© 2001 American Heart Association, Inc.
Molecular Medicine |
Vasoactive Potential of the B1 Bradykinin Receptor in Normotension and Hypertension
From the Hypertension and Atherosclerosis Section of the Department of Medicine, Boston University School of Medicine, Boston, Mass.
Correspondence to Haralambos Gavras, MD, Chief, Hypertension and Atherosclerosis Section, Boston University School of Medicine, 715 Albany St, Boston, MA 02118. E-mail hgavras{at}bu.edu
Abstract—The B1 type receptor of bradykinin (Bk B1R) is believed to be physiologically inert but highly inducible by inflammatory mediators and tissue damage. To explore the potential participation of the Bk B1R in blood pressure (BP) regulation, we studied mice with deleted Bk B2R gene with induced experimental hypertension, either salt-dependent (subtotal nephrectomy with 0.5% NaCl as drinking water) or renin/angiotensin-dependent (renovascular 2-kidney–1-clip). Compared with the wild-type controls, the B2R gene knockout mice had a higher baseline BP (109.7±1.1 versus 101.1±1.3 mm Hg, P=0.002), developed salt-induced hypertension faster (in 19.3±2.3 versus 27.7±2.4 days, P=0.024), and had a more severe end point BP (148±3.7 versus 133±3.1 mm Hg, P<0.05). On the contrary, renovascular hypertension developed to the same extent (149.7±4.3 versus 148±3.6 mm Hg) and in the same time frame (14±2.2 versus 14±2.1 days). A bolus infusion of a selective B1R antagonist at baseline produced a significant hypertensive response (by 11.4±2 mm Hg) in the knockout mice only. Injection of graded doses of a selective B1R agonist produced a dose-dependent hypotensive response in the knockout mice only. Assessment of tissue expression of B1R and B2R genes by reverse transcription–polymerase chain reaction techniques revealed significantly higher B1R mRNA levels in the B2R knockout mice at all times (normotensive baseline and hypertensive end points). At the hypertensive end points, there was always an increase in B1R gene expression over the baseline values. This increase was significant in cardiac and renal tissues in all hypertensive wild-type mice but only in the clipped kidney of the renovascular knockout mice. The B2R gene expression in the wild-type mice remained unaffected by experimental manipulations. These results confirm the known vasodilatory and natriuretic function of the Bk B2R; they also indicate that in its absence, the B1R can become upregulated and assume some of the hemodynamic properties of the B2R. Furthermore, they indicate that experimental manipulations to produce hypertension also induce upregulation of the B1R, but not the B2R, in cardiac and renal tissues.
Key Words: bradykinin receptors • gene knockout mice • blood pressure • tissue gene expression
This article has been cited by other articles:
 |
|
 |
|
  V. Griol-Charhbili, L. Sabbah, J. Colucci, M.-P. Vincent, V. Baudrie, D. Laude, J.-L. Elghozi, P. Bruneval, N. Picard, P. Meneton, et al. Tissue kallikrein deficiency and renovascular hypertension in the mouse Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1385 - R1391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xu, O. A. Carretero, E. G. Shesely, N.-E. Rhaleb, J. J. Yang, M. Bader, and X.-P. Yang The kinin B1 receptor contributes to the cardioprotective effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in mice Exp Physiol, March 1, 2009; 94(3): 322 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Mori, R. C. Araujo, F. C.G. Reis, D. G. Sgai, R. G. Fonseca, C. C. Barros, V. F. Merino, M. Passadore, A. M. Barbosa, B. Ferrari, et al. Kinin B1 Receptor Deficiency Leads to Leptin Hypersensitivity and Resistance to Obesity Diabetes, June 1, 2008; 57(6): 1491 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Buleon, J. Allard, A. Jaafar, F. Praddaude, Z. Dickson, M.-T. Ranera, C. Pecher, J.