Systemic α_1A-adrenoceptor antagonist inhibits neointimal growth after balloon injury of rat carotid artery

Abstract

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.

Blockade of both α1A- and α1B-adrenergic receptor subtype signaling is required to inhibit neointimal formation in the mouse femoral artery

“…Furthermore, other studies have revealed that the functional role of ␣ 1 -ARs in the cardiovascular system is not only vasoconstriction but also postnatal cardiac development (20). In addition, previous studies using rat aorta, artery, and cultured cells with selective ␣ 1 -antagonists have demonstrated that the activation of the ␣ 1 -AR subtype (particularly, the ␣ 1A -AR subtype, but not the ␣ 1D -AR subtype) can induce neointimal formation (10,12,36), even though the ␣ 1B -AR and ␣ 1D -AR subtypes were mainly expressed in the rat aorta at both the mRNA and protein levels (11). On the other hand, the exact functional role of ␣ 1B -AR subtypes in neointimal formation still remains unclear because of lack of appropriate ␣ 1B -selective antagonists and satisfactory methods of quantitative ␣ 1 -AR subtype mRNA expression analysis (10,36,41).…”

“…In addition, previous studies using rat aorta, artery, and cultured cells with selective ␣ 1 -antagonists have demonstrated that the activation of the ␣ 1 -AR subtype (particularly, the ␣ 1A -AR subtype, but not the ␣ 1D -AR subtype) can induce neointimal formation (10,12,36), even though the ␣ 1B -AR and ␣ 1D -AR subtypes were mainly expressed in the rat aorta at both the mRNA and protein levels (11). On the other hand, the exact functional role of ␣ 1B -AR subtypes in neointimal formation still remains unclear because of lack of appropriate ␣ 1B -selective antagonists and satisfactory methods of quantitative ␣ 1 -AR subtype mRNA expression analysis (10,36,41). As in a previous study using rat vessels (10,12,36), our study also showed that lack of the ␣ 1D -AR gene was not required to inhibit neointimal formation in the mouse femoral artery.…”

“…In addition, recent studies using rat vessels with ␣ 1 -antagonists revealed that the ␣ 1A -AR subtype, but not the ␣ 1D -AR subtype, was certainly involved in catecholaminestimulated neointimal formation (10,12). However, the exact functional role of ␣ 1B -AR subtypes in neointimal formation remained unclear (10,36) because of the lack of appropriate ␣ 1B -selective antagonists and satisfactory methods of quantitative ␣ 1 -AR-subtype mRNA expression analysis.…”

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).…”