Inhibition of neutral endopeptidase by thiorphan does not modify coronary vascular responses to angiotensin I, angiotensin II and bradykinin in the isolated guinea pig heart.
Both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) are involved in the regulation of renin-angiotensin and kallikrein-kinin systems. The aim of the present study was to assess the role of NEPand ACE in the regulation of vascular responses to angiotensin I (Ang I), angiotensin II (Ang II) and bradykinin (Bk) in the coronary circulation. For this purpose we used typical inhibitors of ACE and NEP, perindoprilate (1 microM) and thiorphan (1 micromM and 10 microM), respectively, and analyzed their effects on the coronary vasoconstrictor responses to Ang I and Ang II and coronary vasodilator responses to Bk in the isolated guinea pig heart. Perindoprilate abolished coronary vasoconstriction induced by Ang I and potentiated coronary vasodilation evoked by Bk. Thiorphan at a concentration of 1 muM slightly reduced response to Ang I without a significant effect on the responses to Ang II and Bk. However, thiorphan at a concentration of 10 muM abolished coronary vasoconstrictor response to Ang I and enhanced Bk-induced vasodilation. Importantly, in the presence of perindoprilate, addition of thiorphan (10 microM) did not modify further either responses to Ang I, Ang II or to Bk. In conclusion, vascular responses induced by Ang I, Ang II and Bk in the isolated guinea pig heart are regulated by ACE but not by NEP. Moreover, thiorphan is not a perfect tool to asses functional role of NEP as it displays ACE inhibitory activity.
Kozlovski
Valery I
VI
Department of Experimental Pharmacology, Chair of Pharmacology, Jagiellonian University Medical College, Grzegórzecka 16, PL 31-531 Kraków, Poland.
Lomnicka
Magdalena
M
Jakubowski
Andrzej
A
Chlopicki
Stefan
S
D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000517:prevention & control; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010477:Perfusion / Q000379:methods; D015244:Thiorphan / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D006020:Glycopeptides; D007211:Indoles; D000804:Angiotensin II; C053500:perindoprilat; D000803:Angiotensin I; D015244:Thiorphan; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin; D001920:Bradykinin; C008890:phosphoramidon