ABSTRACT
Hindlimb unweighting (HLU) in rats mimics the fluid shift experienced by astronauts and may serve as a model for ground-based orthostatic hypotension. It has been shown that the abdominal aorta of HLU rats exhibits a deficit in contractile response to adrenergic agonists. The hypothesis of the present study was that decreased activity in the RhoA/Rho-kinase pathway could contribute to that deficit. Wistar rats were subjected to 20 days of HLU treatment. Abdominal aorta rings from HLU and control rats were suspended in baths for measurement of contraction. Concentration response curves were obtained to the alpha adrenergic agonist, phenylephrine and the thromboxane-mimetic, U46619. HLU treatment caused decreased contraction in response to both. The Rho-kinase inhibitor, Y27632, caused a reduction in the phenylephrine-induced contraction in control, but not HLU aorta. Other rings were frozen after stimulation 1 microM U46619 or phenylephrine. Western analysis revealed a decreased expression of RhoA, but increased expression of both Rho kinase and MYPT1, the regulatory subunit of myosin light chain (MLC) phosphatase. MYPT1 and MLC phosphorylation was decreased by HLU in phenylephrine stimulated aorta. Decreased activity in the RhoA/Rho-kinase pathway may be involved in the decreased contraction seen in the HLU abdominal aorta.
Subject(s)
Aorta, Abdominal/physiology , Hindlimb Suspension/physiology , Signal Transduction/physiology , rho-Associated Kinases/physiology , rhoA GTP-Binding Protein/physiology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Animals , Blotting, Western , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Male , Muscle Contraction/physiology , Myosin Light Chains/metabolism , Permeability , Phosphorylation , Rats , Rats, Wistar , Vasoconstrictor Agents/pharmacology , rho-Associated Kinases/antagonists & inhibitorsABSTRACT
BACKGROUND: Chronic renal insufficiency (CRI) is associated with a high incidence of hypertension (HTN), endothelial dysfunction, atherosclerosis and cardiovascular disease. Sedentary life style increases, whereas regular exercise reduces the risk of cardiovascular disease. This study was designed to test the effect of regular exercise on vasodilatory and vasoconstrictive responses of the thoracic aorta in rats with renal mass reduction. METHODS: One week after 5/6 nephrectomy (CRI) or sham operation (control), rats were housed in either regular cages or cages equipped with running wheels for 4 weeks. Thereafter, thoracic aorta was harvested and contractile response to potassium and phenylephrine (PhE), and relaxation response to acetylcholine (ACh) and sodium nitroprusside (SNP) were determined. RESULTS: Compared with the control animals, sedentary CRI animals exhibited significant azotemia, proteinuria, HTN, oxidative stress, and increased sensitivity to potassium and PhE, and reduced sensitivity to ACh and SNP. Exercise training for 4 weeks reduced oxidative stress, reversed CRI-induced heightened sensitivity of the aorta to PhE and potassium, and restored its sensitivity to ACh (but not SNP) without affecting arterial pressure or renal function. CONCLUSIONS: CRI results in heightened sensitivity to potassium- and alpha-1 adrenergic-mediated contractility and depressed sensitivity to endothelium-dependent relaxation in the aorta. Regular exercise improves these abnormalities without affecting arterial pressure or renal function. These observations suggest that exercise training can improve vascular function in animals, and perhaps humans, with chronic kidney disease.
Subject(s)
Aorta, Thoracic/physiopathology , Physical Exertion , Renal Insufficiency, Chronic/physiopathology , Vasoconstriction , Vasodilation , Acetylcholine/pharmacology , Animals , Aorta, Thoracic/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Nephrectomy , Nitroprusside/pharmacology , Phenylephrine/pharmacology , Potassium Chloride/pharmacology , Rats , Rats, Sprague-Dawley , Renal Insufficiency, Chronic/metabolism , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
BACKGROUND: Hindlimb unloading (HLU) is used to simulate microgravity in rats and has been shown to decrease contractile response in the abdominal aorta. The thoracic aorta has not been studied as thoroughly. METHODS: Wistar and Sprague-Dawley rats were subjected to HLU for 20 d and the thoracic aortas were isolated and sectioned into 3-mm rings for the measurement of isometric force development. Concentration response curves (CRCs) to phenylephrine (PHE) were obtained in endothelium-intact and -denuded rings from both strains of rats. Acetylcholine, methylfurmethide (MFM), and sodium nitroprusside (SNP) CRCs were obtained in the Wistar rats. RESULTS: HLU had no effect on the contractions of endothelium-intact Wistar aortas to PHE, but decreased the maximal PHE-induced contraction (2.82 +/- 0.16 g Control vs. 2.18 +/- 0.11 g HLU) in intact Sprague-Dawley aortas. After endothelium removal, HLU increased the contractions of Wistar, but not Sprague-Dawley, aortas to PHE (1.91 +/- 0.12 g Control vs. 2.95 +/- 0.13 g HLU). HLU had no effect on the relaxation to acetylcholine, but increased the sensitivity to the relaxing effects of MFM (LOG EC50 -6.96 +/- 0.12 Control vs.-7.31 +/- 0.17 HLU) and SNP (LOG EC50 -7.90 +/- 0.15 Control vs.-8.35 +/- 0.10 HLU) in the Wistar rats. SUMMARY: It is concluded that HLU increased smooth muscle contracting and endothelium-dependent relaxing capacities equally in the Wistar aortas, and had no effect on smooth muscle, but increased endothelium-dependent relaxation, in the Sprague-Dawley aortas.
