Examination by radioligand binding of the α1-adrenoceptors in the mesenteric arterial vasculature during the development of salt-sensitive hypertension

Abstract

Previous experiments have suggested that the vascular smooth muscle of Dahl salt-sensitive (DS) rats may possess a difference in the alpha1-adrenoceptor population or its transduction processes compared to Dahl salt-resistant (DR) rats. The purpose of the current research is to study the role of alpha1-adrenoceptors in the specific supersensitivity to norepinephrine (NE) seen prior to and early in the development of hypertension in the DS rat. Experiments in isolated perfused superior mesenteric arterial vasculature from DS rats chronically fed a high (7%) salt diet for 5 days or 3 weeks, in the absence or presence of an elevation in systolic blood pressure, respectively, demonstrated a specific supersensitivity to NE relative to DR rats. The enhanced responsiveness was specific to NE after 5 days of high salt since no differences in sensitivity of these preparations was observed to either KCl or 5-HT. A small but significant elevation in sensitivity to KCl following 3 weeks of treatment suggests that multiple factors may contribute to tissue responsiveness at this time. Radioligand binding experiments were performed using [125I]-HEAT to study the alpha1-adrenoceptor population and its subtypes. Saturation experiments using membranes prepared from the superior mesenteric arterial vasculature or mesenteric arterial branches showed no significant differences in overall alpha1-adrenoceptor population between DS and DR rats fed a high-salt diet for 5 days or 3 weeks. Competition experiments using membranes prepared from the superior mesenteric arterial branches in the presence of the alpha1A-subtype selective antagonist 5-methylurapidil showed two binding sites (high and low affinity) in these resistance vessels but no significant differences in nature or ratio of these sites between the DS and DR groups. These results suggest that changes in the alpha1-adrenoceptor population are not responsible for the specific supersensitivity to NE, which may be an early event in the induction and development of hypertension.

Modulation by Cytochrome P450-4A ω-Hydroxylase Enzymes of Adrenergic Vasoconstriction and Response to Reduced PO2 in Mesenteric Resistance Arteries of Dahl Salt-Sensitive Rats

“…A variety of studies in the literature indicate that vessel sensitivity to adrenergic agonists [2,18,38,58] and other vasoconstrictors, for example, angiotensin II [9] and vasopressin [44], but not ET‐1 [44], is increased in various hypertensive models. In SS rat studies where blood pressure [2], isometric contractile force in aortas [38], or perfusion pressure of mesenteric vascular beds [18] are studied, elevated dietary salt intake results in an enhanced responsiveness to NE. In contrast to those reports, the respective vasoconstrictor sensitivities to NE and ET‐1 in this study were similar in small mesenteric arteries from SS rats fed LS and HS diet.…”

“…Nonetheless, the effect of HS diet per se on vasoconstrictor or pressor responses in normotensive and hypertensive subjects is incompletely understood. For example, there are conflicting reports as to whether HS diet affects vascular responses to norepinephrine [2,16,18,37,38,42,53] or angiotensin II [16,34,53] in SS and salt‐insensitive experimental models. This is an important question, because any increase in the sensitivity to vasoconstrictor stimuli may aggravate the consequences of endothelial dysfunction and impaired vascular relaxation, contributing to an elevation of total peripheral resistance and an increase in arterial blood pressure.…”

Mechanism of Ca2+release and entry during contraction elicited by norepinephrine in rat resistance arteries

“…Indeed, the characterization of ␣ 1 -adrenoceptor population in small resistance arteries shows that NE mainly activates ␣ 1 -adrenoceptor population, which belongs to ␣ 1A -, ␣ 1B -, and the pharmacologically defined ␣ IL -subtypes (8,12,33). Further studies are needed to better understand the nature of the receptor subtypes implicated in the observed different pathways in these arteries.…”

Role of the α 1D - Adrenegric Receptor in the Development of Salt-Induced Hypertension

“…However, at the vascular level, 2 factors seem to be involved in the pathogenesis of this condition: (1) structural changes in blood vessel walls and (2) hypersensitivity of blood vessels to vasoconstrictor stimuli. [3][4][5][6] Structural changes could represent an adaptive phenomenon in which the arterial wall thickens in response to an increase in BP. 5 Consequently, hypertension predisposes the individual to the cardiovascular diseases, renal failure, and stroke.…”