumen was almost completely accounted for by active Na absorption both in normal and aldosterone-treated rats. The changes in Na efflux rate produced by voltage clamping suggested that only part of Na efflux was due to simple diffusion. With lower [NaCl] in the lumen, the short-circuit current exceeded that atributable to active Na absorption, the discrepancy increasing with reduction of [NaCl].5. The luminal [Na] at which Na efflux and influx rates were equal was reduced by aldosterone, an effect which is probably responsible for the low stool [Na] of aldosterone treated animals. The significance of this finding in terms of the mode of action of aldosterone is discussed.PHY 210 34

SUMMARY1. An investigation has been carried out into various factors which influence the transmucosal potential difference (p.d.) of rat colon in vivo when the p.d. is either high (> 30 mV) or low (< 20 mV).2. 6. The following factors studied were without effect on p.d.: presence of glucose within the lumen; considerable osmotic gradients across the mucosa; variation of luminal pH over the range 5-2-9-8; intravenous administration of acetazolamide, chlorothiazide, frusemide, triamterene, ethacrynic acid or ouabain. Ouabain in the luminal solution also had no effect in all but two rats in which a small fall of p.d. was seen.7. 2,4-dinitrophenol, 10-2M, in the lumen caused a small fall of p.d. only if the p.d. was high.8. Experiments were done to determine the effect on p.

The effect of aldosterone on the colonic transmucosal potential difference (p.d.) was examined in normal, adrenalectomized and Na+ depleted rats. Continuous intravenous infusion of aldosterone in conscious animals was more effective than single i.v. injection and over the dose range 0\m=.\5\p=n-\50 \g=m\g./hr. for 6 hr., p.d. increased linearly with log dose and returned to the pre-infusion levels 16\p=n-\24 hr. after stopping infusion. Only a region 2\p=n-\4 cm. from the anus responded to low doses, but with high doses an increasing length of colon responded. Cortisone (250 \g=m\g.daily) intramuscularly maintained adrenalectomized rats even when severely Na+ depleted without affecting the p.d. Cortisone (2\m=.\5mg. daily, i.m.) raised the p.d. but the effect of low doses of aldosterone was unchanged. Neither Na+ depletion nor pentobarbitone anaesthesia affected the action of aldosterone but large doses of spironolactone reduced it. Aldosterone was effective when applied locally by submucosal injection in very low dose but was almost ineffective even in very large dose in the lumen. Again the most sensitive region was 2\ p=n-\ 4 cm. from the anus. Ouabain (10-3m) injected into the submucosa rapidly reduced the increased p.d. but was ineffective in the lumen.

Clozapine is considered a prototype of the 'so-called' atypical antipsychotic drug class. It has affinity for a broad range of receptors and, in comparison to typical antipsychotic drugs, produces less extrapyramidal side effects. However, its mechanism of action remains unclear. Differential display polymerase chain reaction (ddPCR) was implemented in this study to contribute to the current understanding of this mechanism at the genetic level and to identify novel genes regulated by clozapine. This technique generated approximately 2400 gene sequences that were analyzed for differential gene expression following protracted clozapine treatment. One of these sequences, originally termed Clozapine Regulated Gene (CRG), was shown to be significantly upregulated following the treatment. Northern hybridization confirmation of this finding revealed that chronic clozapine administration caused a five-fold increase in CRG mRNA. Elongation of the 5 0 -and 3 0 -ends of CRG indicated that the fragment was in fact rat gliaderived nexin mRNA. Western blotting demonstrated that levels of the mRNA's associated protein also increased comparably (three-fold) following chronic treatment with the antipsychotic drug. This study presents a possible neuroprotective role of nexin in clozapine treatment, particularly in the prevention of neuronal proteolytic degradation, since nexin has been shown to be a protease inhibitor.

Transmucosal electrical potential difference (p.d.), short-circuit current, electrical resistance and Na+ influx rate of the descending colon were similar in euthyroid and hypothyroid rats, the latter having been treated earlier with an ablation dose of 131I. However, in contrast to the considerable p.d. increase found in normal rats, little change of p.d. was found in hypothyroid rats when they were Na+ depleted or given an intravenous aldosterone infusion. A single small dose of tri-iodothyronine (T3) (1\g=m\g/100gbody weight) or a larger dose of thyroxine given to hypothyroid rats 10-16 h before aldosterone, restored the p.d. response to normal, although these doses did not influence the animal's oxygen consumption. Fasting for 3 days or giving actinomycin D (8 \g=m\g/100g body weight) abolished the effect of T3 but this did not influence the action of aldosterone in euthyroid animals.

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