Effects of the dual metallopeptidase inhibitor, MDL 100,240, on regional haemodynamic responses to vasoactive peptides in conscious rats

• Published in: British journal of pharmacology Vol. 122; no. 8; pp. 1687 - 1693
• 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: angiotensin I; Angiotensin I - pharmacology; angiotensin II; Angiotensin II - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; ANP; Atrial Natriuretic Factor - pharmacology; Benzazepines - pharmacology; big endothelin‐1; Biological and medical sciences; bradykinin; Bradykinin - pharmacology; Cardiovascular system; Dual metallopeptidase inhibitor; Endothelin-1 - pharmacology; endothelin‐1; Fundamental and applied biological sciences. Psychology; Hemodynamics - drug effects; Hemodynamics - physiology; Hemodynamics. Rheology; Male; Medical sciences; Neprilysin - antagonists & inhibitors; Pharmacology. Drug treatments; Protease Inhibitors - pharmacology; Pyridines - pharmacology; Rats; Vasodilator agents. Cerebral vasodilators; Vertebrates: cardiovascular system; Heart; Vasodilator agent; Intravenous administration; Peptides; Rat; Peptide hormone; Metalloendopeptidases; Atrial natriuretic peptide; Peripheral hemodynamics; Mechanism; Regulation(control); Vasomotricity; Natriuretic hormone; Peptidyl-dipeptidase A; Bradykinin; Blood vessel; Arterial pressure; Angiotensin II; Mechanism of action; Enzyme; Angiotensin I; Rodentia; Enzyme inhibitor; Endothelin 1; Peptidases; Renin angiotensin system; Vertebrata; Mammalia; Bolus injection; Perfusion; Animal; Hydrolases; Peptidyl-dipeptidases; Neprilysin; Circulatory system
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701550

1
The effects of combined inhibition of neutral endopeptidase 24.11 and angiotensin‐converting enzyme, with the dual metallopeptidase inhibitor, MDL 100,240 (3 mg kg−1 bolus, 3 mg kg−1, h−1 infusion), on baseline haemodynamics and on responses to a variety of vasoactive peptides were studied in conscious Long Evans rats (350–450 g: n=9) chronically instrumented for the assessment of regional haemodynamics.
2
The experiments ran over 4 consecutive days. On the first 2 days the animals received the vehicle for MDL 100,240, and were given bolus i.v. injections of angiotensin I (AI; 250 pmol kg−1), angiotensin II (AII; 125 pmol kg−1), bradykinin (BK: 3 nmol kg−1) and endothelin‐1 (ET‐1; 250 pmol kg−1) on one day and AI (as above), atrial natriuretic peptide (ANP: 500 pmol kg−1) and big endothelin‐1 (big ET‐1; 500 pmol kg−1) on the other day in a random manner. On the third and fourth experimental days the vasoactive peptides were given in the same order as before, but in the presence of MDL 100,240.
3
Thirty minutes after onset of administration of vehicle, on the first or second experimental day, there were no consistent cardiovascular changes. However, at the same time following onset of MDL 100,240 administration on the third experimental day, there was a significant, but slight, reduction in mean arterial blood pressure (MAP; −5±2 mmHg) together with tachycardia (41±12 beats min−1) and increases in renal and mesenteric flows (17±3 and 13±4%, respectively) and vascular conductances (23±4 and 19±5%, respectively). The mesenteric vasodilator effect of MDL 100,240 was still present on the fourth experimental day before administration of the drug on that day, but otherwise the pattern of response to MDL 100,240 was similar to that on the previous day.
4
In the presence of vehicle, AI caused hypertension, bradycardia, and reductions in renal mesenteric and hindquarters vascular conductances; all these effects were abolished by MDL 100,240.
5
In the presence of vehicle, AII caused effects similar to those of AI. MDL 100,240 did not affect the pressor, bradycardic or hindquarters vasoconstrictor effects of AII. However, in the presence of MDL 100,240, the overall renal and mesenteric vasoconstrictor effects of AII were enhanced, probably because of the renal and mesenteric vasodilatation caused by MDL 100,240.
6
In the presence of vehicle, BK had a slight pressor effect, accompanied by tachycardia and transient increases in conductances in renal, mesenteric and hindquarters vascular beds. In the presence of MDL 100,240 BK caused marked hypotension, but an attenuated tachycardia; renal, mesenteric and hindquarters vasodilator responses were enhanced.
7
In the presence of vehicle, ANP caused slight hypotension and tachycardia, together with reductions in renal and mesenteric vascular conductances, and transient increases in hindquarters conductance. MDL 100,240 enhanced the hypotensive effect of ANP and promoted a delayed hindquarters vasoconstriction.
8
Big ET‐1, in the presence of vehicle, caused a marked and prolonged increase in MAP, accompanied by bradycardia and reductions in renal, mesenteric and hindquarters vascular conductances. Although MDL 100,240 significantly attenuated the magnitude of the pressor effect of big ET‐1, its bradycardic and renal, mesenteric and hindquarters haemodynamic actions were not reduced significantly.
9
In the presence of vehicle, ET‐1 caused an initial hypotension, tachycardia and vasodilatation in the hindquarters, but reductions in renal and mesenteric vascular conductances; thereafter there was a rise in MAP and bradycardia with vasoconstriction in all three vascular beds. MDL 100,240 had no effect on the initial hypotensive, tachycardic or hindquarters haemodynamic effects of ET‐1. Moreover the subsequent pressor and bradycardic actions of ET‐1 were unchanged, but its renal and mesenteric vasoconstrictor effects were enhanced, possibly because of the dilatation caused by MDL 100,240 in these vascular beds.
10
Overall, the results are consistent with MDL 100,240 exerting important haemodynamic actions in conscious rats through inhibition of angiotensin‐converting enzyme and neutral endopeptidase.