Original Article
Revisiting the slow force response: The role of the PKG signaling pathway in the normal and the ischemic heart
Resposta inotrópica tardia: o papel da via de sinalização da PKG no miocárdio normal e na isquemia)
Ricardo Castro-Ferreira1, João Sérgio Neves1, Ricardo Ladeiras-Lopes1, André M. Leite-Moreira, Manuel Neiva-Sousa, João Almeida-Coelho, João Ferreira-Martins, Adelino F. Leite-Moreira
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Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal
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Leite-Moreira, Manuel Neiva-Sousa, João Almeida-Coelho, João Ferreira-Martins, Adelino F. Leite-Moreira" "autores" => array:8 [ 0 => array:3 [ "nombre" => "Ricardo" "apellidos" => "Castro-Ferreira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn1" ] ] ] 1 => array:3 [ "nombre" => "João Sérgio" "apellidos" => "Neves" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn1" ] ] ] 2 => array:3 [ "nombre" => "Ricardo" "apellidos" => "Ladeiras-Lopes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn1" ] ] ] 3 => array:2 [ "nombre" => "André M." "apellidos" => "Leite-Moreira" ] 4 => array:2 [ "nombre" => "Manuel" "apellidos" => "Neiva-Sousa" ] 5 => array:2 [ "nombre" => "João" "apellidos" => "Almeida-Coelho" ] 6 => array:2 [ "nombre" => "João" "apellidos" => "Ferreira-Martins" ] 7 => array:4 [ "nombre" => "Adelino" "apellidos" => "F. Leite-Moreira" "email" => array:1 [ 0 => "amoreira@med.up.pt" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Resposta inotrópica tardia: o papel da via de sinalização da PKG no miocárdio normal e na isquemia)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3279 "Ancho" => 1617 "Tamanyo" => 159247 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Representative bands of the contractile response to acute stretch (upper images) in the control group (A) and Isch group (B) and schematic illustration of experimental protocols (bottom diagrams). Gray bar: stabilization period; white bar: presence of O<span class="elsevierStyleInf">2</span> and glucose; dark bar: absence of O<span class="elsevierStyleInf">2</span> and glucose (ischemia). AT: active tension.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0050" class="elsevierStylePara elsevierViewall">The heart is able to adapt continuously to ever-changing hemodynamic conditions. An acute hemodynamic overload, such as the beginning of aerobic exercise, increases venous return, eliciting myocardial stretch and an increase in end-diastolic volume (EDV) and pressure. The systolic arm of the response to myocardial stretch was first described over a century ago by Ernest Starling and Otto Frank,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–5</span></a> who discovered that increased EDV promotes an immediate increase in contractility and stroke volume, the Frank-Starling mechanism (FSM). After the initial response, there is a progressive and time-dependent increase in contractility, first described in 1912 by von Anrep<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and later explored by Parmley and Chuck in 1973.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In vivo, this mechanism allows the return of EDV to its initial value and is known as the von Anrep effect. Its in-vitro counterpart is known as the slow force response (SFR).</p><p id="par0055" class="elsevierStylePara elsevierViewall">The SFR is a consequence of an increase in magnitude of calcium transients, due to activation of the Na<span class="elsevierStyleSup">+</span>/H<span class="elsevierStyleSup">+</span> antiporter. This mechanism favors the reverse operating mode of the Na<span class="elsevierStyleSup">+</span>/Ca<span class="elsevierStyleSup">2+</span> antiporter, leading to an increase in intracellular calcium.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8–10</span></a> This phase of the myocardial response to stretch is known to be dependent on various signaling pathways and acutely modulated by various neurohumoral mediators.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9,11</span></a> Despite the importance of the PKG signaling pathway in cardiovascular homeostasis, its role in the SFR still mostly unexplored. Pharmacological modulation of this pathway, mostly by drugs that activate NO pathways (nitrates), is extremely common in ischemic heart disease and myocardial infarction. Recently, there has been considerable interest in the beneficial effects of phosphodiesterase 5 (PDE5) inhibitors in the treatment of acute myocardial ischemia.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> Myocardial ischemia promotes contractile dysfunction and acute hemodynamic overload, thereby leading to myocardial stretch. Therefore, discerning the influence of the PKG pathway on the contractile response to stretch under ischemic conditions and, particularly, its pharmacological modulation (by NO donors and PDE5 inhibitors) is central to more accurate treatment decisions.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Modulation of the PKG signaling pathway during acute myocardial stretch</span><p id="par0060" class="elsevierStylePara elsevierViewall">The effects of acute muscle stretch from 92 to 100% of maximum length (L<span class="elsevierStyleInf">max</span>) on contractile function of rabbit papillary muscles were assessed under basal conditions, in the absence (control group, n=8) or the presence of a cell-permeable PKG activator (8-bromo-cGMP, 10<span class="elsevierStyleSup">−6</span> M; PKGa group, n=7) and a PKG inhibitor (Rp-8-Br-PET-cGMPS, 10<span class="elsevierStyleSup">−6</span> M; PKGi group, n=7). These substances were dissolved in Krebs-Ringer solution and myocardial stretch was elicited 20 min later.