| Abstract | Insulin activation of the phosphatidylinositol 3-kinase (PI3K) pathway stimulates glucose uptake in peripheral tissues and synthesis of nitric oxide (NO) in the endothelium. Insulin resistance (IR) and hypertension frequently coexist, particularly among individuals with salt-sensitive hypertension. The mechanisms underlying this association are poorly understood. We investigated these mechanisms in a model of salt-sensitive hypertension in which we have previously shown that endothelial dysfunction is mediated by superoxide anion (O(2)(-)) linked to local ANG II. Dahl salt-sensitive rats were fed, for 6 wk, a normal salt diet (NS; 0.5% NaCl), high-salt diet (HS; 4% NaCl), HS plus the ANG II type 1 receptor (AT(1)R) blocker (ARB) candesartan (10 mg.kg(-1).day(-1)), or HS plus the antioxidant tempol (172 mg/l in drinking water). Hypertensive (mean arterial pressure: 145 +/- 4 vs. 102 +/- 5 mmHg in NS, P < 0.05) rats manifested increased aortic AT(1)R mRNA (210%) and protein (101%) expression and O(2)(-) production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response (E(max)): 68 +/- 9 vs. 91 +/- 8% in NS, P < 0.05]. ARB or tempol normalized O(2)(-) and EDR despite that they did not normalize mean arterial pressure, which was reduced only 25%. Hypertensive rats manifested metabolic IR (36% reduction in the glucose infusion rate by insulin clamp), impaired NO-mediated insulin-induced EDR (E(max): 12 +/- 5 vs. 32 +/- 4% in NS, P < 0.05), and impaired insulin activation of PI3K/endothelial NO synthase. ARB or tempol improved insulin-mediated EDR, PI3K, Akt/ endothelial NO synthase phosphorylation, and metabolic IR (all P < 0.05). This study provides insight into the mechanisms that underlie the association between metabolic and hypertensive cardiovascular diseases and support the notion that O(2)(-) overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues. |
| Authors | Ming-Sheng Zhou, Ivonne Hernandez Schulman, Leopoldo Raij
(Affiliation: Nephrology-Hypertension Sect., Veterans Affairs Medical Center, and Vascular Biology Institute, Miller School of Medicine, Univ. of Miami, 1201 NW 16th St., Rm. A-1009, Miami, FL 33125, USA. mzhou2 at med.miami.edu)
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| Journal | American journal of physiology. Heart and circulatory physiology
(Am J Physiol Heart Circ Physiol)
Vol. 296
Issue 3
Pg. H833-9
(Mar 2009)
ISSN: 0363-6135 [Print] United States |
| PMID | 19151253
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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| Chemical References |
- Angiotensin II Type 1 Receptor Blockers
- Antioxidants
- Benzimidazoles
- Cyclic N-Oxides
- RNA, Messenger
- Receptor, Angiotensin, Type 1
- Receptor, Angiotensin, Type 2
- Sodium Chloride, Dietary
- Spin Labels
- Tetrazoles
- Vasodilator Agents
- Insulin
- Angiotensin II
- candesartan
- tempol
- Acetylcholine
- C-Reactive Protein
- Nitric Oxide Synthase Type III
- Nos3 protein, rat
- Superoxide Dismutase
- 1-Phosphatidylinositol 3-Kinase
- JNK Mitogen-Activated Protein Kinases
- Proto-Oncogene Proteins c-akt
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| Topics |
- 1-Phosphatidylinositol 3-Kinase
(metabolism)
- Acetylcholine
(pharmacology)
- Angiotensin II
(metabolism)
- Angiotensin II Type 1 Receptor Blockers
(pharmacology)
- Animals
- Antioxidants
(pharmacology)
- Benzimidazoles
(pharmacology)
- Blood Pressure
- Body Weight
- C-Reactive Protein
(metabolism)
- Cyclic N-Oxides
(pharmacology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Endothelium, Vascular
(drug effects, metabolism, physiopathology)
- Hypertension
(drug therapy, etiology, metabolism, physiopathology)
- Insulin
(metabolism)
- Insulin Resistance
- JNK Mitogen-Activated Protein Kinases
(metabolism)
- Male
- Nitric Oxide Synthase Type III
(metabolism)
- Oxidative Stress
(drug effects)
- Phosphorylation
- Proto-Oncogene Proteins c-akt
(metabolism)
- RNA, Messenger
(metabolism)
- Rats
- Rats, Inbred Dahl
- Receptor, Angiotensin, Type 1
(metabolism)
- Receptor, Angiotensin, Type 2
(metabolism)
- Signal Transduction
(drug effects)
- Sodium Chloride, Dietary
- Spin Labels
- Superoxide Dismutase
(metabolism)
- Tetrazoles
(pharmacology)
- Vasodilation
- Vasodilator Agents
(pharmacology)
|
