Role of cGMP-inhibited Phosphodiesterase and Sarcoplasmic Calcium in Mediating the Increase in Basal Heart Rate with Nitric Oxide Donors

doi:10.1006/jmcc.2000.1216

Journal of Molecular and Cellular Cardiology

Volume 32, Issue 10, October 2000, Pages 1831-1840

https://doi.org/10.1006/jmcc.2000.1216 Get rights and content

Abstract

Nitric oxide (NO) donors increase heart rate (HR) through a guanylyl cyclase-dependent stimulation of the pacemaker current I_f, without affecting basal I_Ca-L. The activity of I_fis known to be enhanced by cyclic nucleotides and by an increase in cytosolic Ca²⁺. We examined the role of cGMP-dependent signaling pathways and intracelluar Ca²⁺stores in mediating the positive chronotropic effect of NO donors. In isolated guinea pig atria, the increase in HR in response to 1–100 μ mol/l 3-morpholino-sydnonimine (SIN-1; with superoxide dismutase, n=6) or diethylamine-NO (DEA-NO, n=8) was significantly attenuated by blockers of the cGMP-inhibited phosphodiesterase (PDE3; trequinsin, milrinone or Ro-13-6438, n=22). In addition, the rate response to DEA-NO or sodium nitroprusside (SNP) was significantly reduced following inhibition of PKA (KT5720 or H-89,n =15) but not PKG (KT5728 or Rp-8-pCPT-cGMPs, n=16). Suppression of sarcoplasmic (SR) Ca²⁺release by pretreatment of isolated atria with ryanodine or cyclopiazonic acid (2 μ mol/l and 60 μ mol/l, n=16) significantly reduced the chronotropic response to 1–100 μ mol/l SIN-1 or DEA-NO. Moreover, in isolated guinea pig sinoatrial node cells 5 μ mol/l SNP significantly increased diastolic and peak Ca²⁺fluorescence (+13±1% and +28±1%,n =6, P<0.05). Our findings are consistent with a functionally significant role of cAMP/PKA signaling (via cGMP inhibition of PDE3) and SR Ca²⁺in mediating the positive chronotropic effect of NO donors.

