Racial Variation in ACE--Genetic and Physiologic Bases

Hypertension Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00005757
• Other study ID #: 5115
• Secondary ID: R29HL056963
• Status: Completed
• Phase: N/A
• First received: May 25, 2000
• Last updated: November 23, 2016
• Start date: September 1997
• Est. completion date: August 2001

Study information

• Verified date: November 2016
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Observational

Clinical Trial Summary

To determine whether differences in the activity of the renin-angiotensin and bradykinin systems are involved in the pathogenesis of blood pressure variation in African Americans.

Description:

BACKGROUND:

Each year, more than 40,000 new patients require treatment for end stage renal disease, a condition which is 4-fold higher among African Americans than Caucasians. Trials of angiotensin converting enzyme inhibitors (ACEIs) in Caucasians support a role of the renin-angiotensin system in the pathogenesis of glomerulosclerosis. Yet, despite the high prevalence of nephropathy among African Americans, Blacks have been under-represented in studies in ACEIs. Data from our laboratory suggest that the renal effects of ACEI may differ in African Americans. African Americans are resistant to the anti-hypertensive effects of ACEI and, thus, may be resistant to the renoprotective effects as well. The ACE deletion allele, a variant associated with increased ACE activity and progression of renal diseases, is increased in frequency in African Americans, while the frequency of the Ang AT1 receptor C allele, a variant associated with antihypertensive responsiveness to ACEI is decreased. Moreover, African Americans exhibit decreased sensitivity to Ang I and increased sensitivity to bradykinin. Taken together, these data suggest the hypothesis that ACE activity is increased in African Americans, leading to decreased bradykinin levels ( and receptor sensitization) and increased tissue Ang II (and receptor desensitization).

DESIGN NARRATIVE:

The study tests the hypothesis that ACE activity is increased in African Americans, leading to decreased bradykinin levels (and receptor sensitization) and increased tissue Ang II (and receptor desensitization). The effects of race, hypertension and ACE insertion/deletion genotype on ACE activity will be determined, as measured by the pressor and renal vasoconstrictor responses to Ang I and Ang II and the vasodilator response to bradykinin. Specific bradykinin and angiotensin receptor antagonists will be used to determine the relative contribution of increased bradykinin and decreased angiotensin II to the renal hemodynamic effects of ACEIs in African Americans and Caucasians.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 293
• Est. completion date: August 2001
• Est. primary completion date: August 2001
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A to 100 Years
• Eligibility: No eligibility criteria

Study Design

Observational Model: Case-Crossover

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Heart Diseases
• Hypertension

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University	National Heart, Lung, and Blood Institute (NHLBI)

References & Publications (9)

Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension. 1998 Dec;32(6):965-71. — View Citation

Brown NJ, Nakamura S, Ma L, Nakamura I, Donnert E, Freeman M, Vaughan DE, Fogo AB. Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int. 2000 Sep;58(3):1219-27. — View Citation

Gainer JV, Brown NJ, Bachvarova M, Bastien L, Maltais I, Marceau F, Bachvarov DR. Altered frequency of a promoter polymorphism of the kinin B2 receptor gene in hypertensive African-Americans. Am J Hypertens. 2000 Dec;13(12):1268-73. — View Citation

Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998 Oct 29;339(18):1285-92. — View Citation

Murphey LJ, Gainer JV, Vaughan DE, Brown NJ. Angiotensin-converting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin. Circulation. 2000 Aug 22;102(8):829-32. — View Citation

Murphey LJ, Hachey DL, Oates JA, Morrow JD, Brown NJ. Metabolism of bradykinin In vivo in humans: identification of BK1-5 as a stable plasma peptide metabolite. J Pharmacol Exp Ther. 2000 Jul;294(1):263-9. — View Citation

Murphey LJ, Hachey DL, Vaughan DE, Brown NJ, Morrow JD. Quantification of BK1-5, the stable bradykinin plasma metabolite in humans, by a highly accurate liquid-chromatographic tandem mass spectrometric assay. Anal Biochem. 2001 May 1;292(1):87-93. — View Citation

Murphey LJ, Kumar S, Brown NJ. Endogenous bradykinin and the renin and pressor responses to furosemide in humans. J Pharmacol Exp Ther. 2000 Nov;295(2):644-8. — View Citation

Wilsdorf T, Gainer JV, Murphey LJ, Vaughan DE, Brown NJ. Angiotensin-(1-7) does not affect vasodilator or TPA responses to bradykinin in human forearm. Hypertension. 2001 Apr;37(4):1136-40. — View Citation