No abstract

We explored in 43 healthy subjects the afferent mechanisms of the initial heart rate response to standing by comparing free standing, 70 degrees head-up tilt, handgrip, and contraction of abdominal and leg muscles. The results indicate the following. 1) Standing evokes an immediate, large, bimodal increase of heart rate (HR) of about 20 s duration that far exceeds the gradual HR rise induced by 70 degrees head-up tilt. 2) The immediate HR increase with active standing is due to the exercise reflex and results in a first peak about 3 s after standing briskly. 3) The secondary, more gradual HR increase after 5 s of standing and the subsequent rapid decrease of HR between about 12 and 20 s corresponds through the baroreceptor reflex with a striking fall, recovery, and sometimes overshoot of arterial pressure. 4) The maximum HR increase found after about 12 s of standing is augmented and delayed after rest. 5) The time course of the initial HR response is not modified by physical training. We conclude that active and passive changes of posture result in fundamentally different cardiovascular effects for about 20 s and that "central command," muscle receptors, high-pressure receptors, low-pressure receptors, and the plasma catecholamine level are probably all involved in the initial HR response to standing.

Background-Inflammation plays an important role in atherogenesis. The toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharides and also recognizes cellular fibronectin and heat shock protein 60, endogenous peptides that are produced in response to tissue injury. To explore a possible role for this receptor in arterial obstructive disease, we determined the expression of TLR4 in the atherosclerotic arterial wall, including adventitia, and studied the effect of adventitial TLR4 activation on neointima formation in a mouse model. Methods and Results-Localization of TLR4 was studied in human atherosclerotic coronary arteries by immunohistochemistry and detected in plaque and adventitia. In the adventitia, not all TLR4-positive cells colocalized with macrophages. In primary human adventitial fibroblasts, expression of TLR4 was demonstrated by immunofluorescence, Western blot, and reverse transcriptase-polymerase chain reaction. Adding lipopolysaccharide to these fibroblasts induced activation of NF-B and an increase of mRNAs of various cytokines. The effect of adventitial stimulation of TLR4 was studied in a mouse model. A peri-adventitial cuff was placed around the femoral artery. Application of lipopolysaccharide between cuff and artery augmented neointima formation induced by the cuff (intimal areaϮSEM, 9134Ϯ1714 versus 2353Ϯ1076 m 2 , PϽ0.01). In TLR4-defective mice, application of cuff and lipopolysaccharide resulted in a smaller neointima than in wild-type mice (intimal area, 3859Ϯ904 m 2 , Pϭ0.02 versus wild type). Conclusions-A functional TLR4 is expressed in human adventitial fibroblasts and macrophages. Adventitial TLR4 activation augmented neointima formation in a mouse model. These results provide evidence for a link between the immune receptor TLR4 and intimal lesion formation.