A comparison of vasodilator activity of agents activating cyclic nucleotides with those inhibiting their metabolism in rabbit isolated ear artery.
1. The effects of forskolin, a direct activator of adenylate cyclase and sodium nitroprusside, a direct activator of guanylate cyclase, were studied on rabbit isolated ear arteries preconstricted with 80 mM potassium. 2. Bolus injection of these two compounds resulted in vasodilatation. They had similar potencies in this tissue but forskolin had a significantly longer duration of action than sodium nitroprusside. 3. In the same tissue, perfusion with isobutylmethylxanthine (IBMX), a non-selective phosphodiesterase (PDE) inhibitor, or zaprinast, selective for the PDE primarily responsible for the metabolism of guanosine 3':5'-cyclic monophosphate (cyclic GMP), resulted in vasodilatation. However, SK&F 94120 selective for cyclic AMP-PDE (PDE III), primarily responsible for the metabolism of adenosine 3':5'-cyclic monophosphate (cyclic AMP), resulted in vasodilatation only at very high concentrations. The rank order of potency for the compounds was IBMX greater than zaprinast greater than SK&F 94120. 4. The effects of these three PDE inhibitors were studied on the vasoconstriction produced by perivascular sympathetic nerve stimulation in the absence of raised potassium. IBMX and zaprinast, caused a reduction in the response at 50 Hz stimulation frequency and a shift in the frequency-response curve to the right. SK&F 94120 did not displace the frequency-response curve but did reduce the response at 50 Hz. The same order of potency for the inhibition of the vasoconstrictor responses to perivascular sympathetic nerve stimulation was found as for vasodilatation i.e. IBMX greater than zaprinast greater than SK&F 94120. 5. These results indicate that in the same tissue direct activation of adenylate and guanylate cyclase results in vasodilatation. Non-specific PDE and cyclic GMP-PDE inhibition also resulted in vasodilatation and inhibition of vasoconstrictor responses to sympathetic nerve stimulation. However a selective cyclic AMP-PDE (PDE III) inhibitor did not result in vasodilatation, except at very high concentrations, or inhibit sympathetic vasoconstrictor responses except to reduce the response at 50Hz stimulation. These findings provide further support for the ability of PDE inhibitors to be tissue selective.
Wood
L M
LM
Department of Pharmacology, Smith Kline & French Research Ltd, Welwyn, Hertfordshire.
Owen
D A
DA
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism / Q000494:pharmacology*; D004431:Ear, External / Q000098:blood supply; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors; D012039:Regional Blood Flow / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D010726:Phosphodiesterase Inhibitors; D009599:Nitroprusside; D005576:Colforsin; D000242:Cyclic AMP; D006152:Cyclic GMP