title: Haemodynamic effects of the selective phosphodiesterase 5 inhibitor, UK-357,903, in conscious SHR.
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.
authors.affiliation: Centre for Integrated Systems Biology & Medicine, School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. sheila.gardiner@nottingham.ac.uk
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Gardiner
authors.forename: Julie E
authors.initials: JE
authors.lastname: March
authors.forename: Philip A
authors.initials: PA
authors.lastname: Kemp
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ballard
authors.forename: Ed
authors.initials: E
authors.lastname: Hawkeswood
authors.forename: Bernadette
authors.initials: B
authors.lastname: Hughes
authors.forename: Terence
authors.initials: T
authors.lastname: Bennett
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000803:Angiotensin I / Q000737:chemistry; D000818:Animals; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D006152:Cyclic GMP / Q000096:biosynthesis / Q000097:blood; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000097:blood / Q000737:chemistry / Q000187:drug effects*; D010879:Piperazines / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000096:biosynthesis / Q000097:blood; D013450:Sulfones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011744:Pyrimidinones; D013450:Sulfones; C495331:UK 357,903; D004656:Enalapril; D000803:Angiotensin I; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D012083:Renin; D006152:Cyclic GMP