Previous studies suggesting that norepinephrine is directly trophic for the vascular wall have been confounded by concomitant hemodynamic disturbances. Herein, a microcatheter connected to an osmotic minipump was implanted adjacent to the rat carotid for 2-wk perivascular suffusion of agents at systemic levels ϳ1,000 times below the threshold for altering arterial pressure. Norepinephrine decreased lumen and adventitial areas and circumference by 10, 14, and 5%, respectively (all P Ͻ 0.05); a nonsubtype-specific ␣ 1-adrenoceptor (AR) antagonist had no effect. When begun at the time of balloon injury, 2-wk norepinephrine increased lumen loss by 45%, increased neointimal area by 64% and collagen content by 33%, and reduced vessel circumference by 5% (all P Ͻ 0.05). ␣ 1-AR antagonists decreased neointimal area by 33% (all P Ͻ 0.05). ␣ 1A-AR antagonist reduced lumen loss by 70%, neointimal area by 54%, circumference decline by 84%, and adventitial thickening by 87% (all P Ͻ 0.05), whereas ␣ 1B-, ␣1D-, ␣2-and ␤-AR antagonists were without effect. These are the first in vivo studies demonstrating that norepinephrine is directly trophic for the vascular wall and augments injury-induced intimal lesion growth. artery; smooth muscle; adventitia; injury; adrenergic VASCULAR HYPERTROPHY and remodeling are adaptive structural changes in response to sustained increases in arterial pressure or altered shear stress that favor restoration of normal physiological regulation. On the other hand, excessive wall growth, fibrosis, and inward or inadequate outward remodeling cause failure of surgical procedures (e.g., restenosis after angioplasty/ stent, atherectomy, and bypass grafting) and underlie diseases such as atherosclerosis, pulmonary hypertension, and accelerated arteriosclerosis (31,35). Thus the mechanisms regulating growth of vascular wall cells are under intense investigation. Besides the vasoactive actions of norepinephrine (NE), there is growing evidence that NE may be a trophic mediator for vascular smooth muscle cells (SMCs) and adventitial fibroblasts (AFBs). In vivo studies using surgical or systemic sympathetic denervation (16), systemic infusion of catecholamines (7, 21), or ␣-adrenoceptor (AR) antagonists (20), as well as positive correlation of plasma catecholamines with wall hypertrophy and stiffness (8) and severity of atherosclerosis (22) in humans, suggest that NE may have direct trophic effects on the normal and diseased vascular wall. Moreover, in the ballooninjured rat and rabbit carotid, chronic systemic ␣ 1 -AR antagonists reduced cell proliferation, neointimal growth, and restenosis by at least 50% (14,18,30,34). ␣ 1 -AR antagonists also attenuated angiotensin II-induced DNA synthesis (33) and atherogenesis (26,29). However, interpretation of these past in vivo studies is complicated by concomitant hemodynamic disturbances that, themselves, have trophic effects. For example, chemical or immunological systemic denervation and systemic ␣-AR antagonists cause significant hypotension and humoral changes. A...

Previous in vitro and in vivo studies have shown that norepinephrine, acting through alpha(1A)-adrenoceptors, stimulates hypertrophy, proliferation, and migration of vascular smooth muscle cells and adventitial fibroblasts and may contribute to neointimal growth, lumen loss, and inward remodeling caused by iatrogenic wall injury and vascular disease. Our present aim was to determine whether intravenous administration of the alpha(1A)-adrenoceptor antagonist KMD-3213, at dosages without systemic hemodynamic effects, inhibits wall growth after injury. Inhibition of alpha(1A)-adrenoceptors with 12.8 and 32 microg/kg KMD-3213 had no effect on arterial pressure or renal and hindquarter resistances in anesthetized rats. A second group then received carotid balloon injury and continuous intravenous KMD-3213 at 4 and 10 microg x kg(-1) x h(-1) for 2 wk. Mean, systolic, and diastolic arterial pressures and heart rate of conscious unrestrained rats were unaffected. KMD-3213 reduced neointima growth by approximately 30 and 46% at the two doses (P < 0.01). These data support the novel hypothesis that a direct alpha(1A)-adrenoceptor-dependent trophic action of catecholamines is augmented by injury and may contribute significantly to hypertrophic vascular disease.

Stimulation of alpha1-adrenoceptors (ARs) induces proliferation, hypertrophy, and migration of vascular smooth muscle cells and adventitial fibroblasts in cell and organ culture. In vivo studies have confirmed this direct trophic action and found that endogenous catecholamines contribute to neointimal formation and wall hypertrophy induced by mechanical injury. In murine carotid artery, these effects are mediated by alpha 1B-ARs, whereas alpha 1D-ARs mediate contraction and alpha 1A-ARs are not expressed. Herein, we examined whether catecholamines also contribute to arterial wall growth in a noninjury model, i.e., flow-mediated remodeling. In wild-type mice or mice deficient in norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase knockout (DBH-KO)], all distal branches of the left carotid artery (LC) except the thyroid artery were ligated to reduce flow in the LC and increase flow in the right carotid artery (RC). Twenty-one days later, negative hypertrophic remodeling of the LC [i.e., -20% (decrease) in lumen area, -2% in circumference of the external elastic lamina (CEEL), +98% (increase) in thickness of the intima media, and +71% in thickness for adventitia; P < 0.01 vs. sham ligation] and positive eutrophic remodeling of the RC [+23% in lumen area, +11% in CEEL; P < 0.01 vs. sham ligation] were inhibited in DBH-KO mice [LC: +10% intima media and +3% adventitia; RC: +9% lumen area and +3% CEEL]. This inhibition was associated with reduced proliferation in the RC and reduced apoptosis and leukocyte accumulation in the RC and LC when examined 5 days after ligation. Carotid remodeling in alpha 1D-AR-knockout mice evidenced little or no inhibition, which suggests dependence on alpha 1B-ARs. These findings suggest that catecholamine-induced trophic activity contributes to both flow-mediated negative remodeling and adaptive positive arterial remodeling.

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