Effect of increased myocardial cyclic GMP induced by cyclic GMP-phosphodiesterase inhibition on oxygen consumption and supply of rabbit hearts.
1. We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O2 consumption and areas of low O2 supply/consumption balance, using zaprinast, a selective cyclic GMP-phosphodiesterase inhibitor. 2. The study was conducted in three groups (vehicle, 10(-3) and 3 x 10(-3) mol/L zaprinast) of anaesthetized open-chest New Zealand white rabbits (n = 24). Coronary blood flow (radioactive microspheres), arterial and venous O2 saturation (microspectrophotometry), O2 consumption, cyclic GMP content (competitive binding) and cyclic GMP-phosphodiesterase activity (conversion of 3H-cyclic GMP to 3H-GMP) were determined. 3. Agents were applied to a patch on the myocardial surface and did not cause significant haemodynamic changes, except for bradycardia in the vehicle and low dose group. 4. The total myocardial cyclic GMP-phosphodiesterase activity was 148 +/- 14 while the zaprinast (10 mumol/L) inhibitable activity averaged 63 +/- 8 pmol/mg protein per min. Cyclic GMP content was increased with increasing doses of zaprinast (vehicle, 4.308 +/- 0.349 pmol/g; low dose zaprinast, 4.803 +/- 0.279 and high dose zaprinast, 7.938 +/- 1.304 pmol/g). 5. Coronary blood flow was not different after treatment (198 +/- 11, 209 +/- 10 and 153 +/- 9 mL/min per 100 g for the vehicle, low and high dose zaprinast, respectively). 6. Under control conditions, 48% of the small veins had O2 saturations below 50%. With zaprinast, this value was reduced to 19% for the low and 24% for the high dose. 7. Average venous O2 saturation increased with zaprinast (49 +/- 2%, 61 +/- 3% and 59 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS)
Weiss
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HR
Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854.
Rodriguez
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Tse
J
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Scholz
P M
PM
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008863:Microspheres; D009206:Myocardium / Q000201:enzymology*; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011688:Purinones / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D013056:Spectrophotometry, Ultraviolet
D011688:Purinones; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C011145:zaprinast; D006152:Cyclic GMP; D010100:Oxygen