Potassium channels in venous muscle membranes may be important modulators of venous excitability and reactivity during acute and chronic changes in vascular distending pressures. Increased venous tone may contribute to the development and maintenance of hypertension. In the Parent Grant, evidence was shown that K+ channels may be important controllers of vascular tone in arteries from spontaneously hypertensive rats. Large conductance, Ca2+- activated K+ channels [IK(Ca) channels] in aortic membranes showed an increased open state probability compared to their normotensive (WKY) counterparts, which was associated with suppression of arterial excitability in isolated aortic muscle. Despite this finding of IK(Ca) alteration in arteries exposed to high pressure, and studies indicating that IK(Ca) channels are important regulators of arterial excitability during agonist stimulation of normal arteries, little is known about the identity or regulation of K+ channel types in venous membranes of animals or man, where these channels may also be cellular determinants of venous tone and blood return to the heart. In the rat saphenous vein, chronic pressure load resulted in hyperpolarization, that may be a result of increased membrane K+ permeability. We propose to investigate and characterize the biophysical and pharmacological properties of K+ channels in human and rat saphenous veins. We also propose to compare the K+ channels of rat saphenous vein exposed to chronically elevated intraluminal pressure compared to control veins. For the chronic, non- invasive elevation of venous pressure we propose to use the tilt technique, that was developed by our group. To define the role of K+ channels in modulating venous smooth muscle responses to acutely and chronically increased pressure, the single-channel data obtained with the patch-clamp technique will be correlated with studies of membrane potential and diameter measurements of isolated vein segments during K+ channel inhibition. In addition, saphenous veins are widely used as grafts in coronary or femoral bypass surgeries, identification of K+ channel types will define potential targets for vasodilation therapy. Therefore it is important to characterize the biophysical and pharmacological properties of the K+ channels in this particular vein. The integrated approach of defining venous K+ channel function from the level of the single-channel to the changes of diameter and membrane potential of venous segment will provide critical information on the mechanisms and physiological role of venous K+ channels during acute and chronic pressure load.

R03TW000350

1993-09-30

1995-09-29