Haemodynamic effects of the selective phosphodiesterase 5 inhibitor, UK-357,903, in conscious SHR
| Autor: | Gardiner, Sheila M, March, Julie E, Kemp, Philip A, Ballard, Stephen A, Hawkeswood, Ed, Hughes, Bernadette, Bennett, Terence |
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| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Cyclic Nucleotide Phosphodiesterases
Type 5 Male Time Factors Dose-Response Relationship Drug Phosphodiesterase Inhibitors Phosphoric Diester Hydrolases Hemodynamics Radioimmunoassay Pyrimidinones Piperazines Rats Cardiovascular Physiological Phenomena Disease Models Animal Enalapril 3' 5'-Cyclic-GMP Phosphodiesterases Rats Inbred SHR Papers Renin Animals Sulfones Angiotensin I Hypotension Infusions Intravenous Cyclic GMP |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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