(Hypertension. 2000;35:367.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Decreased Endothelium-Dependent Vascular Relaxation During Reduction of Uterine Perfusion Pressure in Pregnant Rat
From the Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson.
Correspondence to Raouf A. Khalil, MD, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216. E-mail rkhalil{at}physiology.umsmed.edu
Abstract—Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10-5 mol/L) caused an increase in active stress to 4.5±0.4x103 N/m2 in normal pregnant rats and a larger increase to 9.4±0.7x103 N/m2 in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4±0.6x103 N/m2) but not RUPP (9.95±0.95x103 N/m2) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED50 0.1x10-6 mol/L) than in RUPP (ED50 1.2x10-6 mol/L) rats. Pretreatment of endothelium-intact strips with NG-nitro-L-arginine methyl ester(100 µmol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.2±0.5x103 N/m2) but not RUPP (9.5±0.85x103 N/m2) rats. Pretreatment of endothelium-intact strips with methylene blue (10 µmol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9±0.65x103 N/m2) but not RUPP (9.3±0.7x103 N/m2) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension.
Key Words: arteries • blood pressure • endothelium • nitric oxide • muscle, smooth, vascular
This article has been cited by other articles:
 |
|
 |
|
  S. K. Walsh, F. A. English, E. J. Johns, and L. C. Kenny Plasma-Mediated Vascular Dysfunction in the Reduced Uterine Perfusion Pressure Model of Preeclampsia: A Microvascular Characterization Hypertension, August 1, 2009; 54(2): 345 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Stennett, X. Qiao, A. E. Falone, V. V. Koledova, and R. A. Khalil Increased vascular angiotensin type 2 receptor expression and NOS-mediated mechanisms of vascular relaxation in pregnant rats Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H745 - H755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chen and R. A. Khalil Differential [Ca2+]i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1962 - R1972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. LaMarca, J. Gilbert, and J. P. Granger Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia Hypertension, April 1, 2008; 51(4): 982 - 988. [Full Text] [PDF]
|
|
|
|
|
|
J. S. Gilbert, M. J. Ryan, B. B. LaMarca, M. Sedeek, S. R. Murphy, and J. P. Granger Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H541 - H550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Verlohren, M. Niehoff, L. Hering, N. Geusens, F. Herse, A. N. Tintu, A. Plagemann, F. LeNoble, R. Pijnenborg, D. N. Muller, et al. Uterine Vascular Function in a Transgenic Preeclampsia Rat Model Hypertension, February 1, 2008; 51(2): 547 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Gilbert, S. A. Babcock, and J. P. Granger Hypertension Produced by Reduced Uterine Perfusion in Pregnant Rats Is Associated With Increased Soluble Fms-Like Tyrosine Kinase-1 Expression Hypertension, December 1, 2007; 50(6): 1142 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Sholook, J. S. Gilbert, M. H. Sedeek, M. Huang, R. L. Hester, and J. P. Granger Systemic hemodynamic and regional blood flow changes in response to chronic reductions in uterine perfusion pressure in pregnant rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2080 - H2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Granger Response to Modeling Preeclampsia: The True Model for the Uniquely Human Disease Preeclampsia Is the Human Female Not the Pregnant Rat Hypertension, April 1, 2007; 49(4): e22 - e22. [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Anderson, F. Lopez, H.-Y. Zhang, Y. Shirasawa, K. Pavlish, and J. N. Benoit Mesenteric Vascular Responsiveness in a Rat Model of Pregnancy-Induced Hypertension Experimental Biology and Medicine, September 1, 2006; 231(8): 1398 - 1402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Anderson, F. Lopez, H.-Y. Zhang, K. Pavlish, and J. N. Benoit Reduced Uteroplacental Perfusion Alters Uterine Arcuate Artery Function in the Pregnant Sprague-Dawley Rat Biol Reprod, March 1, 2005; 72(3): 762 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Myers, G. Mires, M. Macleod, and P. Baker In Preeclampsia, the Circulating Factors Capable of Altering In Vitro Endothelial Function Precede Clinical Disease Hypertension, February 1, 2005; 45(2): 258 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Cherla and E. A. Jaimes Role of L-Arginine in the Pathogenesis and Treatment of Renal Disease J. Nutr., October 1, 2004; 134(10): 2801S - 2806S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Orshal and R. A. Khalil Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1013 - R1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. T. Alexander, M. T. Llinas, W. C. Kruckeberg, and J. P. Granger L-Arginine Attenuates Hypertension in Pregnant Rats With Reduced Uterine Perfusion Pressure Hypertension, April 1, 2004; 43(4): 832 - 836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Orshal and R. A. Khalil Reduced Endothelial NO-cGMP-Mediated Vascular Relaxation and Hypertension in IL-6-Infused Pregnant Rats Hypertension, February 1, 2004; 43(2): 434 - 444. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Payne, B. T. Alexander, and R. A. Khalil Decreased Endothelium-Dependent NO-cGMP Vascular Relaxation and Hypertension in Growth-Restricted Rats on a High-Salt Diet Hypertension, February 1, 2004; 43(2): 420 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Payne, B. T. Alexander, and R. A. Khalil Reduced Endothelial Vascular Relaxation in Growth-Restricted Offspring of Pregnant Rats With Reduced Uterine Perfusion Hypertension, October 1, 2003; 42(4): 768 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Martinez-Orgado, R. Gonzalez, S. Tovar, J. Marin, M. Salaices, and M. J. Alonso Administration of N{omega}-L-Arginine Methyl Ester (L-NAME) Impairs Endothelium-Dependent Relaxation in Gravid But Not Nongravid Rats Reproductive Sciences, February 1, 2003; 10(2): 74 - 81. [Abstract] [PDF]
|
|
|
|
|
|
J. G. Murphy, J. N. Herrington, J. P. Granger, and R. A. Khalil Enhanced [Ca2+]i in renal arterial smooth muscle cells of pregnant rats with reduced uterine perfusion pressure Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H393 - H403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Khalil and J. P. Granger Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R29 - R45. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Giardina, G. M. Green, K. L. Cockrell, J. P. Granger, and R. A. Khalil TNF-alpha enhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R130 - R143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Davis, J. B. Giardina, G. M. Green, B. T. Alexander, J. P. Granger, and R. A. Khalil Reduced endothelial NO-cGMP vascular relaxation pathway during TNF-alpha -induced hypertension in pregnant rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2002; 282(2): R390 - R399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Giardina, K. L. Cockrell, J. P. Granger, and R. A. Khalil Low-Salt Diet Enhances Vascular Reactivity and Ca2+ Entry in Pregnant Rats With Normal and Reduced Uterine Perfusion Pressure Hypertension, February 1, 2002; 39(2): 368 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Barron, J. B. Giardina, J. P. Granger, and R. A. Khalil High-Salt Diet Enhances Vascular Reactivity in Pregnant Rats With Normal and Reduced Uterine Perfusion Pressure Hypertension, September 1, 2001; 38(3): 730 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. BOHLENDER, D. GANTEN, and F. C. LUFT Rats Transgenic for Human Renin and Human Angiotensinogen as a Model for Gestational Hypertension J. Am. Soc. Nephrol., November 1, 2000; 11(11): 2056 - 2061. [Abstract] [Full Text]
|
|