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Regarding the HR, tachycardia can be seen at first moment as the baroreceptors unloading in response to the fall in the blood pressure. However, several studies revealed that low concentrations of NO donors could also increase the spontaneous beating rate by the direct stimulation of the hyperpolarization-activated pacemaker current (If) in sinoatrial nodal cells through a NO-sGC-cGMP- dependent pathway which increase the repolarization and diastolic depolarization rates [84–86]. Our results of cardiovascular parameters are similar to the findings of França-Silva and colleagues (2012) [45] which studied the NO donor NDBP, an isomer of NDIBP.
Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 μM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo–[4,3-a]quinoxalin-1-one (ODQ, 10 μM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 μM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K⁺ channels in vascular smooth muscle.
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In rabbit denervated hearts, NO donor increased HR by 10% (Hogan et al., 1999a), similar to what was observed in patients receiving intravenous infusion of NO donors, with blood pressure held constant (Hogan et al., 1999b). In SAN cells, NO-induced cGMP levels inhibit PDE3, increasing cAMP signaling and SR Ca2+ release, both responsible for the positive chronotropic response (Musialek et al., 2000). During β-AR stimulation, activation of the NO/cGMP pathway has a transient stimulatory effect that is If-dependent, and is limited in magnitude and duration by cGMP-stimulation of PDE2 (Herring et al., 2001).
The sinoatrial node (SAN) is the natural pacemaker of the heart, producing the electrical impulse that initiates every heart beat. Its activity is tightly controlled by the autonomic nervous system, and by circulating and locally released factors. Neurohumoral regulation of heart rate plays a crucial role in the integration of vital functions and influences behavior and ability to respond to changing environmental conditions. At the cellular level, modulation of SAN activity occurs through intracellular signaling pathways involving cyclic nucleotides: cyclic AMP (cAMP) and cyclic GMP (cGMP). In this Review, dedicated to Professor Dario DiFrancesco and his accomplishements in the field of cardiac pacemaking, we summarize all findings on the role of cyclic nucleotides signaling in regulating the key actors of cardiac automatism, and we provide an up-to-date review on cAMP- and cGMP-phosphodiesterases (PDEs), compellingly involved in this modulation.
Exogenous nitric oxide triggers classic ischemic preconditioning by preventing intracellular Ca<sup>2+</sup> overload in cardiomyocytes
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The involvement of nitric oxide (NO) in the late phase of ischemic preconditioning is well established. However, the role of NO as a trigger or mediator of “classic preconditioning” remains to be determined. The present study was designed to investigate the effects of NO on calcium homeostasis in cultured newborn rat cardiomyocytes in normoxia and hypoxia. We found that treatment with the NO donor, sodium nitroprusside (SNP) induced a sustained elevation of intracellular calcium level ([Ca²⁺]_i) followed by a decrease to control levels. Elevation of extracellular calcium, which generally occurs during ischemia, caused an immediate increase in [Ca²⁺]_i and arrhythmia in cultures of newborn cardiomyocytes. Treatment with SNP decreased [Ca²⁺]_i to control levels and re-established synchronized beating of cardiomyocytes. A decrease in extracellular [Na⁺], which inhibits the Na⁺/Ca²⁺ exchanger, did not prevent [Ca²⁺]_i reduction by SNP. In contrast, application of thapsigargin, an inhibitor of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a), increased [Ca²⁺]_i, and in its presence, SNP did not reduce [Ca²⁺]_i, indicating that Ca²⁺ reduction is achieved via activation of SERCA2a. The results obtained suggest that activation of SERCA2a by SNP increases Ca²⁺ uptake into the sarcoplasmic reticulum (SR) and prevents cytosolic Ca²⁺ overload, which might explain the protective effect of SNP from hypoxic damage.
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Effects of cGMP on cAMP Hydrolytic Activity—Our third objective was to examine the effect of cGMP on cAMP hydrolysis in subcellular fractions. Because cGMP is a competitive inhibitor of PDE3 activity, and because cGMP analogues and agents that raise cGMP content can raise intracellular cAMP content in cardiac myocytes (21, 28-30), our expectation was that cGMP would inhibit cAMP hydrolysis under different conditions to an extent that would reflect the contribution of PDE3 to total cAMP hydrolytic activity. We first examined the effects of 1.0 μm cGMP on rtPDE3A activity at different concentrations of cAMP in the absence or presence of Ca2+/calmodulin.
Three isoforms of PDE3 (cGMP-inhibited) cyclic nucleotide phosphodiesterase regulate cAMP content in different intracellular compartments of cardiac myocytes in response to different signals. We characterized the catalytic activity and inhibitor sensitivity of these isoforms by using recombinant proteins. We determined their contribution to cAMP hydrolysis in cytosolic and microsomal fractions of human myocardium at 0.1 and 1.0 μm cAMP in the absence and presence of Ca²⁺/calmodulin. We examined the effects of cGMP on cAMP hydrolysis in these fractions. PDE3A-136, PDE3A-118, and PDE3A-94 have similar K_m and k_cat values for cAMP and are equal in their sensitivities to inhibition by cGMP and cilostazol. In microsomes, PDE3A-136, PDE3A-118, and PDE3A-94 comprise the majority of cAMP hydrolytic activity under all conditions. In cytosolic fractions, PDE3A-118 and PDE3A-94 comprise >50% of the cAMP hydrolytic activity at 0.1 μm cAMP, in the absence of Ca²⁺/calmodulin. At 1.0 μm cAMP, in the presence of Ca²⁺/calmodulin, activation of Ca²⁺/calmodulin-activated (PDE1) and other non-PDE3 phosphodiesterases reduces their contribution to <20% of cAMP hydrolytic activity. cGMP inhibits cAMP hydrolysis in microsomal fractions by inhibiting PDE3 and in cytosolic fractions by inhibiting both PDE3 and PDE1. These findings indicate that the contribution of PDE3 isoforms to the regulation of cAMP hydrolysis in intracellular compartments of human myocardium and the effects of PDE3 inhibition on cAMP hydrolysis in these compartments are highly dependent on intracellular [Ca²⁺] and [cAMP], which are lower in failing hearts than in normal hearts. cGMP may amplify cAMP-mediated signaling in intracellular compartments of human myocardium by PDE3-dependent and PDE3-independent mechanisms.
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^☆: Please address all correspondence to: Piotr Musialek, MD, DPhil or Barbara Casadei, MD, DPhil, MRCP, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford OX3 9DU, UK. Fax: +44-1865-768844. E-mail: [email protected]; [email protected]