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Modulation of the PKG signaling pathway during acute myocardial stretch under ischemic conditions</span><p id="par0065" class="elsevierStylePara elsevierViewall">In a second set of protocols, the contractile response to stretch was studied under ischemic conditions. After stabilization, the bathing solution was replaced by another without glucose and without O<span class="elsevierStyleInf">2</span> supply. After 5 min of ischemia, muscles were stretched from 92 to 100% of L<span class="elsevierStyleInf">max</span> (Isch group, n=8). Furthermore, to explore the influence of modulation of the PKG pathway on the systolic response to stretch during ischemia, the latter protocol was also performed in the presence of a PKG activator (8-bromo-cGMP, 10<span class="elsevierStyleSup">−6</span> M); Isch-PKGa group, n=7; (H) an NO donor (S-nitroso-N-acetyl-penicillamine (SNAP), 10<span class="elsevierStyleSup">−5</span> M; Isch-NO group, n=9) and (I) a PDE5 inhibitor (sildenafil, 10<span class="elsevierStyleSup">−6</span> M; Isch-PDE5i group, n=7). These drugs interfere with the NO/PKG pathway at different targets and allow better characterization of SFR modulation. Ischemia was maintained for 15 min. To confirm myocardial viability after the ischemic period, the muscles were reperfused with a glucose-containing Krebs-Ringer solution and O<span class="elsevierStyleInf">2</span> supply.</p><p id="par0070" class="elsevierStylePara elsevierViewall">A schematic representation of the protocols is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The doses were selected according to the literature data and our preliminary studies. All chemicals were obtained from Sigma-Aldrich (St. Louis, MO, USA).</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Values are means<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard error. Within the same group, the effects of acute muscle stretch on the various experimental parameters at specific time points were analyzed with a paired Student's t test. The time-dependent effects of muscle stretch within the same group were analyzed by repeated measures one-way ANOVA, while repeated measures two-way ANOVA was used to compare the time-dependent effects of muscle stretch between several groups. When significant differences were detected with any of the ANOVA tests, the Holm-Sidak method was used to perform multiple comparisons. A value of p<0.05 was accepted as significant.</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Basal pharmacological effects</span><p id="par0085" class="elsevierStylePara elsevierViewall">The muscles stabilized in the presence of the drug for 20 min, during which no significant variations in active tension were observed.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Contractile response to acute stretch in normal myocardium</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the control group, active tension (AT) at L<span class="elsevierStyleInf">max</span>, following stretch, was 23.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.8 mN/mm<span class="elsevierStyleSup">2</span>. In the following 15 min there was a progressive increase in AT to 29.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.3 mN/mm<span class="elsevierStyleSup">2</span> (p<0.001), corresponding to an SFR of 27.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.9%. A representative band of the contractile response of a muscle in the control group is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>A.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">PKG-mediated effects</span><p id="par0095" class="elsevierStylePara elsevierViewall">In the PKGa group no differences were found in SFR after 15 min (20.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>8.13% vs. 27.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.9%, p=0.324) (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>). On the other hand, myocardial stretch in the presence of the PKG inhibitor was associated with a significant attenuation of SFR (SFR at 15 min: 11.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>5.9% vs. 27.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.9% in controls, p=0.034) (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Adaptation of contractile function to myocardial stretch under ischemic conditions</span><p id="par0100" class="elsevierStylePara elsevierViewall">In the first 5 min of ischemia a significant decrease in myocardial contractility of 51.0<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.0% was seen (AT decreased from 20.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.1 mN/mm<span class="elsevierStyleSup">2</span> to 10.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.2 mN/mm<span class="elsevierStyleSup">2</span>, p<0.001). After stretch, muscles did not display SFR; instead, they exhibited a significant and progressive decrease in contractility (AT decreased from 12.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.3 mN/mm<span class="elsevierStyleSup">2</span> to 5.