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

• Published in: British journal of pharmacology Vol. 141; no. 1; pp. 114 - 122
• Main Authors: Gardiner, Sheila M, March, Julie E, Kemp, Philip A, Ballard, Stephen A, Hawkeswood, Ed, Hughes, Bernadette, Bennett, Terence
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.01.2004; Nature Publishing
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Angiotensin I - chemistry; angiotensin‐converting enzyme inhibitors; Animals; Biological and medical sciences; Cardiovascular Physiological Phenomena - drug effects; Cyclic GMP - biosynthesis; Cyclic GMP - blood; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; enalapril; Enalapril - administration & dosage; Enalapril - pharmacology; haemodynamics; Hemodynamics - drug effects; Hemodynamics - physiology; Hypotension - chemically induced; Infusions, Intravenous; Male; Medical sciences; Pharmacology. Drug treatments; Phosphodiesterase 5 inhibitors; 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; spontaneously hypertensive rats; Sulfones - blood; Sulfones - chemistry; Sulfones - pharmacology; Time Factors; United Kingdom; Europe; Hypertension; angiotensin-converting enzyme inhibitors; Rat; Enzyme; 3',5'-Cyclic-GMP phosphodiesterase; Rodentia; Enzyme inhibitor; Cardiovascular disease; Esterases; Phosphoric diester hydrolases; Peptidases; Vertebrata; Mammalia; Enalapril; Peptidyl-dipeptidase A; Animal; Phosphodiesterase 5 inhibitors; spontaneously hypertensive rats; Hydrolases; Peptidyl-dipeptidases; Antihypertensive agent; Hemodynamics; ACE inhibitor; haemodynamics
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705581

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 kg−1 h−1) were measured in conscious spontaneously hypertensive rats, and compared with those of enalapril (1 mg kg−1 h−1). 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. 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. 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. 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. British Journal of Pharmacology (2004) 141, 114–122. doi:10.1038/sj.bjp.0705581