Regulation of cardiac Ca2+ channels by cGMP and NO

Fischmeister, Rodolphe; Méry, Pierre‐François

doi:10.1007/978-94-011-3990-8_9

Cited by 9 publications

(9 citation statements)

References 161 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the one hand, sildenafil might possess consid-erable affinity for PDEs V and III. On the other hand, an intracellular cGMP-dependent inhibition of PDE III resulting in increased myocardial cAMP (2,12) and consequently in increased cardiac performance might be a potential explanation. The inhibition of AMP breakdown by GMP has already been shown in a platelet cell model by Maurice and Haslam in 1990 (13).…”

Section: Discussionmentioning

confidence: 99%

“…By a complex mechanism, increased intracellular cGMP leads to the hyperpolarization of smooth-muscle membranes and subsequent vascular relaxation. Moreover, cGMP is involved in the regulation of myocardial L-type Ca 2 ϩ channel current (ICa): In guinea pig, frog, and human cardiomyocytes, cGMP can also stimulate ICa via inhibition of cGMP-inhibited cyclic adenosine monophosphate (cAMP) PDE (PDE III) (2), thus augmenting cardiac output. PDE isozyme types I, III, IV, and V are present in the human pulmonary artery (3).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Sildenafil Modulates Hemodynamics and Pulmonary Gas Exchange

Kleinsasser

Loeckinger

Hoermann

et al. 2001

Am J Respir Crit Care Med

View full text Add to dashboard Cite

The effects of sildenafil (Viagra) on hemodynamics and pulmonary gas exchange remain uncertain. The aim of this study was to investigate what effect sildenafil had on gas exchange. A total of 24 anesthetized pigs were randomly assigned into four groups of six animals each: Group Low received 25 mg of sildenafil, which is equivalent to half the recommended dose for humans; group Normal received 50 mg; group High received 100 mg; and one group served as control. Inert gas and hemodynamic measurements were performed to define dose-dependent effects of sildenafil on cardiac and pulmonary function. Measurements were taken 30, 60, and 90 min after the administration of sildenafil via gastric tube. All doses of sildenafil caused significant increases in intrapulmonary shunt flow (maximum amplitude, 4.4 +/- 0.3 to 11.9 +/- 0.5%; mean +/- SEM), which was reflected by marked decreases in PaO2. Sildenafil elicited some significant increases in cardiac index (CI) (high dose, 142 +/- 10 to 196 +/- 13 ml x kg(-1), mean +/- SEM). Mean arterial pressure was significantly depressed after the high dose of sildenafil. Pulmonary artery pressure was decreased after high-dose sildenafil (maximum amplitude, 16 +/- 1.6 to 14 +/- 1.8, mean +/- SEM). No significant differences between the three treatment groups were found. Sildenafil represents and orally active substance with phosphodiesterase V inhibitory and cardiac output-increasing actions. PaO2 decrease after 50 and 100 mg of sildenafil was observed in the presence of significant rises in pulmonary shunt flow and CI.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Sildenafil Modulates Hemodynamics and Pulmonary Gas Exchange

Kleinsasser

Loeckinger

Hoermann

et al. 2001

Am J Respir Crit Care Med

View full text Add to dashboard Cite

show abstract

“…The mechanism for the increase in cardiac output is unclear; this could be secondary to a reduction in right ventricular afterload, or to a myocardial effect of an increase in cGMP. cGMP has been previously shown in isolated preparations to inhibit myocardial cyclic-AMP breakdown by PDE-3, and thus could theoretically augment cardiac performance (17).…”

Section: Control Groupmentioning

confidence: 99%

Intravenous Sildenafil Lowers Pulmonary Vascular Resistance in a Model of Neonatal Pulmonary Hypertension

