Nitric Oxide Reduces Myocardial Contractility in Isoproterenol-Stimulated Rat Hearts by a Mechanism Independent of Cyclic GMP or Cyclic AMP

Abstract

Nitric oxide has been shown to decrease myocardial contractility and O₂ consumption. This study was designed to evaluate the hypothesis that nitric oxide-mediated increases in cyclic GMP require elevated cyclic AMP to produce cardiac depression. Using isolated, Langendorff-perfused rat hearts, we determined the effects of intracoronary nitroprusside (NP, 1 and 10 mM) in the absence and presence of isoproterenol (ISO, 10^–8 M) on cardiac function, O₂ consumption, cyclic GMP and cyclic AMP. ISO, with and without NP, increased cyclic AMP (from 287 ± 21 to 477 ± 33 pmol/g) without altering cyclic GMP. Left-ventricular pressure increased from 97 ± 12 to 178 ± 9 mmHg and dP/dt_maxfrom 1,786 ± 275 to 4,049 ± 354 mm Hg/s. NP increased cyclic GMP (from 4 to 30 pmol/g) in both the absence and presence of ISO, but NP did not alter cyclic AMP. Without ISO, NP insignificantly altered left-ventricular pressure; however, in the presence of ISO, NP significantly decreased left-ventricular pressure by –25 ± 4 mm Hg and decreased dP/dt_max by –619 ± 142 mm Hg/s. Isoproterenol increased O₂ consumption, but the changes with NP were not significant. When this study was repeated in the presence of LY83583, a guanylate cyclase inhibitor, NP still produced cardiac depression in the presence of ISO. Therefore, cardiodepressant effects of NP were only observed against a background of inotropic stimulation with ISO. However, effects of NP on contractility were unrelated to increases in cyclic GMP or cyclic GMP-induced changes in cyclic AMP.

Different sensitivity of isoprenaline‐induced responses in ventricular muscle to sodium nitroprusside in normotensive and spontaneously hypertensive rats 1

“…This assumption is supported by the fact that 8-Br-cGMP, a known permeable and structural cGMP analogue, produced an inhibition of the contractile response elicited by isoprenaline only in WKY rat strips. Although NO may regulate cardiac contraction in a cGMP-dependent (Kelly et al, 1996;Balligand & Cannon, 1997) or independent manner (Weiss, Sadoff, Scholz & Klabunde, 1997), our results suggest that, in our experimental conditions, NO modulates negatively the isoprenaline-induced positive inotropic effect in strips from WKY rats through guanylyl cyclase activation and generation of cGMP. Increases in intracellular cGMP may activate cGMP-dependent protein kinases, which decrease calcium current through regulation of L-type calcium channels (Mery et al, 1991;Wahler & Dollinger, 1995) or decrease cardiac myofilament sensitivity to calcium through phosphorylation of troponin I Gauthier et al, 1998), and cGMP-stimulated phosphodiesterases (Beavo, 1995), which decrease cAMP levels (Mery et al, 1993).…”

“…The physiological relevance of the endogenous NO on myocardial contractility regulation has repeatedly been a matter of controversy. Although it is likely that NO generation per se does not alter cardiodynamics (Weyrich et al, 1994), there is increasingly emerging evidence that endogenous NO mediates the myocardial contractile response to various other agents (Joe et al, 1998;Kotchi et al, 1998;Weiss et al, 1997;Ebihara & Karamzyn, 1996;Flesch et al, 1997). In this way, a recent study has demonstrated that NO as well as guanylate cyclase inhibitors attenuate b-adrenoceptor-mediated cardiac responses supporting the concept that NO serves as an endogenous regulator of b-adrenoceptor-mediated effects of catecholamines in the heart (Ebihara & Karamzyn, 1996).…”

Pravastatin Reduces Myocardial Infarct Size Via Increasing Protein Kinase C-Dependent Nitric Oxide, Decreasing Oxyradicals and Opening the Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channels in Rabbits

“…On the other hand, there are reports that NO has a cardiodepressive action after ischemia -reperfusion. 29,30 However, whether NO acts as a cardiodepressant agent or as a cardioprotective agent depends on the level of oxidative stress in the myocardium. Because NO has an extremely high affinity for superoxide radicals, it rapidly lose its biological activity through reaction with them.…”

Simvastatin reduces myocardial infarct size via increased nitric oxide production in normocholesterolemic rabbits

“…NO has been reported to mediate both early-and latephase ischemic preconditioning in rabbits [6,21], suggesting that NO is a common mediator of simvastatin's effect and ischemic preconditioning to reduce infarct size. Although multiple reports have demonstrated that NO has a cardiodepressive action after ischemia-reperfusion [22,23], whether NO functions as a cardiodepressant or cardioprotective agent depends on the level of oxidative stress in the myocardium. If the increased production of NO is balanced by a similar increase in oxygen radical formation, NO will exert beneficial effects.…”