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.9 mN/mm<span class="elsevierStyleSup">2</span>, p<0.001) (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>). A representative band of a muscle of the Isch group is shown in the <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>B.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">NO-mediated effects under ischemic conditions</span><p id="par0105" class="elsevierStylePara elsevierViewall">The use of an NO donor did not significantly influence the myocardial response to acute stretch under ischemic conditions (AT variation after stretch: −27.7<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>15.2% in Isch-NO vs. −52.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.9% in Isch, p=0.229) (<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>).</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">PKG-mediated effects under ischemic conditions</span><p id="par0110" class="elsevierStylePara elsevierViewall">The decrease in contractility over the 15 min after stretch was not significantly different in the presence of the PKG activator compared to the Isch group (−34.9<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>18.2% vs. −52.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.9% in Isch, p=0.373) (<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>).</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">PDE5 inhibition under ischemic conditions</span><p id="par0115" class="elsevierStylePara elsevierViewall">In contrast to Isch-PKGa, PDE5 inhibition significantly prevented the decrease in contractility after stretch (−8.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>17.6% vs. −52.4<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.9% in Isch, p=0.018) (<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>).</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">The effect of ischemia on myocardial response to stretch</span><p id="par0120" class="elsevierStylePara elsevierViewall">Acute myocardial ischemia induces immediate contractile dysfunction, resulting in sudden hemodynamic overload. Hence, it is interesting to characterize the myocardial response to stretch under ischemic conditions. Despite its importance, there is limited knowledge about the effect of ischemia on the myocardial adaptation to stretch. We reported a reversed SFR in ischemic myocardium. This observation may be related to the profound changes in calcium sensitivity observed during ischemia.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> Other mechanisms contributing to this dysfunction may include the limited availability of adenosine triphosphate under ischemic conditions, which is known to cause an immediate increase in contractility<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and to promote the development of myocardial rigor due to impairment of sarcomere cross-bridge cycling.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17,18</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">PKG signaling pathways in the contractile response to stretch</span><p id="par0125" class="elsevierStylePara elsevierViewall">We describe some interesting results regarding the role of PKG in the myocardial response to stretch. Our work demonstrates that inhibition of PKG leads to reduced SFR, but activation does not affect this response. These results suggest a permissive role of the PKG signaling pathway in the normal SFR. These results can be explained by a dynamic interaction between PKG and PDE (<a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>). Under normal conditions, the basal concentration of cGMP in the human myocardium inhibits PDE3, thus preventing the hydrolysis of cAMP,<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19,20</span></a> the presence of which contributes to the normal SFR.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> We therefore hypothesize that removal of the basal PKG pathway increases the action of PDE3, reducing cAMP levels and thereby the SFR. Another possible mechanism linking PKG activity to the SFR is the troponin I (TnI) phosphorylation level. PKG is known to phosphorylate TnI at serine 23/24, increasing the cross-bridge cycling rate,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> which probably contributes to a more efficient SFR.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">One of the most intriguing results of our work is the observation that sildenafil, but neither 8-bromo-cGMP nor an NO donor significantly prevented the gradual decrease in contractility after acute stretch in ischemia. As the best-characterized action of sildenafil is PDE5 inhibition, preventing cGMP degradation, its effects would be expected to be similar to those of a cGMP analog. Interestingly, data published by Elrod et al.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> suggest a cardioprotective role for sildenafil, independent of its action on the NO/cGMP pathway. It is possible that the contractile preservation in ischemia induced by sildenafil is dependent on a still obscure effect of this molecule, independent of its action on PDE5.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Our findings in the rabbit myocardium should be extrapolated to other species with caution. The known intracellular mechanisms of the SFR depend on the animal species under consideration.