-P. Girolami, and I. Tack Pharmacological blockade of B2-kinin receptor reduces renal protective effect of angiotensin-converting enzyme inhibition in db/db mice model Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1249 - F1256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Duka, E. Kintsurashvili, I. Duka, D. Ona, T. A. Hopkins, M. Bader, I. Gavras, and H. Gavras Angiotensin-Converting Enzyme Inhibition After Experimental Myocardial Infarct: Role of the Kinin B1 and B2 Receptors Hypertension, May 1, 2008; 51(5): 1352 - 1357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L. M. Quintao, G. F. Passos, R. Medeiros, A. F. Paszcuk, F. L. Motta, J. B. Pesquero, M. M. Campos, and J. B. Calixto Neuropathic Pain-Like Behavior after Brachial Plexus Avulsion in Mice: The Relevance of Kinin B1 and B2 Receptors J. Neurosci., March 12, 2008; 28(11): 2856 - 2863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Qian, P. Harding, Y. Liu, E. Shesely, X.-P. Yang, and M. C. LaPointe Reduced Cardiac Remodeling and Function in Cardiac-Specific EP4 Receptor Knockout Mice With Myocardial Infarction Hypertension, February 1, 2008; 51(2): 560 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Isbell, S. Voros, Z. Yang, J. M. DiMaria, S. S. Berr, B. A. French, F. H. Epstein, S. P. Bishop, H. Wang, R. J. Roy, et al. Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3372 - H3378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cayla, M. Todiras, R. Iliescu, V. V. Saul, V. Gross, B. Pilz, G. Chai, V. F. Merino, J. B. Pesquero, O. C. Baltatu, et al. Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension FASEB J, June 1, 2007; 21(8): 1689 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kakoki, R. W. McGarrah, H.-S. Kim, and O. Smithies Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury PNAS, May 1, 2007; 104(18): 7576 - 7581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Duka, I. Duka, G. Gao, S. Shenouda, I. Gavras, and H. Gavras Role of bradykinin B1 and B2 receptors in normal blood pressure regulation Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E268 - E274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Shariat-Madar, F. Mahdi, M. Warnock, J. W. Homeister, S. Srikanth, Y. Krijanovski, L. J. Murphey, A. A. Jaffa, and A. H. Schmaier Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin Blood, July 1, 2006; 108(1): 192 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Picard, M. Van Abel, C. Campone, M. Seiler, M. Bloch-Faure, J. G.J. Hoenderop, J. Loffing, P. Meneton, R. J.M. Bindels, M. Paillard, et al. Tissue Kallikrein-Deficient Mice Display a Defect in Renal Tubular Calcium Absorption J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3602 - 3610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Ignjacev-Lazich, E. Kintsurashvili, C. Johns, O. Vitseva, A. Duka, S. Shenouda, I. Gavras, and H. Gavras Angiotensin-converting enzyme regulates bradykinin receptor gene expression Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1814 - H1820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kintsurashvili, A. Duka, I. Ignjacev, G. Pattakos, I. Gavras, and H. Gavras Age-related changes of bradykinin B1 and B2 receptors in rat heart Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H202 - H205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L.M. Cruden, G. H. Tse, K. A.A. Fox, C. A. Ludlam, I. Megson, and D. E. Newby B1 Kinin Receptor Does Not Contribute to Vascular Tone or Tissue Plasminogen Activator Release in the Peripheral Circulation of Patients With Heart Failure Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 772 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, O. A. Carretero, Y. Sun, E. G. Shesely, N.-E. Rhaleb, Y.-H. Liu, T.-D. Liao, J. J. Yang, M. Bader, and X.-P. Yang Role of the B1 Kinin Receptor in the Regulation of Cardiac Function and Remodeling After Myocardial Infarction Hypertension, April 1, 2005; 45(4): 747 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ignjatovic, S. Stanisavljevic, V. Brovkovych, R. A. Skidgel, and E. G. Erdos Kinin B1 Receptors Stimulate Nitric Oxide Production in Endothelial Cells: Signaling Pathways Activated by Angiotensin I-Converting Enzyme Inhibitors and Peptide Ligands Mol. Pharmacol., November 1, 2004; 66(5): 1310 - 1316. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kakoki, N. Takahashi, J. C. Jennette, and O. Smithies Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor PNAS, September 7, 2004; 101(36): 13302 - 13305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lazartigues, A. J. Lawrence, F. S. Lamb, and R. L. Davisson Renovascular Hypertension in Mice With Brain-Selective Overexpression of AT1a Receptors Is Buffered by Increased Nitric Oxide Production in the Periphery Circ. Res., September 3, 2004; 95(5): 523 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Liu, X.-P. Yang, E. G. Shesely, S. S. Sankey, and O. A. Carretero Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1473 - 1480. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Duka, A. Duka, E. Kintsurashvili, C. Johns, I. Gavras, and H. Gavras Mechanisms Mediating the Vasoactive Effects of the B1 Receptors of Bradykinin Hypertension, November 1, 2003; 42(5): 1021 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Fortin, F. Gobeil Jr, A. Adam, D. Regoli, and F. Marceau Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B1 receptor? Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H277 - H282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ongali, H. d. S. Buck, F. Cloutier, F. Legault, D. Regoli, C. Lambert, G. Thibault, and R. Couture Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Chronic effects of angiotensin-converting enzyme inhibition on kinin receptor binding sites in the rat spinal cord Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1949 - H1958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Xiao, S. Fuchs, J. M. Cole, K. M. Disher, R. L. Sutliff, and K. E. Bernstein Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting-Enzyme Systems: Role of bradykinin in angiotensin-converting enzyme knockout mice Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1969 - H1977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Maestri, A. F. Milia, M. B. Salis, G. Graiani, C. Lagrasta, M. Monica, D. Corradi, C. Emanueli, and P. Madeddu Cardiac Hypertrophy and Microvascular Deficit in Kinin B2 Receptor Knockout Mice Hypertension, May 1, 2003; 41(5): 1151 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Trabold, S. Pons, A. A. Hagege, M. Bloch-Faure, F. Alhenc-Gelas, J.-F. Giudicelli, C. Richer-Giudicelli, and P. Meneton Cardiovascular Phenotypes of Kinin B2 Receptor- and Tissue Kallikrein-Deficient Mice Hypertension, July 1, 2002; 40(1): 90 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ignjatovic, F. Tan, V. Brovkovych, R. A. Skidgel, and E. G. Erdos Novel Mode of Action of Angiotensin I Converting Enzyme Inhibitors. DIRECT ACTIVATION OF BRADYKININ B1 RECEPTOR J. Biol. Chem., May 3, 2002; 277(19): 16847 - 16852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. Marin-Castano, J. P. Schanstra, E. Neau, F. Praddaude, C. Pecher, J.-L. Ader, J.-P. Girolami, and J.-L. Bascands Induction of Functional Bradykinin B1-Receptors in Normotensive Rats and Mice Under Chronic Angiotensin-Converting Enzyme Inhibitor Treatment Circulation, February 5, 2002; 105(5): 627 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Duka, S. Shenouda, C. Johns, E. Kintsurashvili, I. Gavras, and H. Gavras Role of the B2 Receptor of Bradykinin in Insulin Sensitivity Hypertension, December 1, 2001; 38(6): 1355 - 1360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kintsurashvili, I. Duka, I. Gavras, C. Johns, D. Farmakiotis, and H. Gavras Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1778 - H1783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Majima, M. Katori, N.-E. Rhaleb, X.-P. Yang, M. Nanba, E. G. Shesely, O. A. Carretero, P. Madeddu, N.-E. Rhaleb, X.-P. Yang, et al. Effect of Chronic Blockade of the Kallikrein-Kinin System on the Development of Hypertension in Rats * Response * Role of Kinins in Blood Pressure Regulation: Reality or Fiction * Response Hypertension, October 1, 2001; 38 (4): e21 - e23. [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
|
|