title: Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension.
abstract: 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 beta-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.
authors.affiliation: Dept. of Health and Kinesiology, Texas A & M University, College Station, Texas, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lesniewski
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Behnke
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Woodman
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
authors.forename: Chester A
authors.initials: CA
authors.lastname: Ray
authors.forename: Michael D
authors.initials: MD
authors.lastname: Delp
mesh_terms: D000818:Animals; D001160:Arterioles / Q000201:enzymology / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine / Q000494:pharmacology; D011189:Potassium Chloride; D011236:Prediabetic State / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007328:Insulin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D011189:Potassium Chloride; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine