Sympathoinhibitory Function of the α _2A -Adrenergic Receptor Subtype

Abstract

Abstract-Presynaptic ␣ 2 -adrenergic receptors (␣ 2 -AR) are distributed throughout the central nervous system and are highly concentrated in the brain stem, where they contribute to neural baroreflex control of blood pressure (BP). To explore the role of the ␣ 2A -AR subtype in this function, we compared BP and plasma norepinephrine and epinephrine levels in genetically engineered mice with deleted ␣ 2A -AR gene to their wild-type controls. At baseline, the ␣ 2A -AR gene knockouts (nϭ11) versus controls (nϭ10) had higher systolic BP (123Ϯ2.5 versus 115Ϯ2.5 mm Hg, PϽ0.05), heart rate (730Ϯ15 versus 600Ϯ18 b/min, PϽ0.001), and norepinephrine (1.005Ϯ0.078 versus 0.587Ϯ0.095 ng/mL, PϽ0.01), respectively. When submitted to subtotal nephrectomy and given 1% saline as drinking water, both ␣ 2A -AR gene knockouts (nϭ14) and controls (nϭ14) became hypertensive, but the former required 15.6Ϯ2.5 days versus 29.3Ϯ1.4 days for the controls (PϽ0.001). End-point systolic BP was similar for both at 155Ϯ2.1 versus 152Ϯ5.2 mm Hg, but norepinephrine and epinephrine levels were twice as high in the knockouts at 1.386Ϯ0.283 and 0.577Ϯ0.143 versus 0.712Ϯ0.110 and 0.255Ϯ0.032 ng/mL, respectively, PϽ0.05 for both. We conclude that the ␣ 2A -AR subtype exerts a sympathoinhibitory effect, and its loss leads to a hypertensive, hyperadrenergic state.(Hypertension. 1999;34:403-407.)Key Words: adrenergic receptors Ⅲ mice, knockout Ⅲ hypertension, sodium-dependent Ⅲ hyperadrenergic state T he sympathetic nervous system (SNS) is one of the major pressor systems involved in the regulation of blood pressure (BP). Aberrant function of various neuroendocrine components of the SNS contributes to abnormal BP in response to environmental stimuli, such as excessive sodium intake. Indeed, a large body of literature indicates that 1 of the mechanisms by which salt-loading raises BP is via activation of the central SNS, which leads to increased sympathetic outflow. 1,2 Experimental studies in animals with pharmacological probes in vivo 3-5 and radioligand techniques in vitro 6,7 have suggested that salt-induced hypertension is associated with alterations in the functional characteristics of the ␣ 2 -adrenergic receptors (␣ 2 -AR) in the central nervous system (CNS). None of these methods, however, can differentiate among the ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , or ␣ 2 c) involved in this process.Recently, genetically engineered mice that are deficient in each one of the ␣ 2 -AR subtypes became available. 8,9 In our first series of experiments with these mice, we used animals deficient for the ␣ 2B -AR gene (ϩ/Ϫ) and ␣ 2C -AR gene knockouts (Ϫ/Ϫ) compared with their wild-type counterparts (␣ 2B ϩ/ϩ and ␣ 2C ϩ/ϩ, respectively) to study the role of each subtype in determining salt-sensitivity. We found that the ability to develop hypertension in response to salt-loading requires a full complement of the ␣ 2B -AR subtype gene. Indeed, the ␣ 2B ϩ/Ϫ mice failed to raise their BP after subtotal nephrectomy and dietary salt-loading for 5 weeks, whereas their wild-ty...

Modulation of the baroreceptor reflex by α2A‐adrenoceptors: a study in α2A knockout mice

“…Animals were then placed in individual cages and allowed at least 4 h to recover from surgery. Preliminary experiments showed that extending the postsurgery period to 24 h did not change the cardiovascular parameters (unpublished results; compare also baseline values for mean arterial pressure and heart rate in the present study with Altman et al (1999) and Makaritsis et al (1999)). …”

“…injection per se had no effect on cardiovascular parameters, showing that at least this manipulation was not a stressful stimulus. Second, loss of a 2A -adrenoceptors leads to higher resting sympathetic tone, as shown by the increased plasma noradrenaline levels and presumably also the higher baseline heart rates ( Table 2 of the present study Makaritsis et al, 1999). It seems unlikely, however, that these differences in baseline can explain the attenuated heart rate responses in a 2A -KO mice.…”

Lys418Asn Polymorphism of the α2-Adrenoceptor Gene Relates to Serum Uric Acid Levels But Not to Insulin Sensitivity

“…Several investigators showed that the ␣2A-adrenoceptor-mediated inhibition of sympathetic tone and its loss leads to a hyperadrenergic state. [25][26][27] Thus, the ␣2-adrenoceptor is required for inhibition of NE release. In the present study, the findings that subjects carrying the Asn418 allele (especially homozygous for the Asn418 allele) had higher plasma NE as well as UA compared with the subjects without the Asn418 allele are in accordance with the investigations that Asn418 of the Lys418Asn is associated with an impaired sympathoinhibitory effect on the ␣2A-presynaptic adrenoceptor gene.…”

Dual Alpha2C/5HT1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility

“…Accordingly, we proposed that selective α2B/C-AR agonists may represent a novel group of gastroprotective agents, which are devoid of several side effects mediated by the α2A-AR subtype, such as hypotension, bradycardia or sedation [17]. However, although the site of gastroprotective action is likely to be central, it should be considered that α2B-ARs are located also postsynaptically on vessels [18,19] and appear to be involved in the vasoconstrictor response to α2-AR agonists [20] and in salt-induced hypertension [21]. Consequently, selective α2C-AR stimulants are likely to be even more favourable and safer potential therapeutic agents against gastric mucosal injury than the mixed α2B/C-AR agonists, since they are devoid of adverse effects due to activation of both α2A-and α2B-ARs.…”