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Laboratory and Animal Investigations |

Hypertension Plus Diabetes Mimics the Cardiomyopathy Induced by Nitric Oxide Inhibition in Rats*

Rita C. Sampaio, BS; Jose E. Tanus-Santos, MD, PhD; Silvia E. S. F. C. Melo, PharmD; Stephen Hyslop, PhD; Kleber G. Franchini, MD, PhD; Iara M. Luca, PhD; Heitor Moreno, Jr, MD, PhD
Author and Funding Information

*From the Departments of Pharmacology (Drs. Sampaio, Tanus-Santos, Melo, Hyslop, and Moreno) and Medicine (Dr. Franchini), Faculty of Medical Sciences, and Department of Histology (Dr. Luca), Institute of Biology, State University of Campinas, Campinas, Brazil.

Correspondence to: Jose E. Tanus-Santos, MD, PhD, University of Sao Paulo, Faculty of Medicine of Ribeirao Preto, Dept of Pharmacology, Av Bandeirantes, 3900, Ribeirao Preto, SP, Brazil 14049-900; e-mail: tanussantos@yahoo.com



Chest. 2002;122(4):1412-1420. doi:10.1378/chest.122.4.1412
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Study objectives: We compared the myocardial lesions caused by the long-term inhibition of nitric oxide (NO) biosynthesis with those associated with renovascular hypertension (two-kidney, one-clip model [2K-1C]) and superimposed streptozotocin-induced diabetes mellitus (DM).

Design: Prospective trial.

Setting: University laboratory.

Interventions: Male Wistar rats were classified into the following groups: (1) a control group; (2) the L-NAME group (treatment with the NO synthase inhibitor Nω-nitro-L-arginine methyl ester [L-NAME], 75 μmol per rat per day, orally); (3) the 2K-1C group (renovascular hypertension); (4) the DM group (treatment with streptozotocin, 60 mg/kg via intraperitoneal route); and (5) the 2K-1C plus DM group (renovascular hypertension and streptozotocin-induced DM). Arterial BP was measured by a tail-cuff method for 3 weeks, after which histologic and stereological analysis of the heart was done and cardiac NO synthase type 3 (NOS3) levels were assessed by Western blotting. The circulating levels of nitrates/nitrites and thromboxane B2 (TXB2, the stable metabolite of thromboxane A2) were also measured.

Results: In DM and 2K-1C rats, the myocardial lesions consisted mainly of recent myocardial infarcts, which were more severe in the 2K-1C plus DM group. In L-NAME–treated rats, multiple foci of reparative fibrosis and fresh myocardial necrosis resembled the severe lesions found in the 2K-1C plus DM group. Although NOS3 protein expression increased (19 to 44%; p < 0.05) in all treated groups, serum nitrate/nitrite levels decreased only in the L-NAME group and the 2K-1C plus DM group. These two groups also showed a more pronounced increase in TXB2 concentrations.

Conclusions: These results indicate that the association of hypertension and DM mimics the alterations induced by L-NAME in rats, which suggests a role for NO in the pathophysiology of hypertensive-diabetic cardiomyopathy.

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