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Molecular Interventions 5:340-342, (2005)
© American Society for Pharmacology and Experimental Therapeutics
10.1124/mi.5.6.6
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Increased Expression and Function of Vascular {alpha}1D-Adrenoceptors May Mediate The Prohypertensive Effects Of Angiotensin II

Rafael Villalobos-Molina and Maximiliano Ibarra

Unidad de Biomedicina, Facultad de Estudios Superiores-Iztacala, Universidad Nacional Autónoma de Mexico, Tlalnepantla, México.

SUMMARY

The peptide Angiotensin II (Ang II), part of the renin-angiotensin system (RAS), participates in the control of systemic arterial pressure. Ang II participates in increasing smooth muscle tone, and its positive effects on smooth muscle cell DNA synthesis are inhibited by treatment with prazosin, an {alpha}1-adrenoceptor agonist. Ang II also induces the expression of {alpha}1-adrenoceptor, especially the {alpha}1D subtype. Other findings suggest that the molecular signals activated by Ang II and by {alpha}1D-adrenoceptor might interweave, thus leading to the augmentation of smooth muscle tone and hypertension.

Angiotensin II (Ang II) is synthesized by the renin-angiotensin system (RAS) and participates in regulating systemic arterial pressure. Ang II acts as a potent vasoconstrictor to activate Ang II type 1 (AT1) receptors on vascular smooth muscle and affects cardiac and vascular remodeling, cardiac contractility, and pulse rate through increased sympathetic nervous system tone (by promoting presynaptic facilitatory modulation of noradrenaline release) (1). Physiological parameters regulated by RAS, such as plasma renin activity, plasma angiotensinogen concentration (2, 3), and kidney renin release (3, 4) are known to be elevated in young spontaneously hypertensive rats (SHR), suggesting that they might contribute to the pathogenesis of genetic hypertension.

Is there crosstalk between RAS and adrenergic peripheral pathways in the genesis of hypertension? Schiffrin and coworkers (5) observed an increased density of {alpha}1-adrenoceptors and Ang II receptors in the vasculature of four-week-old SHR before the development of hypertension. The stimulatory effect of Ang II on smooth muscle cell DNA synthesis in vivo was markedly decreased by cotreatment with the {alpha}1-adrenoceptor antagonist prazosin (6). Another study demonstrated that high doses of captopril, an Angiotensin Converting Enzyme inhibitor, inhibited the abnormal hypersensitivity of resistance vessels to phenylephrine, an {alpha}1-adrenoceptor agonist (3, 7). Moreover, RAS blockade by pharmacological means with ACE inhibitors or AT1 receptor antagonists in young SHR may attenuate or even prevent the development of hypertension (8–12).

On the other hand, Hoffman and coworkers demonstrated that Ang II induces {alpha}1-adrenoceptor expression, mainly {alpha}1D- subtype, in isolated rat aorta smooth muscle cells (13), and Faber and colleagues elegantly showed that {alpha}1D-adrenoceptor activation increased protein synthesis in arterial smooth muscle (14). These data suggest that Ang II may facilitate aorta smooth muscle hypersensitivity and hypertrophy through {alpha}1D-adrenoceptors expression.

Several arteries in SHR functionally express {alpha}1D-adrenoceptors, and once stimulated, these receptors mediate contraction (15–17). In addition, increasing evidence has revealed that vascular {alpha}1D-adrenoceptors are functionally important for the genesis and/or maintenance of hypertension: the receptors appear to be present prior to the establishment of hypertension and their effect increases with aging in SHR. Also, an augmented population of constitutively active {alpha}1D-adrenoceptors might be responsible for the pathologic consequences of sympathoadrenal-mediated increased smooth muscle tone in SHR (8, 15–20).

