Endothelial modulation of alpha-1 adrenoceptor-mediated contraction of vascular smooth muscle

The level of the initial vessel wall tension (i.e. vessel wall “preload”) alters the endothelium effect on vascular smooth muscle (VSM) contraction to alpha-1 adrenoceptor agonists at the below-normal preloads. Prolonged vessel exposure to alpha-1 adrenoceptor agonists reduces (desensitizes) force development and the sensitivity of VSM at the below-normal preloads. This research investigated the preload effect on the role of the endothelium in the regulation of VSM contraction to an alpha-1 adrenoceptor agonist, phenylephrine (PHE), across a wide preload range.; Our studies determined the maximum force development (Fmax) and the sensitivity (pD₂) of VSM to PHE, and determined the effect of prolonged vessel exposure to PHE on Fmax and pD₂ at the below-normal to above-normal preloads. Our experiments used segments of thoracic aorta that had an intact endothelium, and segments that had a disrupted endothelium. Aortic rings were put on one of 14 preloads (1.0 to 14.0 grams). Each ring was pretreated simultaneously with acetylcholine (ACH, 1 μM) and PHE (1 μM), washed, contracted with six cumulative doses of PHE (0.01–3.0 μM); and then relaxed with ACH (3.0 μM). This same protocol was repeated to give a total of 4 concentration-response curves over a 5-hour period after the initial vessel exposure to PHE.; Our data demonstrate eight important new findings. (1) The endothelium releases at least one Fmax-depressing factor in response to PHE to limit Fmax by VSM at the below-normal preloads. (2) The endothelium releases a factor to enhance PHE-mediated Fmax at the above-normal preloads. (3) The endothelium appears to have no effect on PHE-stimulated Fmax of VSM at the normal preloads. (4) The endothelium appears to release at least one sensitivity-lowering endothelial factor to reduce VSM sensitivity to PHE across a wide preload range, with a greater endothelium-mediated reduction in VSM sensitivity at the below-normal preloads. (5) Repeated vessel exposure to PHE reduces adrenoceptor-induced Fmax of VSM at the below-normal and above-normal preloads; (6) induces endothelium release of one or more factors which further depress adrenoceptor-induced Fmax of VSM at all preloads; (7) desensitizes receptor-signal-transduction pathways in both VSM and the endothelium at the below-normal preloads; and (8) does not desensitize the signal-transduction pathways of either VSM or the endothelium at the above-normal preloads.; These new findings raise new questions about the role of the endothelium in modulating alpha-1 adrenoceptor-mediated contraction of VSM during pathophysiologic states, such as hypertension and hypodynamic sepsis, which involve altered vessel wall preloads.