Mechanisms mediating heterogeneous endothelium-dependent relaxation in small arteries from the coronary, mesenteric and skeletal muscle vascular beds in Golden Syrian and cardiomyopathic hamsters

Abstract

V asodilatory substances released from the endothelium are important regulators of vascular smooth muscle tone. Endothelium-dependent relaxation of large arteries is mediated primarily by nitric oxide (NO). Mechanisms mediating relaxation of small arteries (150-250 μm intraluminal diameter; ID) are not well understood. Additionally, endothelium-derived relaxing factors (EDRFs) may differentially modulate vascular tone and · relaxation in arteries from different vascular beds. The mechanisms mediating basal tone and endothelium-dependent vascular relaxation were determined in skeletal (Ske ), coronary (Cor) and mesenteric (Mes) small arteries isolated from male Golden Syrian hamsters. Baseline ID of small arteries was measured before and after pretreatment with inhibitors. Blockade of delayed-rectifying K+ channels CKmJ decreased baseline ID in Ske -small arteries, only. Blockade of large ca++ -dependent K+ channels (BKcJ decreased baseline ID in Cor small arteries, only. Blockade of inwardly-rectifying K+ channels (Km) decreased baseline ID in Cor and Mes small arteries. Therefore, basal 'tone is mediated by KDR channels in isolated Ske, K1R channels in isolated Mes, and K1R and BKca channels in isolated Cor small arteries. Acetylcholine (ACh, 10-9 to 3 x 10-5 M) produced concentration-dependent relaxation in Ske, Cor and Mes small arteries. Cor small arteries demonstrated a lower sensitivity to ACh. Relaxation to ACh was completely abolished after removing the endothelium and was unaffected by inhibition of cyclooxygenase (COX) in Ske, Mes, and Cor small arteries. Inhibition of nitric oxi~e synthase (NOS) significantly reduced maximal relaxation and reduced the sensitivity to ACh in Cor, but had no effect in Ske or Mes, small arteries. High extracellular K+ largely reduced relaxation to A Ch in all ~~ssels. Blockade. of KnR or K1R channels decreased the sensitiyity to ACh in S~e, but had no effect in Cor or Mes small arteries. Blockad~ of ca++ -dependent K+ channels (KcJ ·did iiot. alter relaxation in Mes, significantly reduced relaxation in Ske, and abolished relaxation to ACh in Cor small arteries. These results indicate that relaxation to A Ch is mediated partially by NO and an endothelium-deriveq hyperpolarizingfactor (EDHF), other than NO in Cor small arteries by opening Kea channels. Relaxation to A Ch is mediated by EDHF in Ske small arteries by opening Kea, ~DR and ~R channels. Relaxation to A Ch is mediated by EDHF in Mes small arteries, but the specific K+ channels contributing to relaxation remain unkn.own. Although the chemical identity of EDHF is unknown, it may be a metabolite of arachidonic acid (AA) produced by cytochrome P450 monooxygenase ( cP450). Inhibition of cP450 significantly inhibited relaxation to ACh in all vessels. These results indicate that relaxation to A Ch· that is resistant to inhibition of NOS or COX is dependent on cP450 metabolites in all vessels. In many diseases, mechanisms mediating normal vascular function are altered. Blockade of BKca channels in Cor and Mes small arteries from control hamsters and Cor / small arteries from cardiomyopathic hamsters caused contraction from baseline. Therefore, basal tone is regulated by BKea channels in Cor small arteries from control and cardiomyopathic hamsters and regulation of basal tone by BKea channels is impaired in Mes small arteries from cardiomyopathic hamsters. Concentration-response curves to A Ch were similar between vessels from both groups. COX inhibition decreased relaxation to A Ch in cardiomyopathic, but not control, Cor small arteries. NOS inhibition reduced the sensitivity to ACh similarly in Mes small arteries from both groups;. However, NOS inhibition decreased relaxation to ACh to a lesser extent in cardiomyopathic compared to control hamster Cor small artetjes. NOS inhibition decreased maximum relaxation and reduced the sensitivity to ACh in Cor small arteries from control hamsters, but had no effect on maximum relaxation in vessels from cardiomyopathic hamsters. This ·_indicates that the contribution of NO-mediated relaxation is reduced in- vessels from cardiomyopathic hamsters. Blockade of Kea comple_tely abolished relaxation to A Ch in Cor, but not Mes . . small arteries from both groups. Ther~fore, A Ch~induced relaxation of Cor small arteries from control hamsters is mediated by NO and EDHF via opening Kea channels. AChinduced relaxation of Cor small arteries from cardiomyopathic hamsters is primarily mediated by NO and EDHF, slightly by PG/2 by opening Kea channels. ACh-induced relaxation of Mes small arteries from control and cardio1,:,yopathic hamsters is mediated by NO and EDHF, but does not require opening of Kea channels. Measurement of mean arterial pressure (MAP), mesenteric vascular resistance (MVR) and hindquarter vascular resistance (HVR) was examined in anesthetized control . and cardiomyopathic hamsters after inhibition of NOS · or BKca channels. NOS inhibition increased MAP and MVR to a lesser extent in cardiomyopathic compared to control hamsters and increased HVR in co~trol, but not cardiomyopathic hamsters. Blockade of BKca channels increased MAP and MVR similarly in both groups, but increased HVR significantly less in cardiomyopathic hamsters. These results indicate that regulation of MVR by NOS, and of HVR by both NOS and BKca channels, is reduced.