Tsujimoto and coworkers showed that genetic disruption of the {alpha}1D-adrenoceptor gene generates hypotensive mice, suggesting that these receptors are important for blood pressure control (21). Similarly, D’Ocon’s group reported that a constitutively active {alpha}1D-adrenoceptor population (putatively involved in the pathology of the SHR) functionally disappeared in arteries where that subtype predominates for contraction, after a long term and high dose of captopril therapy (8), further implicating {alpha}1D-adrenoceptor in pathological hypertension. We have found that prehypertensive SHR have augmented basal amounts of {alpha}1D-adrenoceptor mRNA and protein as compared to those amounts observed in normotensive Wistar Kyoto rats. These data suggest that the Ang II and {alpha}1D-adrenoceptor systems might impinge upon each other in the onset of hypertension. Thus, we hypothesize that Ang II facilitates hypertension through stimulation of vascular {alpha}1D-adrenoceptor expression and function (Figure 1Go) and that this specific adrenoreceptor may mediate blood vessel hypertrophy and hypersensitivity.



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  		Figure 1. Suggested signal transduction mechanism involving Ang II-AT1 receptor and its influence on {alpha}1D-adrenoceptor expression and function. In the orange box are conditions where Ang II levels are elevated, which favor increased {alpha}1D-adrenoceptor expression and function. PLC, phospholipase C; PKC, protein kinase C; ß-arr, ß-arrestin; GRK, G protein receptor coupled kinase; Src, a tyrosine kinase.

 
The use of aryl hydrocarbon receptor (Ahr) knockout mice—which exhibit hypertension and cardiac hypertrophy, and have higher than normal circulating concentrations of Ang II and endothelin 1(22)—should support our hypothesis. Ahr-deficient mice express {alpha}1D-adrenoceptors for aortic smooth muscle contraction. Aorta from Ahr-deficient mice will likely respond with a greater maximal contraction to {alpha}1-agonists, owing to elevated Ang II—mediated increased expression of {alpha}1D-adrenoceptors as compared to the contractile effects and amounts of {alpha}1D-adrenoceptors found in wild-type mice aortas.


Rafael Villalobos-Molina, PhD, is a biochemist interested in vascular {alpha}1-adrenoceptor pharmacology and their role in the genesis/maintenance of hypertension. He is currently Chairman of the Biomedicine Unit at Facultad de Estudios Superiores-Iztacala, National Autonomous University of Mexico, in Tlalnepantla, Mexico. Please send correspondence to RV-M. E-mail villalobos{at}campus.iztacala.unam.mx; fax (52 55) 5623-1138.


Maximiliano Ibarra, PhD, is a pharmacologist interested in vascular {alpha}1-adrenoceptors and their interaction with endothelial function, such as nitric oxide synthases and cyclooxygenases during aging and hypertension. He is an Associate Professor in the Biomedicine Unit at Facultad de Estudios Superiores-Iztacala, National Autonomous University of Mexico, in Tlalnepantla, Mexico. E-mail maxibarrab{at}correo.unam.mx; fax. (52 55) 5623-1138

ACKNOWLEDGMENTS

Authors thank PAPIIT IN230205 (RV-M), IN210702 (MI) and Fundación Miguel Alemán (RV-M) for support grants.

