Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 ± 6 mmHg by day 21 from control levels of 150 ± 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg ⋅ kg−1 ⋅ 24 h−1). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 ± 6.9 mg/24 h on day 21 from 9.0 ± 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 ± 17 to 277 ± 104 pg ⋅ 100 g body wt−1 ⋅ 24 h−1 associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 ± 1.1 to 12.2 ± 1.9 ng ⋅ 100 g body wt−1 ⋅ 24 h−1( days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [3H]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [3H]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SBP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.

.-We investigated the role of nitric oxide (NO) in the control of myocardial O 2 consumption in the hearts of female Xenopus frogs, which lack a coronary vascular endothelium and in which the endocardial endothelium is the only source of NO to regulate cardiac myocyte function. Hence, frogs are an ideal model in which to explore the role of diffusion of NO from the endocardial endothelium (EE) without vascular endothelial or cardiac cell NO production. In Xenopus hearts we examined the regulation of cardiac O 2 consumption in vitro at 25°C and 37°C. The NO-mediated control of O2 consumption by bradykinin or carbachol was significantly (P Ͻ 0.05) lower at 25°C (79 Ϯ 13 or 73 Ϯ 11 nmol/min) than at 37°C (159 Ϯ 26 or 201 Ϯ 13 nmol/min). The response to the NO donor S-nitroso-Nacetyl penicillamine was also markedly lower at 25°C (90 Ϯ 8 nmol/min) compared with 37°C (218 Ϯ 15 nmol/min). When Triton X-100 was perfused into hearts, the inhibition of myocardial O 2 consumption by bradykinin (18 Ϯ 2 nmol/min) or carbachol (29 Ϯ 4 nmol/min) was abolished. Hematoxylin and eosin slides of Triton X-100-perfused heart tissue confirmed the absence of the EE. Although endothelial NO synthase protein levels were decreased to a variable degree in the Triton X-100-perfused heart, NO 2 production (indicating eNOS activity) decreased by Ͼ80%. It appears that the EE of the frog heart is the sole source of NO to regulate myocyte O 2 consumption. When these cells are removed, the ability of NO to regulate O2 consumption is severely limited. Thus our results suggest that the EE produces enough NO, which diffuses from the EE to cardiac myocytes, to regulate myocardial O 2 consumption. Because of the close proximity of the EE to underlying myocytes, NO can diffuse over a distance and act as a messenger between the EE and the rest of the heart to control mitochondrial function and O 2 consumption. nitric oxide; Western blot analysis; Triton X-100; mitochondria; Griess reaction THE ENDOCARDIAL ENDOTHELIUM (EE) plays a vital role in the regulation of myocardial performance and electrical activity as recently reviewed by Brutsaert (3). Located between luminal blood and the underlying cardiac muscle, the EE synthesizes and releases nitric oxide (NO) in amounts sufficient to regulate myocardial contraction under basal conditions (4,24). NO is also known to regulate O 2 consumption under a variety of conditions (2,12,15,22,25). This regulation of myocardial metabolism may be one of NO's most significant roles. We have proposed that endothelial NO synthase (eNOS), which is the most highly expressed isoform of NOS in vascular tissue under physiological conditions, contributes to the control of tissue O 2 consumption by NO (16,25).As a model to determine the significance of the diffusion of NO in the control of cardiac cell O 2 consumption, the frog heart is of much interest because it has no coronary circulation and can therefore be used to study the interaction between the EE and the myocardium without interference from the vascular endothelium (...

Pregnant mice (Mus musculus), strain Swiss Webster, were exposed to a continuous electromagnetic field (12.8V/m) beginning in the third week of pregnancy. Histological and hematological analysis showed gender specific responses in 21 day-old mice after in-utero and post-natal continuous exposure. Automated lymphocyte percentage and total white blood cell counts were significantly elevated in exposed 21 day-old female mice compared to control mice. Lymphoma-like cells were seen in higher numbers in exposed 21 day-old male mice. Megaloblastic changes, such as hypersegmented neutrophils, were observed in exposed mice. The blood from control neonatal mice was more viscous than that of exposed mice, enough to interfere with making a blood smear. The adult female mice showed no significant differences in the above hematologic parameters between exposed and control groups. Histological study showed the following pathological changes in the adrenal cortex: degeneration/necrosis in the zona glomerulosa; hypertrophy in zona reticularis; degeneration/necrosis, intracytoplasmic inclusions and inflammation in the zona fasciculata/reticularis, more prominent in exposed female neonates; and lipidosis in the zona fasciculata. In the adrenal medulla: atrophy was more common in exposed female neonates; and intracytoplasmic inclusions and vacuolation were more common in exposed male neonates. Cystic proliferations were found in the cortical area of the thymus. In the medulla of the thymus, there was vacuolation, inflammation, or eosinophilic intracytoplasmic inclusions in exposed adults. Behavioral differences occurred in both neonates and adult females. Control neonates were able to manipulate through a maze more quickly than exposed neonates; and control adult females displayed more thorough grooming behavior than exposed mothers, and maintained more distance between the nest and dropping location than did the exposed group.

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