Comparative effects of the dual metallopeptidase inhibitor, MDL 100,240 and of enalaprilat on regional and on cardiac haemodynamics in conscious, hypertensive, transgenic ((mRen‐2)27) rats

• Published in: British journal of pharmacology Vol. 122; no. 8; pp. 1694 - 1701
• Main Authors: Gardiner, S M., Kemp, P A., Brunner‐Ferber, F., Bennett, T.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-1997; Nature Publishing
• Subjects: Adrenergic beta-Antagonists - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Animals, Genetically Modified; Antihypertensive agents; Benzazepines - pharmacology; Biological and medical sciences; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Cardiovascular system; dual metallopeptidase inhibitor; enalaprilat; Enalaprilat - pharmacology; Hemodynamics - drug effects; Hemodynamics - physiology; Hypertension - physiopathology; Male; MDL 100,240; Medical sciences; Metalloendopeptidases - antagonists & inhibitors; Pharmacology. Drug treatments; Protease Inhibitors - pharmacology; Pyridines - pharmacology; Rats; transgenic rats; Heart; Vasodilator agent; Intravenous administration; Peptides; Rat; Continuous; Transgenic animal; Cardiovascular disease; Metalloendopeptidases; Peptidyl-dipeptidase A; Arterial pressure; Angiotensin II; Mechanism of action; Hypertension; Enzyme; Rodentia; Peptidases; Vertebrata; Mammalia; Perfusion; Enalaprilat; Hydrolases; Peptidyl-dipeptidases; Antihypertensive agent; Self regulation; Neprilysin; Circulatory system; Hemodynamics; Comparative study; ACE inhibitor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701551

1
Heterozygous, male, hypertensive, transgenic ((mRen‐2)27) rats (350–450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin‐converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg−1, 3 mg kg−1 h−1; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B2)‐receptor antagonist, Hoe 140 (1 mg kg−1, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin.
2
Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (−54 ± 9 mmHg) was greater than that of enalaprilat (−38 ± 4 mmHg), because the former caused a significantly greater reduction in cardiac index.
3
Between 8–24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds.
4
There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug.
5
These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen‐2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.