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,25,26</span></a> However, the increase in calcium transients due to activation of the Na<span class="elsevierStyleSup">+</span>/H<span class="elsevierStyleSup">+</span> exchanger and reverse operating mode of the Na<span class="elsevierStyleSup">+</span>/Ca<span class="elsevierStyleSup">2+</span> exchanger seems to be angiotensin-II independent in both rabbit and human myocardium, depending on acute mechanical stretch alone.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,26</span></a> In this way, it is probably easier to extrapolate the findings of this work to the human myocardium than to the other commonly used animal models such as cat, rat, and mouse.</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusions and potential therapeutic implications</span><p id="par0140" class="elsevierStylePara elsevierViewall">In this work, we evaluated the contractile adaptation to acute stretch in the presence of modulators of PKG signaling pathways, crucial therapeutic weapons in ischemic heart disease and myocardial infarction. From a clinical perspective, we showed that the well-known protective effect of nitrates during an ischemic insult is not associated with further contractile deterioration in response to the hemodynamic overload that typically occurs during cardiac ischemia. We also described an interesting and previously unknown protective effect of sildenafil on the contractile function of the heart following stretch in ischemic conditions. We can thus conjecture that patients chronically using this PDE5 inhibitor may exhibit a better cardiac performance during an ischemic heart event.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Ethical disclosures</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Protection of human and animal subjects</span><p id="par0145" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Confidentiality of data</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Right to privacy and informed consent</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article.</p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflicts of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres373494" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec352593" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres373495" "titulo" => array:5 [ 0 => "Resumo" 1 => "Introdução" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusões" ] ] 3 => array:2 [ "identificador" => "xpalclavsec352594" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Modulation of the PKG signaling pathway during acute myocardial stretch" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Modulation of the PKG signaling pathway during acute myocardial stretch under ischemic conditions" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Basal pharmacological effects" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Contractile response to acute stretch in normal myocardium" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "PKG-mediated effects" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Adaptation of contractile function to myocardial stretch under ischemic conditions" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "NO-mediated effects under ischemic conditions" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "PKG-mediated effects under ischemic conditions" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "PDE5 inhibition under ischemic conditions" ] ] ] 7 => array:3 [ "identificador" => "sec0070" "titulo" => "Discussion" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "The effect of ischemia on myocardial response to stretch" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "PKG signaling pathways in the contractile response to stretch" ] ] ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusions and potential therapeutic implications" ] 9 => array:3 [ "identificador" => "sec0090" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0105" "titulo" => "Right to privacy and informed consent" ] ] ] 10 => array:2 [ "identificador" => "sec0110" "titulo" => "Conflicts of interest" ] 11 => array:2 [ "identificador" => "xack95241" "titulo" => "Acknowledgment" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-06-04" "fechaAceptado" => "2014-03-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec352593" "palabras" => array:5 [ 0 => "Cyclic GMP-dependent protein kinase type I" 1 => "Nitric oxide" 2 => "Phosphodiesterase 5 inhibitors" 3 => "Myocardial ischemia" 4 => "Cardiovascular physiology" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec352594" "palabras" => array:5 [ 0 => "Proteína cínase dependente do GMP cíclico tipo 1" 1 => "Óxido nítrico" 2 => "Inibidores da fosfodiesterase 5" 3 => "Isquemia miocárdica" 4 => "Fisiologia cardiovascular" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The myocardial response to acute stretch consists of a two-phase increase in contractility: an acute increase by the Frank-Starling mechanism and a gradual and time-dependent increase in force generated known as the slow force response (SFR). The SFR is actively modulated by different signaling pathways, but the role of protein kinase G (PKG) signaling is unknown. In this study we aim to characterize the role of the PKG signaling pathway in the SFR under normal and ischemic conditions.