High salt-induced hypertension in B2 knockout mice is corrected by the ETA antagonist, A127722.

BACKGROUND AND PURPOSE: The contribution of endothelin-1 (ET-1) in a B2KO mouse model of a high salt-induced arterial hypertension was investigated. EXPERIMENTAL APPROACH: Wild-type (WT) or B2KO mice receiving a normal diet (ND) or a high-salt diet (HSD) were monitored by radiotelemetry up to a maximum of 18 weeks. At the 12th week of diet, subgroups under ND or HSD received by gavage the ETA antagonist A127722 during 5 days. In addition, blood samples were collected and, following euthanasia, the lungs, heart and kidneys were extracted, homogenized and assayed for ET-1 by RIA. In a separate series of experiments, the ETA antagonist, BQ123 was tested against the pressor responses to a NOS inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) in anaesthetized WT and B2KO mice. KEY RESULTS: In B2KO, but not WT mice, 12 weeks of HSD triggered a maximal increase of the mean arterial pressure (MAP) of 19.1 ± 2.8 mmHg, which was corrected by A127722 to MAP levels found in B2KO mice under ND. Significant increases in immunoreactive ET-1 were detected only in the lungs of B2KO mice under HSD. On the other hand, metabolic studies showed that sodium urinary excretion was markedly reduced in B2KO compared with WT mice under ND. Finally, BQ123 (2 mg·kg(-1)) reduced by 50% the pressor response to L-NAME (2 mg·kg(-1)) in B2KO, but not WT mice under anaesthesia. CONCLUSIONS AND IMPLICATIONS: Our results support the concept that functional B2 receptors oppose high salt-induced increments in MAP, which are corrected by an ETA receptor antagonist in this mouse model of experimental hypertension.

Endothelin-1 (1-31): from chymase-dependent synthesis to cardiovascular pathologies.

The mast cell-derived serine protease chymase is importantly involved not only in degradation, but in synthesis of bioactive peptides as well. Several studies suggest that chymase is the predominant enzyme in the production of angiotensin II (Ang II) from angiotensin-I in interstitial tissues. Interestingly, chymase has also been suggested to mature endothelin-1 (ET-1) from its precursor, big-ET-1 in vitro. The lack of availability of specific chymase inhibitors, beyond the chymotrypsin-like inhibitor chymostatin, currently hampers the investigation of the chymase/ET-1/Ang II paradigm in physiology and cardiovascular diseases. Nonetheless, the recent advent of highly selective chymase inhibitors is shedding new light on the role of this enzymatic pathway in the several inflammatory prone vascular diseases as summarized in the present review. Considering increasing evidence towards significant interactions between Ang II and ET-1 in cardiovascular diseases, the present review will address the role of chymase in the production of those two peptides. Whether chymase-dependent production of ET-1 plays an important role in cardiovascular pathologies will also be discussed.

Control of hepatitis A through routine vaccination of children.

CONTEXT: The impact of routine hepatitis A vaccination of children living in large communities with elevated disease rates has not been evaluated. OBJECTIVE: To determine the effect of routine vaccination of children on disease incidence in a community with recurrent hepatitis A epidemics. DESIGN, SETTING, AND PARTICIPANTS: Community-based demonstration project conducted from January 12, 1995, through December 31, 2000, in Butte County, California, among children aged 2 to 17 years. INTERVENTION: In 1995, vaccination was offered to children aged 2 to 12 years during vaccination clinics conducted on 2 occasions 6 to 12 months apart at most schools in the county. In 1996-2000, vaccine was distributed to community health care clinicians, who vaccinated eligible children without charge. Vaccine was also available at health department clinics, selected child care centers, and other sites. MAIN OUTCOME MEASURES: Hepatitis A vaccination coverage, hepatitis A incidence, and vaccine effectiveness. RESULTS: During the study period, 29 789 (66.2%) of an estimated 44 982 eligible children received at least 1 vaccine dose; 17 681 (39.3%) received a second dose. The number of hepatitis A cases among the entire county population declined 93.5% during the study period, from 57 cases in 1995 to 4 in 2000, the lowest number of cases reported in the county since hepatitis A surveillance began in 1966. The 2000 incidence rate of 1.9 per 100 000 population was the lowest of any county in the state. Of the 245 cases reported during the 6-year period, 40 (16.3%) occurred among children 17 years of age or younger, of which 16 (40%) occurred in 1995 and only 1 in 2000. One of the 27 case patients eligible for vaccination had been vaccinated, having received the first dose 3 days before symptom onset. The estimated protective vaccine efficacy was 98% (95% confidence interval, 86%-100%). CONCLUSIONS: In this population, hepatitis A vaccine was highly effective in preventing disease among recipients. Childhood vaccination appears to have decreased hepatitis A incidence among children and adults and controlled the disease in a community with recurrent epidemics.

The pathologist as a consultant in a rural area.

In this article, the author discusses some of the problems a pathologist serving as a consultant in a rural hospital may encounter, and ways in which the advisor can maintain good relations with the technologists, physicians, nurses, and administrators.