Long-term reduction of intimal hyperplasia by the selective alpha-1 adrenergic antagonist doxazosin

Abstract

Studies have shown that alpha 1-adrenergic blockade reduces intimal hyperplasia in the rabbit aorta. In this study a selective alpha 1-adrenergic antagonist, doxazosin, has been used to examine whether this effect is persistent and dose dependent. Forty-eight New Zealand White rabbits underwent endothelial denudation of the abdominal aorta using a Fogarty balloon catheter. Test rabbits were given low-dose (2 mg) or high-dose (8 mg) doxazosin daily and all animals killed at either 1 or 12 weeks after the procedure. The aortas were harvested after fixation in situ with 4 per cent glutaraldehyde and neointimal hyperplasia was measured, using an x-y digitizer, as the percentage reduction in luminal cross-sectional area. At 1 week after surgery, rabbits receiving the low dose had a median area reduction of 7.7 per cent and those receiving the high dose a reduction of 8.2 per cent; both had significantly less intimal hyperplasia than control rabbits, which had a median area reduction of 14.8 per cent (P < 0.01). However, at 12 weeks, when compared with the 32.6 per cent reduction in the control group, only those rabbits receiving high-dose doxazosin had significantly less intimal hyperplasia, with a reduction of 5.5 per cent (P < 0.001). It is concluded that selective alpha 1-adrenergic blockade significantly reduces neointimal hyperplasia, that this effect is dose dependent, and that it persists for at least 3 months.

α1-Adrenoceptor stimulation directly induces growth of vascular wall in vivo

“…Importantly, our results suggest that earlier findings of attenuated neointimal growth after balloon injury by systemic infusion of ␣ 1 -AR antagonists (14,18,29,34) likely resulted from blockade of the direct hypertrophic effect of NE identified herein and possibly also from reduction in arterial pressure or in downstream resistance and thus flow-induced outward remodeling. The present antagonist results suggest that even basal endogenous NE levels in the vascular wall may increase wall growth induced by injury.…”

“…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).…”

Immobilization Stress Inhibits Intimal Fibromuscular Proliferation in the Process of Arterial Remodeling in Rats

“…Catecholamines are released and act as activating hormones to fight the external stress (12). α-and β-Adrenergic blockades were reported to inhibit the formation of neointima after endothelial denudation of an artery in animal models (13,14), and the β-adrenergic blockade has a protective function against myocardial ischemic events, including plaque rupture, in humans (14). Besides these pathways, β-endorphin (END), an endogenous opioid, is also produced in the pituitary gland; it is released into the circulating blood to act as a relaxing factor against stress (15)(16)(17).…”

Normalization of catecholamine production following resection of phaeochromocytoma positively influences carotid vascular remodelling

“…They show that eutrophic (collagen deposition and fibrosis) and hypertrophic (proliferation and migration of smooth muscle cells and of adventitial fibroblasts) remodelling characterizes the damages caused by catecholamines on the vascular wall (1,(4)(5)(6)(7)(8)(9). These observations have also been indirectly confirmed by using a-adrenoceptor antagonists (9)(10)(11)(12)(13) and by experiments in animals submitted to local or systemic sympathetic denervation (14). In humans, even in physiological conditions, the elevated catecholaminergic tone associated with aging increases vascular (femoral) wall thickness (28).…”

“…Moreover, in animal models employing balloon injury of the carotid or aorta, an exacerbation of this action may be observed with proliferation, hypertrophy and migration of smooth muscle cells and adventitial fibroblasts, leading to hypertrophic remodelling (1,(4)(5)(6)(7)(8)(9). The direct influence of sympathetic neurotransmitters on vascular wall structure has been supported by studies using a-adrenoceptor antagonists that showed a reduction in proliferation of vascular wall cells and in neointimal growth after vascular injury (9)(10)(11)(12)(13). Finally, these findings have also been confirmed by the suppression in wall growth observed after local or systemic sympathetic denervation in animal experiments (14).…”