Shekerdemian

Ravn

Penny

2002

Am J Respir Crit Care Med

152

View full text Add to dashboard Cite

Persistent pulmonary hypertension secondary to meconium aspiration syndrome is an important cause of morbidity and mortality in the neonatal population. We investigated the use of the phosphodiesterase-5 inhibitor sildenafil, in its intravenous form, as a pulmonary vasodilator in a model of meconium aspiration syndrome. Pulmonary hypertension was induced in 18 piglets, by endotracheal instillation of human meconium, 6 piglets subsequently received an infusion of intravenous sildenafil for 2 hours, 6 received inhaled nitric oxide for 2 hours, and 6 control animals received no additional intervention. Meconium aspiration increased pulmonary vascular resistance by 70%, and increased oxygenation index by over 100%. Pulmonary vascular resistance remained elevated for the remainder of the study period in control animals. Inhaled nitric oxide reduced the pulmonary vascular resistance by 40% after 2 hours of treatment; intravenous sildenafil completely reversed the increase in pulmonary vascular resistance within 1 hour of commencing the infusion. Neither agent had an effect on systemic hemodynamics. Sildenafil also increased cardiac output by 30%, but while doing so did not adversely influence oxygenation. Intravenous sildenafil is a selective and highly effective pulmonary vasodilator, which is at least as effective as inhaled nitric oxide, in this model of neonatal persistent pulmonary hypertension.

show abstract

“…NO modulates cardiac contractility and rhythm in part via its ability to control the amplitude of I Ca (for reviews see Fischmeister & Méry, 1996; Kelly et al 1996; Kojda & Kottenberg, 1999; Paulus & Shah, 1999; Shah & MacCarthy, 2000). Classically, this regulation is mediated through the generation of cGMP by NO‐stimulated soluble guanylyl cyclase activity.…”

mentioning

confidence: 99%

Cyclic GMP regulation of the L‐type Ca²⁺ channel current in human atrial myocytes

Vandecasteele

Verde

Rücker‐Martin

et al. 2001

The Journal of Physiology

Self Cite

141

102

View full text Add to dashboard Cite

The regulation of the L‐type Ca2+ current (ICa) by intracellular cGMP was investigated in human atrial myocytes using the whole‐cell patch‐clamp technique. Intracellular application of 0.5 μm cGMP produced a strong stimulation of basal ICa (+64 ± 5%, n= 60), whereas a 10‐fold higher cGMP concentration induced a 2‐fold smaller increase (+36 ± 8%, n= 35). The biphasic response of ICa to cGMP was not mimicked by the cGMP‐dependent protein kinase (PKG) activator 8‐bromoguanosine 3′,5′ cyclic monophosphate (8‐bromo‐cGMP, 0.5 or 5 μm), and was not affected by the PKG inhibitor KT 5823 (100 nm). In contrast, cGMP stimulation of ICa was abolished by intracellular perfusion with PKI (10 μm), a selective inhibitor of the cAMP‐dependent protein kinase (PKA). Selective inhibition of the cGMP‐inhibited phosphodiesterase (PDE3) by extracellular cilostamide (100 nm) strongly enhanced basal ICa in control conditions (+78 ± 13%, n= 7) but had only a marginal effect in the presence of intracellular cGMP (+22 ± 7% in addition to 0.5 μm cGMP, n= 11; +20 ± 22% in addition to 5 μm cGMP, n= 7). Application of erythro‐9‐[2‐hydroxy‐3‐nonyl]adenine (EHNA, 30 μm), a selective inhibitor of the cGMP‐stimulated phosphodiesterase (PDE2), fully reversed the secondary inhibitory effect of 5 μm cGMP on ICa (+99 ± 16% stimulation, n= 7). Altogether, these data indicate that intracellular cGMP regulates basal ICa in human atrial myocytes in a similar manner to NO donors. The effect of cGMP involves modulation of the cAMP level and PKA activity via opposite actions of the nucleotide on PDE2 and PDE3.

show abstract

Regulation of cardiac Ca2+ channels by cGMP and NO

Cited by 9 publications

References 161 publications

Sildenafil Modulates Hemodynamics and Pulmonary Gas Exchange

Sildenafil Modulates Hemodynamics and Pulmonary Gas Exchange

Intravenous Sildenafil Lowers Pulmonary Vascular Resistance in a Model of Neonatal Pulmonary Hypertension

Cyclic GMP regulation of the L‐type Ca²⁺ channel current in human atrial myocytes

Contact Info

Product

Resources

About

Regulation of cardiac Ca2+ channels by cGMP and NO

Cited by 9 publications

References 161 publications

Sildenafil Modulates Hemodynamics and Pulmonary Gas Exchange

Sildenafil Modulates Hemodynamics and Pulmonary Gas Exchange

Intravenous Sildenafil Lowers Pulmonary Vascular Resistance in a Model of Neonatal Pulmonary Hypertension

Cyclic GMP regulation of the L‐type Ca2+ channel current in human atrial myocytes

Contact Info

Product

Resources

About

Cyclic GMP regulation of the L‐type Ca²⁺ channel current in human atrial myocytes