The inotropic effect of nitric oxide on mammalian papillary muscle is dependent on the level of beta1-adrenergic stimulation.
We tested the hypothesis that nitric oxide has a positive inotropic effect on mammalian cardiac muscle contractility and that this effect sums with the positive inotropic effect of beta1-adrenergic agonists when both are present. Feline right ventricular papillary muscles were stimulated to contract isometrically at 0.2 Hz in Krebs-Henseleit bicarbonate buffer (KREBS) gassed with 95% O2 and 5% CO2 (26 degrees C; pH 7.34). The nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP, 10(-5) M), and the membrane permeable cGMP analog 8-bromoguanosine-3',5'-cyclophosphate sodium (Br-cGMP, 10(-5) M), significantly increased developed force by 13.3+/-1.5% (n = 11) and 7.8+/-2.8% (n = 7), respectively. SNAP, at 10(-5) M, significantly increased the force developed by papillary muscle treated with 10(-11) M or 10(-9) M dobutamine hydrochloride (a beta1-adrenergic agonist) (n = 25, 11.3+/-2.9% and 10.0+/-3.6%, respectively) when compared with the addition of KREBS (n = 27, 2.6+/-0.9% and 5.5+/-0.9%), but the increase was less than predicted by the sum of inotropic effects of SNAP and dobutamine. SNAP at 10(-5) M did not change developed force in muscles treated with 10(-7) M dobutamine but it significantly decreased developed force in muscles challenged with 10(-5) M dobutamine (n = 18, 29.3+/-5.0%) when compared with KREBS (n = 10, 41.5+/-6.8%). Similarly, 10(-4) M 8-bromo-adenosine cyclic 3',5'-hydrogen phosphate monosodium (a membrane permeable cAMP analog) increased developed force 14.9+/-3.3% and the addition of 10(-5) M Br-cGMP to those muscles significantly reduced developed force by 3.5%+/-1.1% (n = 7). Thus, the positive inotropic effect of NO decreased and ultimately became an attenuation as the level of beta1-adrenergic stimulation increased due at least in part, to an interaction between the cAMP and cGMP second messenger pathways.
Reading
S A
SA
Department of Human Biology and Nutritional Sciences, University of Guelph, ON, Canada. sreading@uoguelph.ca
Barclay
J K
JK
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002415:Cats; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D004280:Dobutamine; D026423:S-Nitroso-N-Acetylpenicillamine; D006152:Cyclic GMP