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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 27, 2004; DOI: 10.1124/jpet.104.071993

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Received for publication May 28, 2004.
Revised September 1, 2004.
Accepted for publication September 23, 2004.

HEMODYNAMIC EFFECTS OF PHOSPHODIESTERASE 5 AND ANGIOTENSIN CONVERTING ENZYME INHIBITION ALONE OR IN COMBINATION IN CONSCIOUS SHR

Sheila Gardiner 1*, Julie March 1, Philip Kemp 1, Stephen Ballard 2, Edward Hawkeswood 2, Bernadette Hughes 2, Terence Bennett 1

1 University of Nottingham 2 Pfizer Global R&D

* Address correspondence to: E-mail: sheila.gardiner{at}nottingham.ac.uk

Abstract

The regional hemodynamic responses to continuous, 4-day, infusion of UK-357,903 (266 µg kg-1 h-1) alone, and in combination with a low dose of enalapril (10 µg kg-1 h-1), were measured in conscious spontaneously hypertensive rats, to test the hypothesis that the renin-angiotensin system may influence the cardiovascular consequences of inhibition of phosphodiesterase 5 (PDE5) by UK-357,903, or vice versa. UK-357,903 alone, caused a fall in mean BP (-12.1mmHg), associated with vasodilatation in the mesenteric and hindquarters vascular beds. The only way in which the effects of enalapril given alone differed significantly from those of the vehicle was in causing mesenteric vasodilatation, which developed over the 4 days of infusion. UK-357,903, given in combination with enalapril, caused hypotension (-17.8 mmHg) and vasodilatation in the renal, mesenteric and hindquarters vascular beds. There was evidence of a significant interaction between the effects of the two compounds on renal Doppler shift and vascular conductance, with the combined action of the two compounds being greater than the sum of their individual effects. However, although there was a trend for the combination to have greater effects than either of the individual agents on blood pressure and mesenteric vascular conductance, there was no statistical evidence of an interaction. The results indicate that inhibition of the renin-angiotensin system uncovers additional renal vasodilator effects of UK-357,903, and/or inhibition of PDE5 enhances the renal vasodilator effects of ACE inhibition.


Key words: angiotensin converting enzyme inhibitors, enalapril, hemodynamics, phosphodiesterase 5 inhibitors, renin angiotensin system, spontaneously hypertensive rats


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S. M. Gardiner, J. E. March, P. A. Kemp, S. A. Ballard, and T. Bennett
Regional Hemodynamic Effects of Neutral Endopeptidase Inhibition and Angiotensin (AT1) Receptor Antagonism Alone or in Combination in Conscious Spontaneously Hypertensive Rats
J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 340 - 348.
[Abstract] [Full Text] [PDF]


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