Haemodynamic effects of the selective phosphodiesterase 5 inhibitor, UK-357,903, in conscious SHR

Br J Pharmacol. 2004 Jan;141(1):114-22. doi: 10.1038/sj.bjp.0705581. Epub 2003 Dec 8.

Abstract

1. Regional haemodynamic responses to a continuous, 4-day infusion of the selective phosphodiesterase type 5 inhibitor, UK-357,903 (0.133 or 1.33 mg x kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg x kg(-1) h(-1)). 2. Both doses of UK-357,903 caused modest reductions in mean blood pressure that were not dose-dependent and only significantly different from the vehicle effects on Day 1 of the study (mean -11.8 and -15.3 mmHg for low and high doses, respectively). UK-357,903 had mesenteric and hindquarters vasodilator effects, which were, again, similar for both dose levels and only significantly different from vehicle on Day 1. Neither dose of UK-357,903 affected renal vascular conductance or heart rate. 3. Although the haemodynamic effects of UK-357,903 were not clearly dose-related and some appeared to wane with time, geometric mean plasma levels of UK-357,903 increased in proportion to dose, and were sustained throughout the infusion period. Furthermore, plasma cyclic guanosine monophosphate, a biomarker of phosphodiesterase 5 inhibition, was persistently elevated, and increased with increasing dose. 4. Enalapril caused a fall in mean blood pressure on day 1 (-14.1 mmHg) that was associated with dilatation in renal, mesenteric and hindquarters vascular beds. The haemodynamic effects of enalapril were sustained or increased over the 4-day infusion, although plasma free drug levels were stable. 5. In conclusion, we have shown regional and temporal changes in the haemodynamic effects of UK-357,903, which may be due to activation of compensatory mechanisms, but there were no signs of functional compensation to the cardiovascular effects of enalapril.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Angiotensin I / chemistry
  • Animals
  • Cardiovascular Physiological Phenomena / drug effects
  • Cyclic GMP / biosynthesis
  • Cyclic GMP / blood
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enalapril / administration & dosage
  • Enalapril / pharmacology
  • Hemodynamics / drug effects*
  • Hemodynamics / physiology
  • Hypotension / chemically induced
  • Infusions, Intravenous
  • Male
  • Phosphodiesterase Inhibitors / blood
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases / blood
  • Phosphoric Diester Hydrolases / chemistry
  • Phosphoric Diester Hydrolases / drug effects*
  • Piperazines / blood
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Pyrimidinones / blood
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Radioimmunoassay / methods
  • Rats
  • Rats, Inbred SHR
  • Renin / biosynthesis
  • Renin / blood
  • Sulfones / blood
  • Sulfones / chemistry
  • Sulfones / pharmacology*
  • Time Factors

Substances

  • Phosphodiesterase Inhibitors
  • Piperazines
  • Pyrimidinones
  • Sulfones
  • UK 357,903
  • Enalapril
  • Angiotensin I
  • Phosphoric Diester Hydrolases
  • 3',5'-Cyclic-GMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • Pde5a protein, rat
  • Renin
  • Cyclic GMP