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Hypertension is characterized by abnormal vascular contractility and function. Arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive rats develop spontaneous tone that is not observed in arteries from normotensive rats. Inhibition of phosphoinositide 3-kinase (PI3-kinase) by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) reduces spontaneous tone development. The Rho/Rho-kinase pathway has been suggested to play a role in hypertension and may be dependent on PI3-kinase activity. We hypothesized that Rhokinase is involved in spontaneous tone development and that Rho/Rho-kinase is a downstream effector of PI3-kinase. Using endothelium-denuded aortic strips in isolated tissue bath, we demonstrated that (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) (Y27632) (1 microM), a Rho-kinase inhibitor, significantly reduced spontaneous tone in the DOCA aorta but that it did not affect sham aorta basal tone (DOCA 63.5 +/- 15.9 versus sham 1.2 +/- 0.4 total change in percentage of phenylephrine contraction). We examined the interaction between the PI3-kinase and Rho pathways by observing the effects of LY294002 on a Rhokinase effector, myosin phosphatase (MYPT), and Y27632 on a PI3-kinase effector, Akt, using Western blot analysis. Inhibition of PI3-kinase reduced spontaneous tone, but it had no effect on the phosphorylation status of MYPT, indicating that PI3-kinase is not a downstream effector of Rho/Rho-kinase. These data indicate that there is little interaction between the Rho/Rhokinase and PI3-kinase pathways in the DOCA-salt aorta, and the two pathways seem to operate in parallel in supporting spontaneous arterial tone. These data reflect spontaneous tone only and do not rule out the possibility of interaction between these pathways in agonist-stimulated tone.

Glial cell line–derived neurotrophic factor (GDNF) is produced by skeletal muscle and affects peripheral motor neurons. Elevated expression of GDNF in skeletal muscle leads to hyperinnervation of neuromuscular junctions, whereas postnatal administration of GDNF causes synaptic remodeling at the neuromuscular junction. Studies have demonstrated that altered physical activity causes changes in the neuromuscular junction. However, the role played by GDNF in this process in not known. The objective of this study was to determine whether changes in neuromuscular activity cause altered GDNF content in rat skeletal muscle. Following 4 weeks of walk‐training on a treadmill, or 2 weeks of hindlimb unloading, soleus, gastrocnemius, and pectoralis major were removed and analyzed for GDNF content by enzyme‐linked immunosorbant assay. Results indicated that walk‐training is associated with increased GDNF content. Skeletal muscle from hindlimb‐unloaded animals showed a decrease in GDNF in soleus and gastrocnemius, and an increase in pectoralis major. The altered production of GDNF may be responsible for activity‐dependent remodeling of the neuromuscular junction and may aid in recovery from injury and disease. © 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 206–211, 2002