Role of cental α2B-adrenergic receptors in blood pressure control and hypertension (2003)

There is a body of evidence supporting that, among α-adrenergic receptors, the α2A subtype is involved in the central regulation of the vasomotor tone. A large number of pharmacological studies have been performed on normotensive and hypertensive animals, as well as on wild-type and genetically engineered animals. All of these studies have provided evidence that drugs acting exclusively as α2A-adrenergic receptor agonists, such as α-methylnoradrenaline and dexmedetomidine, inhibit the sympathetic drive to the cardiovascular end organs and therefore reduce blood pressure. It is now clear that these drugs activate α2A-adrenergic receptors of the nucleus tractus solitarii in particular. Recently, MacMillan et al. [1] demonstrated that α2A-adrenergic agonists do not modify blood pressure of normotensive mice with non-functional α2A-adrenergic receptors while they do reduce blood pressure in α2B-adrenergic receptor knockout animals. Recent studies have focused on the role of the different subtypes of central α2-adrenergic receptors in a particular model of hypertension, namely salt-induced hypertension [2,3]. These authors have accumulated evidence supporting that, in animal models of nephrogenic salt-induced hypertension, α2B-adrenergic receptors are responsible for the central hypertensive sympatho-excitatory response to salt. Based on the results of previous studies performed in genetically engineered mice, it was suggested that the integrity of α2B-adrenergic receptors is required for the development and maintenance of salt-induced hypertension. In their recent work [3], the authors injected intraventricularly antisense oligodeoxynucleotides, targeting a selected sequence of the α2B-adrenergic receptor mRNA in subtotally nephrectomized and salt-loaded rats. This treatment prevented the daytime rise in blood pressure and caused bradycardia. In this issue of the journal, Kintsurashvili et al. [4] report on the prolonged inhibition of central α2B-adrenergic receptor gene expression, and examined the consequences of this genomic manipulation on high blood pressure in subtotally nephrectomized salt-loaded rats. The authors designed a cytomegalovirus promoter-driven antisense against α2B-adrenergic receptor mRNA and delivered it intraventricularly via a plasmid vector. They showed that the antisense plasmid not only reduces systolic blood pressure compared to baseline pressure, but also maintains blood pressure lower than that observed in animals treated with sense plasmid over an 8-day period of salt loading. The authors actually observed an antihypertensive effect of antisense DNA designed plasma vector which was much longer lasting compared to the one obtained in their previous study with antisense DNA and, indeed, this is the major contribution of their elegant study. A prolonged inhibition of the central α2B- adrenergic receptor expression was also found to parallel the antihypertensive effect of α2B-adrenergic receptor antisense DNA, thus confirming that these receptors are definitely involved in the development of salt-induced hypertension. In the study by Kintsurasvili et al. [4], as expected, Western blot analysis shows that the antisense plasmid DNA significantly reduced α2B-adrenergic receptor expression in NG108-15 cells compared to the expression of this protein in cells treated with the gene PORTER. By contrast, overexpression of the gene generated by the transfection of the sense plasmid DNA increased the α2B-adrenergic receptor protein level. In other words, in-vitro experiments were performed very carefully with three different treatments (i.e. gene PORTER, sense and antisense plasmid oligonucleotides). In experiments performed in vivo, the authors compared the blood pressure effects of the antisense plasmid DNA with those of the sense plasmid DNA. They observed a significant antihypertensive effect of the antisense DNA. Nevertheless, it would have been more interesting if this effect was confirmed by comparing antisense DNA-treated animals with control animals treated with scrambled oligonucleotides. In a previous study dealing with the same subject, the authors convincingly used scrambled oligonucleotide-treated animals as controls [3]. The possibility cannot be ruled out that, similar to NG 108-15 cells, the sense DNA might generate an overexpression of α2B-adrenergic receptor proteins in vivo, and this overexpression might increase resting blood pressure. In this case, the difference in blood pressures between antisense and sense DNA-treated animals may be somewhat overestimated. Finally, these authors suggest for the first time that central α2B-adrenergic receptors are involved in the maintenance of hypertension, at least in a particular model of nephrogenic salt-induced hypertension. The present study shows that the longer the antisense DNA for central α2B-adrenergic receptors inhibits gene expression, the longer are the antihypertensive effects of the antisense DNA. Up to now, among α-adrenergic receptors, only α2A-adrenergic receptors have been shown to play a key role in the central regulation of blood pressure. Kintsurasvili et al. [4] have now drawn our attention to the central α2B-adrenergic receptors.