There are substantial data indicating that nitric oxide (NO) can influence in vitro myocyte contractile function and this is partly attributable to the effects of NO on intramuscular cGMP concentration (Kobzik et al. 1994). Recently it has been demonstrated that increases in cGMP, using a weak and non-specific phosphodiesterase (PDE) inhibitor (IBMX) can increase maximal shortening velocity of the extensor digitorum longus muscle by 17 % and that inhibition of NO synthase reduces maximal isometric force (Marechal & Beckers-Bleukx, 1998). The aim of the present study was to establish whether changes in PDE1/5 activity impacts on ischaemic muscle function. Using the canine gracilis model (Timmons et al. 1996), where blood flow through the skeletal muscle is controlled by a peristaltic perfusion system, we examined the effects of the potent PDE1/5 inhibitor, UK-114,542 (PDE1 IC₅₀ = 93 nM and PDE5 IC₅₀ = 1.7 nM) on muscle function. Dogs were anaesthetised (sodium pentobarbitone 45 ± 1 mg kg^-1 body mass) followed by continuous infusion at 0.10 ± 0.01 mg kg^-1 min^-1 and given a terminal bolus at the end of the experiment. A free drug concentration of ~75 nM, sufficient to cause total inhibition of PDE5 but minimal inhibition of PDE1, was maintained with a loading dose of 716 mg kg^-1 and continuous infusion at 71 mg kg^-1 h^-1 with skeletal muscle function being compared with a vehicle control group. The muscle was stimulated to contract, via the obturator nerve (5 Hz, 10 V, 0.2 ms for 10 min) with blood flow being limited to ~16 ml min^-1 100 g^-1 tissue to induce a skeletal muscle fatigue profile that is metabolic in origin (Timmons et al. 1996). The experiments were carried out in accordance with UK legislation. Data are means ± S.E.M. (n = 6) with control data appearing first. All data were statistically analysed using MANOVA followed by a Bonferroni correction. UK-114,542 evoked a 10 % reduction in mean arterial blood pressure (from 119 ± 4 to 109 ± 3 mmHg, P < 0.05). During contraction, perfusion pressure (58 ± 3.2 vs. 67 ± 4.3 mmHg), the extent of phosphocreatine degradation (73.7 ± 3.4 vs. 63.8 ± 5.7 mmol kg^-1 dry mass), oxygen utilisation per unit of tension production (1.72 ± 0.2 vs. 1.98 ± 0.2 ml min^-1 kg^-1 tension) and the decline in muscle tension (74 vs. 71 %) did not significantly differ between groups. In conclusion, no impact on ischaemic muscle function or metabolism was noted following inhibition of PDE1/5 with UK-114,542.

The authors would like to acknowledge Paul E. Rajab and David Fairman for their technical support.