ABSTRACT
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 microg kg(-1) h(-1)) alone and in combination with a low dose of enalapril (10 microg 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.