Investigation of α₁‐adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries

Abstract

1 Cutaneous resistance arteries (c.r.a.) (internal diameter=240.94+5.42 mm, n=67/25 (number arteries/number animals)) from New Zealand white rabbits were mounted in wire myographs and a normalization procedure followed. 2 Cumulative concentration-response curves (CCRCs) were constructed for the a-adrenoceptor agonists noradrenaline (NA), (R)A61603 and phenylephrine (PE) in the presence of cocaine (3 mM), propranolol (1 mM) and corticosterone (10 mM). The eects of competitive a 1 -adrenoceptor antagonists, prazosin, WB4101, 5-methyl-urapidil, HV723, BMY7378 and the irreversible a 1B selective compound chloroethylclonidine (CEC) were examined versus the potency and maximum response of the c.r.a.s to noradrenaline. 3 The high potency of A-61603 relative to PE has been shown to dierentiate both functional and binding site a 1A -or a 1B -adrenoceptors from a 1D -adrenoceptors: A-61603 was 944 times more potent than phenylephrine (at EC 50 ) suggesting the presence of a functional a 1A or a 1B as opposed to an a 1D -subtype. 4 Exposure to chloroethylclonidine (CEC; 100 mM) decreased the maximum response to noradrenaline but did not signi®cantly change noradrenaline sensitivity indicating that a substantial part of noradrenaline-induced vasoconstriction in rabbit cutaneous arteries is CEC-insensitive. 5 The potencies of prazosin (pA 2 =9.14) and WB4101 (pA 2 =9.30) indicate the involvement of prazosin-sensitive functional a 1 -adrenoceptors. The slopes of corresponding Schild plots for prazosin and WB4101 did not include negative unity which implies the possible involvement of more than one functional a 1 -adrenoceptor subtype in noradrenaline-induced vasoconstriction in rabbit cutaneous resistance arteries. In contrast to this, in the case of 5-methyl-urapidil and HV723, the Schild plot slope parameters were not signi®cantly dierent from negative unity over the range of concentrations used; the low pA 2 value for 5-methylurapidil (7.27) suggests the non-involvement of an a 1A -or an a 1D -adrenoceptor; the low pA 2 value for HV723 (8.47) was similar to that against responses postulated as a 1L . 6 We conclude that rabbit cutaneous resistance arteries express a prazosin-sensitive functional a 1 -adrenoceptor resembling the a 1B and another low anity site for prazosin which on the basis of the functional antagonism produced by HV723 most closely resembles the a 1L -adrenoceptor; the low pA2 value for HV723 (8.47) is similar to that against responses postulated as a 1L .

2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults

“…Whereas cardiac adrenergic drive initially supports the performance of the failing heart, long-term activation of the sympathetic nervous system exerts deleterious effects that can be antagonized by the use of beta blockers. Sympathetic activation can increase ventricular volumes and pressure by causing peripheral vasoconstriction 336 and by impairing sodium excretion by the kidneys. 337 Norepinephrine can also induce cardiac hypertrophy but restrict the ability of the coronary arteries to supply blood to the thickened ventricular wall, leading to myocardial ischemia.…”

ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult

“…Finally, by stimulating growth and oxidative stress in terminally differentiated cells, norepinephrine can trigger programmed cell death or apoptosis (254). These deleterious effects are mediated through actions on alpha-1-, beta-1-, and beta-2-adrenergic receptors (138,215,(247)(248)(249)(250)(251)(252)(253)(254).…”

“…Whereas cardiac adrenergic drive initially supports the performance of the failing heart, long-term activation of the sympathetic nervous system exerts deleterious effects that can be antagonized by the use of beta-blockers. Sympathetic activation can increase ventricular volumes and pressure by causing peripheral vasoconstriction (247) and by impairing sodium excretion by the kidneys (248). Norepinephrine can also induce cardiac hypertrophy but restrict the ability of the coronary arteries to supply blood to the thickened ventricular wall, leading to myocardial ischemia (215,249,250).…”

The Adrenergic System in Vascular Smooth Muscle

“…Contractions are reported to be mediated at least partly by α 1Β -adrenoceptors in a number of tissues: rabbit corpus cavernosum [104] and rabbit cutaneous resistance arteries [123]. In studies of blood vessels from adrenoceptor KO mice, it was found that the major subtypes involved in contractions are α 1A and α 1D , but that the α 1Β -adrenoceptor plays a minor but clearly defined role in contractions in aorta, carotid, mesenteric and tail arteries [28].…”

“…WT wild type. (Taken from Bexis and Docherty, unpublished) guinea pig aorta, [101], rabbit cutaneous resistance arteries [123] and rat small mesenteric artery [137] were reported to contain α 1L -adrenoceptors.…”