Around half of all humans with essential hypertension are resistant to salt (blood pressure does not change by more than 5 mm Hg when salt intake is high), and although various inbred strains of rats display salt-insensitive elevated blood pressure, a gene defect to account for the phenotype has not been described. Atrial natriuretic peptide (ANP) is released from the heart in response to atrial stretch and is thought to mediate its natriuretic and vaso-relaxant effects through the guanylyl cyclase-A receptor (GC-A). Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet. Unexpectedly, the blood pressure remains elevated and unchanged in response to either minimal or high salt diets. Aldosterone and ANP concentrations are not affected by the genotype. Therefore, mutations in the GC-A gene could explain some salt-resistant forms of essential hypertension and, coupled with previous work, further suggest that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.

The sequence of events in haematogenous metastasis from colonic carcinoma was analysed, using 1541 necropsy reports from 16 centres. The findings are consistent with the cascade hypothesis that metastases develop in discrete steps, first in the liver, next in the lungs and finally, in other sites. Deviations of necropsy findings from the cascade model are largely explained on the basis of false negative reports. In only 216 of 1194 cases was there suggestive evidence that metastatic patterns (excluding lymph nodes) were causally related to lymphatic or non-haematogenous pathways. The incidence of metastatic involvement in 'other' (quaternary) sites correlated with target organ blood-flow (ml min-) per g, only when bone marrow and thyroid were excluded. In the thyroid the incidence was lower than expected on the basis of blood flow per g tissue; this may indicate that the thyroid is an unfavourable site for metastatic growth of colonic carcinoma. In the bone marrow it is higher; the latter may be due to delivery of cancer cells via both arterial blood and the vertebral venous plexus. Recognition of this pattern of metastases in the bone marrow could be important with respect of diagnosis and therapy, in patients with colonic carcinoma.

No abstract

Heat-stable enterotoxins (STa), which cause an acute secretory diarrhea, have been suggested to mediate their actions through the guanylyl cyclase-C (GC-C) receptor. The GC-C gene was disrupted by insertion of neo into exon 1 and subsequent homologous recombination. GC-C null mice contained no detectable GC-C protein. Intestine mucosal guanylyl cyclase activity was ‫ف‬ 16-fold higher in wild-type mice than in the GC-C null mice, and STa-stimulable guanylyl cyclase activity was absent in the null animals. Thus, GC-C is the major cyclase activity present in the intestine, and also completely accounts for the STa-induced elevations of cGMP. Gavage with STa resulted in marked fluid accumulation within the intestine of wild-type and heterozygous suckling mice, but GC-C null animals were resistant. In addition, infection with enterotoxigenic bacteria that produce STa led to diarrhea and death in wild-type and heterozygous mice, while the null mice were protected. Cholera toxin, in contrast, continued to cause diarrhea in GC-C null mice, demonstrating that the cAMP signaling pathway remained intact. Markedly different diets (high carbohydrate, fat, or protein) or the inclusion of high salt (K ϩ , Na ϩ ) in the drinking water or diet also did not severely affect the null animals. Given that GC-C is a major intestinal receptor in all mammals, the pressure to retain a functional GC-C in the face of diarrhea-inflicted mortality remains unexplained. Therefore, GC-C likely provides a protective effect against stressors not yet tested, possibly pathogens other than noninvasive enterotoxigenic bacteria. ( J. Clin. Invest.

No abstract