ALTERED VASCULAR NOREPINEPHRINE RESPONSES IN PORTAL HYPERTENSIVE INTESTINE - ROLE OF PKA AND GUANYLATE-CYCLASE

The purpose of the present study was to determine whether selective bl ockade of adenosine 3',5'-cyclic monophosphate (cAMP)- or guanosine 3' ,5'-cyclic monophosphate (cGMP)-mediated events modulated norepinephri ne responses in intestinal microvessels of normal and portal hypertens ive rats. Vascular norepinephrine responses were evaluated before and after inhibition of cAMP-dependent protein kinase [protein kinase A (P KA)] with Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS) or g uanylate cyclase with LY-83583. Male Sprague-Dawley rats were divided into two groups: those with portal hypertension by portal vein stenosi s and normal controls. The small intestine was prepared for microcircu latory studies. Arteriolar diameter and erythrocyte velocity were moni tored, and microvascular flow was calculated from velocity and diamete r data. The preparation was challenged with incremental concentrations of norepinephrine before and after addition of Rp-cAMPS (50 mu M) or LY-83583 (30 mu M). Arteriolar diameter and blood flow were significan tly elevated in portal hypertensive rats; norepinephrine responses wer e significantly depressed. LY-83583 did not alter arteriolar diameter, blood flow, or norepinephrine responsiveness in normal or portal hype rtensive rats. Rp-cAMPS did not affect arteriolar diameter, blood flow or norepinephrine responsiveness in normal rats. However, in portal h ypertensive rats, Rp-cAMPS reduced blood flow by similar to 20% (P < 0 .05) and completely restored vascular norepinephrine responses to norm al. The results indicate that cAMP- but not cGMP-dependent events are primarily responsible for the loss of microvascular norepinephrine res ponsiveness in portal hypertensive intestine.