^☆☆: Parts of this work have been previously published in abstract form (Circulation 1997 96: I–357Eur Heart J 1999 20: 123 Circulation 1999 100: I–281 Heart 2000 83: I–P38).

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Regular ArticleRole of cGMP-inhibited Phosphodiesterase and Sarcoplasmic Calcium in Mediating the Increase in Basal Heart Rate with Nitric Oxide Donors☆,☆☆

Abstract

J Biol Chem

Cell Calcium

Biochem Biophys Res Commun

J Mol Cell Cardiol

J Biol Chem

Biochem Biophys Res Commun

Eur J Pharmacol

Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, If

Circ Res

Nitric oxide and cardiac pacemaking

DPhil Thesis. University of Oxford, Oxford, UK

The nitric oxide donor sodium nitroprusside increases heart rate in the absence of changes in arterial blood pressure when applied topically to the sino-atrial node in the anaesthetised pig

J Physiol Lond

Nitric oxide donors can increase heart rate independent of autonomic activation

J Appl Physiol

Effect of exogenous nitric oxide on baroreflex function in humans

Am J Physiol

Direct activation of cardiac pacemaker channels by intracellular cyclic AMP

Nature

A family of hyperpolarization-activated mammalian cation channels

Nature

Relationship between inhibition of cardiac muscle phosphodiesterases, changes in cyclic nucleotide levels, and contractile response for CI-914 and other novel cardiotonics

J Cyclic Nucl Prot Phosph Res

Intracellular cyclic GMP receptor proteins

FASEB J

The role of phosphorylation in the regulation of Ifin rabbit SA node myocytes. Abstract

Biophys J

Differential control of the hyperpolarization-activated current Ifby cAMP gating and phosphatase inhibition in rabbit sino-atrial node myocytes

J Physiol Lond

Modulation by intracellular Ca2+of the hyperpolarization-activated inward current in rabbit single sino-atrial node cells

J Physiol Lond

Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation

Science

Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes

Circ Res

Activation of distinct cAMP-dependent and cGMP-dependent pathways by nitric oxide in cardiac myocytes

Circ Res

Localization and functional significance of ryanodine receptors during beta-adrenoceptor stimulation in the guinea-pig sinoatrial node

Cardiovasc Res

The use of nitric oxide donors in pharmacological studies

Naunyn Schmiedebergs Arch Pharmacol

Regulation of the cardiac ryanodine receptor by protein kinase-dependent phosphorylation

J Biochem

Regular Article
Role of cGMP-inhibited Phosphodiesterase and Sarcoplasmic Calcium in Mediating the Increase in Basal Heart Rate with Nitric Oxide Donors☆,☆☆

Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, I_f

The role of phosphorylation in the regulation of I_fin rabbit SA node myocytes. Abstract

Differential control of the hyperpolarization-activated current I_fby cAMP gating and phosphatase inhibition in rabbit sino-atrial node myocytes

Modulation by intracellular Ca²⁺of the hyperpolarization-activated inward current in rabbit single sino-atrial node cells