References

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  2. Ruiz, P., Basso, N., Cannata, M.A., and Taquini, A.C. The renin-angiotensin system in different stages of spontaneously hypertension in the rat (SHR). Clin. Exp. Hypertension: Theory and Practice A 12, 63–81 (1990).
  3. Zicha, J. and Kune, J. Ontogenetic aspects of hypertension development: Analysis in the rat. Physiol. Rev. 79, 1227–1282 (1999).[Abstract/Free Full Text]
  4. Henrich, W.L. and Levi, M. Ontogeny of renal renin release in spontaneously hypertensive rat and Wistar-Kyoto rat. Am. J. Physiol. 260, F530–F535 (1991).[Medline]
  5. Schiffrin, E.L., Thome, F.S., and Genest, J. Vascular angiotensin II receptors in SHR. Hypertension 6, 682–688 (1984).[Abstract/Free Full Text]
  6. Van Kleef E.M., Smits, J.F.M., De Mey, J.G.R., Cleutjens, J.P.M., Lombardi, D.M., Schwartz, S.M., and Daemen, M.J.A.P. {alpha}1-adrenoceptor blockade reduces the angiotensin II-induced vascular smooth muscle cell DNA synthesis in the rat thoracic aorta and carotid artery. Circ. Res. 70, 1122–1127 (1992).[Abstract/Free Full Text]
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  13. Hu, Z.W., Shi, X.Y., Okazaki, M., and Hoffman, B.B. Angiotensin II induces transcription and expression of alpha-1 adrenergic receptors in vascular smooth muscle cells. Am. J. Physiol. 268, H1006–H1014 (1995). First article to show Ang II-induced {alpha}1-adrenoceptor expression, both mRNA and protein, in isolated rat aorta smooth muscle cells.[Medline]
  14. Xin, X., Yang, N., Eckhart, A.D., and Faber, J.E. {alpha}1D-Adrenergic receptors and mitogen-activated protein kinase mediate increased protein synthesis by arterial smooth muscle. Mol. Pharmacol. 51, 764–775 (1997). The authors report that a1D-adrenoceptor activation is involved in vascular smooth-muscle-cell hypertrophy (a phenomenon observed in hypertension).[Abstract/Free Full Text]
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  17. Ibarra, M., López-Guerrero, J.J., and Villalobos-Molina, R. Further evidence of the predominance of {alpha}1D-adrenoceptors in arteries of normotensive and spontaneously hypertensive rats. Pharmacol. Rev. Comm. 10, 135–142 (1998). The authors report noradrenaline-induced hypersensitivity in those SHR arteries where {alpha}1D-adrenoceptors predominate for contraction (carotid and aorta), compared to WKY. Hypersensitivity is not observed with {alpha}1A- or {alpha}1A/D-adrenoceptor agonists.
  18. Villalobos-Molina, R., López-Guerrero, J.J., and Ibarra, M. Functional evidence of {alpha}1D-adrenoceptors in the vasculature of young and adult spontaneously hypertensive rats. Br. J. Pharmacol. 126, 1534–1536 (1999). This article reports the presence of {alpha}1D-adrenoceptors in pre-hypertensive SHR, not observed in young normotensive WKY, and suggests their role in the genesis and/or maintenance of high blood pressure.
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  20. García-Sáinz, J.A. and Villalobos-Molina, R. The elusive {alpha}1D-adrenergic receptor: Molecular and cellular characteristics and integrative roles. Eur. J. Pharmacol. 500, 113–120 (2004).[CrossRef][Medline]
  21. Tanoue, A., Nasa, Y., Koshimizu, T., Shinoura, H., Oshikawa, S., Kawai, T., Sunada, S., Takeo, S. and Tsujimoto, G. The {alpha}1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction. J. Clin. Invest. 109, 765–775 (2002). The authors generated mice lacking (knockout) the {alpha}1D-adrenoceptor gene. These knockout mice are hypotensive and their {alpha}1D-adrenoceptor-mediated responses are diminished.[CrossRef][Medline]
  22. Lund, A.K., Goens, M.B., Kanagy, N.L., and Walker, M.K. Cardiac hypertrophy in aryl hydrocarbon receptor null mice is correlated with elevated angiotensin II, endothelin-1 and mean arterial blood pressure. Toxicol. Applied Pharmacol. 193, 177–187 (2003). The authors report that knockout of the Ahr gene is associated with hypertension: increased angiotensin II and endothelin-1, and cardiac hypertrophy are observed. Captopril treatment for three months decreased: 1) plasma concentrations of Ang II, 2) mean arterial blood pressure (MAP), and 3) heart hypertrophy.[CrossRef][Medline]



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