Cardiorenal consequences of dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibition in transgenic rats with an extra renin gene.
The cardiovascular consequences of mixed angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibition with alatriopril/alatrioprilat were compared with the consequences of endopeptidase (NEP) inhibition alone with (S)-thiorphan/ecadotril by determining the acute effects of the compounds on hemodynamic, hormonal, and renal parameters in hypertensive transgenic rats harboring an additional mouse renin gene (TGR(mRen2)27). Infusion of alatrioprilat and (S)-thiorphan in anesthetized TGR decreased blood pressure in a dose-dependent manner, but heart rate remained unchanged. The renal excretion of water, sodium, and cGMP also increased dose-dependently, with nearly the same maximal effects after infusion of (S)-thiorphan and alatrioprilat. At the end of infusion, plasma ANP and cGMP were elevated both after (S)-thiorphan and after alatrioprilat, whereas plasma renin activity increased only after alatrioprilat. The ACE inhibition effect was studied in ganglion-blocked rats receiving a continous infusion of angiotensin I. Alatrioprilat decreased the mean blood pressure dose-dependently, but about 30 times higher concentrations were needed to produce the same effects as the ACE inhibitor captopril. At a dose of 30 mg/kg p.o., ecadotril, the orally active prodrug of (S)-thiorphan, decreased the systolic blood pressure in conscious TGR by 22 mmHg for 6 h, whereas alatriopril (100 mg/kg p.o.) also reduced the systolic pressure in these rats with a maximal reduction of 22 mmHg. In addition, ecadotril and alatriopril significantly increased the urinary excretion of sodium. In contrast, ACE inhibition with captopril decreased the excretion of sodium dose-dependently in conscious TGR. In conclusion, combined ACE/NEP inhibition produced a comparable lowering of blood pressure and improvement in renal function as those with NEP inhibition in TGR. Dual ACE/NEP inhibition may therefore be useful in cardiovascular conditions such as hypertension or heart failure.
Bayer AG, Wuppertal, Germany.
M
M
Wegner
C
C
Hirth-Dietrich
A
A
Knorr
J
J
Dressel
D
D
Ganten
J P
JP
Stasch
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D012083:Renin / Q000235:genetics* / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D004149:Dioxoles; C068866:alatriopril; D012083:Renin; D015260:Neprilysin; D000409:Alanine