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CARDIOVASCULAR

Hemodynamic Effects of Phosphodiesterase 5 and Angiotensin-Converting Enzyme Inhibition Alone or in Combination in Conscious SHR

Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, United Kingdom (S.M.G., J.E.M., P.A.K., T.B.); and Pfizer Global Research & Development, Sandwich Laboratories, Kent, United Kingdom (S.A.B., E.H., B.H.)

The regional hemodynamic responses to continuous 4-day infusion of UK-357,903 [1-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2-methoxyethoxy)-5-pyridylsulphonyl}piperazine] (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 blood pressure (-12.1 mm Hg) 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 mm Hg) and vasodilatation in the renal, mesenteric, and hindquarter 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 angiotensin-converting enzyme inhibition.

Address correspondence to: Professor S. M. Gardiner, Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, Floor E, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. E-mail: sheila.gardiner{at}nottingham.ac.uk

This article has been cited by other articles:

				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]