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.
Department of Human Biology and Nutritional Sciences, University of Guelph, ON, Canada. sreading@uoguelph.ca
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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