rxpa380 and quinaprilat

rxpa380 has been researched along with quinaprilat* in 2 studies

Other Studies

2 other study(ies) available for rxpa380 and quinaprilat

ArticleYear
Different contributions of the angiotensin-converting enzyme C-domain and N-domain in subjects with the angiotensin-converting enzyme II and DD genotype.
    Journal of hypertension, 2008, Volume: 26, Issue:4

    Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism-related differences in ACE concentration do not result in differences in angiotensin levels.. To investigate whether this relates to differences in the contribution of the ACE C-domain and N-domain, we quantified, using the C-domain-selective inhibitors quinaprilat and RXPA380, and the N-domain-selective inhibitor RXP407, the contribution of both domains to the metabolism of angiotensin I, bradykinin, the C-domain-selective substrate Mca-BK(1-8), and the N-domain-selective substrate Mca-Ala in serum of IIs, DDs, and 'hyperACE' subjects (i.e., subjects with increased ACE due to enhanced shedding). During incubation with angiotensin I, the highest angiotensin II levels were observed in sera with the highest ACE activity. This confirms that ACE is rate-limiting with regard to angiotensin II generation. C-domain-selective concentrations of quinaprilat fully blocked angiotensin I-II conversion in DDs, whereas additional N-domain blockade was required to fully block conversion in IIs. Both domains contributed to bradykinin hydrolysis in all subjects, and the inhibition profile of RXP407 when using Mca-Ala was identical in IIs and DDs. In contrast, the RXPA380 concentrations required to block C-domain activity when using Mca-BK (1-8) were three-fold higher in IIs than DDs.. The contributions of the C-domain and N-domain differ between DDs and IIs, and RXPA380 is the first inhibitor capable of distinguishing D-allele ACE from I-allele ACE. The lack of angiotensin II accumulation in DDs in vivo is not because of the often quoted concept that ACE is a nonrate-limiting enzyme. It may relate to the fact that in IIs both the N-domain and C- domain generate angiotensin II, whereas in DDs only the C-domain converts angiotensin I.

    Topics: Adult; Aged; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Coronary Vessels; Enzyme Activation; Female; Genotype; Humans; In Vitro Techniques; Male; Middle Aged; Oligopeptides; Peptidyl-Dipeptidase A; Phosphinic Acids; Point Mutation; Protein Structure, Tertiary; Sus scrofa; Tetrahydroisoquinolines; Vasoconstrictor Agents; Vasodilator Agents

2008
Selective angiotensin-converting enzyme C-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction.
    Hypertension (Dallas, Tex. : 1979), 2005, Volume: 45, Issue:1

    Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentration-dependently constricted PFAs. RXPA380, at concentrations >1 mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations < or =0.1 mmol/L. Bradykinin concentration-dependently relaxed PCMAs. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled approximately 50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t(1/2)) of 42+/-3 minutes. Quinaprilat increased the t(1/2) approximately 4-fold, indicating that 71+/-6% of Ang I metabolism was attributable to ACE. RXPA380 (10 micromol/L) and RXP407 (0.1 mmol/L) increased the t(1/2) approximately 2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE (and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I-induced vasoconstriction in vivo but also why ACEi exert blood pressure-independent effects at low (C-domain-blocking) doses.

    Topics: Adolescent; Adult; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Captopril; Coronary Vessels; Dose-Response Relationship, Drug; Female; Femoral Artery; Humans; Male; Microcirculation; Middle Aged; Oligopeptides; Organ Specificity; Peptidyl-Dipeptidase A; Phosphinic Acids; Protein Structure, Tertiary; Solubility; Structure-Activity Relationship; Sus scrofa; Tetrahydroisoquinolines; Vasoconstriction

2005
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