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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/H1840    most recent 00692.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lesniewski, L. A. Articles by Delp, M. D. PubMed PubMed Citation Articles by Lesniewski, L. A. Articles by Delp, M. D.

Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension

¹Department of Health and Kinesiology, Texas A&M University, College Station, Texas; ²Department of Applied Physiology and Kinesiology and Center for Exercise Science, University of Florida, Gainesville, Florida; ³Department of Biomedical Sciences, University of Missouri, Columbia, Missouri; and ⁴Department of Medicine, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, Pennsylvania

Submitted 14 June 2007 ; accepted in final form 30 January 2008

Approximately 40% of patients with type 2 diabetes present with concurrent hypertension at the time of diabetes diagnosis. Increases in peripheral vascular resistance and correspondingly enhanced vasoconstrictor capacity could have profound implications for the development of hypertension and the progression of insulin resistance to overt diabetes. The purpose of this study was to determine whether skeletal muscle arteriolar vasoconstrictor dysfunction precedes or occurs concurrently with the onset of diabetes and hypertension. Male Zucker diabetic fatty (ZDF) rats were studied at 7, 13, and 20 wk of age to represent prediabetic and short-term and long-term diabetic states, respectively. Conscious mean arterial pressure (MAP), fasted plasma insulin and glucose, vasoconstrictor responses, and passive mechanical properties of isolated skeletal muscle arterioles were measured in prediabetic, diabetic, and age-matched control rats. Elevated MAP was manifest in short-term diabetes (control 117 ± 1, diabetic 135 ± 3 mmHg) and persisted with long-term diabetes (control 113 ± 2, diabetic 135 ± 3 mmHg). This higher MAP was preceded by augmented arteriolar vasoconstrictor responses to norepinephrine and endothelin-1 and followed by diminished β-adrenergic vasodilation and enhanced myogenic constriction in long-term diabetes. Furthermore, we demonstrate that diminished nitric oxide (NO) signaling underlies the increases in vasoconstrictor responsiveness in arterioles from prediabetic and diabetic rats. Arteriolar stiffness was not different between control and prediabetic or diabetic rats at any time point studied. Collectively, these results indicate that increases in vasoconstrictor responsiveness resulting from diminished NO signaling in skeletal muscle arterioles precede the development of diabetes and hypertension in ZDF rats.

type 2 diabetes; vasoconstriction; nitric oxide; norepinephrine; endothelin-1