</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Rabbit papillary muscles were stretched from 92 to 100% of maximum length (L<span class="elsevierStyleInf">max</span>) under basal conditions, in the absence (1) or presence of: a PKG agonist (2) and a PKG inhibitor (3); under ischemic conditions in the absence (4) or presence of: a PKG agonist (5); a nitric oxide (NO) donor (6) and a phosphodiesterase 5 (PDE5) inhibitor (7).</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Under normoxia, the SFR was significantly attenuated by inhibition of PKG and remained unaltered with PKG activation. Ischemia induced a progressive decrease in myocardial contractility after stretch. Neither the PKG agonist nor the NO donor altered the myocardial response to stretch under ischemic conditions. However, the use of a PDE5 inhibitor in ischemia partially reversed the progressive deterioration in contractility.</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">PKG activity is essential for the SFR. During ischemia, a progressive decline in the force is observed in response to acute myocardial stretch. This dysfunctional response can be partially reversed by the use of PDE5 inhibitors.</p>" ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introdução</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A resposta ao estiramento agudo do miocárdio consiste num aumento bifásico da contractilidade: um aumento agudo pelo mecanismo de Frank-Starling e um aumento gradual denominado resposta inotrópica tardia (SFR). A SFR é modulável por diferentes vias de sinalização, no entanto, o papel da via da Proteína Cínase G (PKG) permanece desconhecido. Assim, no presente estudo, pretendemos caracterizar o papel da via de sinalização da PKG na SFR em condições normais e em condições isquémicas.</p> <span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Músculos papilares de coelho foram estirados de 92 para 100% de <span class="elsevierStyleItalic">L</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">max</span></span> em condições basais, na ausência (1) ou na presença de: um agonista da PKG (2) e um inibidor da PKG (3); em condições isquémicas, na ausência (4) ou na presença de: um agonista da PKG (5), um dador de óxido nítrico (NO) (6) e um inibidor da fosfodiesterase 5 (PDE5) (7).</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Em condições basais, a SFR foi significativamente atenuada pela inibição da PKG, não tendo sido alterada pela ativação da PKG. A isquemia induziu uma diminuição progressiva da contratilidade após o estiramento agudo. Esta resposta não foi alterada pela adição de agonista da PKG nem pelo uso de um dador de NO. No entanto, o uso de um inibidor da PDE5 durante a isquemia foi capaz de reverter parcialmente a deterioração progressiva da contractilidade.</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusões</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A atividade da PKG é essencial para a SFR. Durante a isquemia observa-se uma diminuição progressiva da contratilidade em resposta ao estiramento agudo. Esta resposta disfuncional pode ser revertida pelo uso de inibidores da PDE5.</p>" ] ] "NotaPie" => array:2 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">These authors equally contributed to this article.</p>" "identificador" => "fn1" ] 1 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Supported by the Portuguese Foundation for Science and Technology Grants PEst-C/SAU/UI0051/2011 and EXCL/BIM-MEC/0055/2012 through the Cardiovascular R&D Unit and by European Commission Grant FP7-Health-2010; MEDIA-261409.</p>" ] ] "nomenclatura" => array:1 [ 0 => array:3 [ "identificador" => "nom0005" "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0065">List of abbreviations</span>" "listaDefinicion" => array:1 [ 0 => array:1 [ "definicion" => array:9 [ 0 => array:2 [ "termino" => "AT" "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">active tension</p>" ] 1 => array:2 [ "termino" => "cGMP" "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">cyclic guanosine monophosphate</p>" ] 2 => array:2 [ "termino" => "EDV" "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">end-diastolic volume</p>" ] 3 => array:2 [ "termino" => "FSM" "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">Frank-Starling mechanism</p>" ] 4 => array:2 [ "termino" => "NO" "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">nitric oxide</p>" ] 5 => array:2 [ "termino" => "PDE" "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">phosphodiesterase</p>" ] 6 => array:2 [ "termino" => "PKG" "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">protein kinase G</p>" ] 7 => array:2 [ "termino" => "SFR" "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">slow force response</p>" ] 8 => array:2 [ "termino" => "TnI" "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">troponin I</p>" ] ] ] ] ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3279 "Ancho" => 1617 "Tamanyo" => 159247 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Representative bands of the contractile response to acute stretch (upper images) in the control group (A) and Isch group (B) and schematic illustration of experimental protocols (bottom diagrams). Gray bar: stabilization period; white bar: presence of O<span class="elsevierStyleInf">2</span> and glucose; dark bar: absence of O<span class="elsevierStyleInf">2</span> and glucose (ischemia). AT: active tension.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1415 "Ancho" => 2429 "Tamanyo" => 137543 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Modulation of the SFR by PKG under normoxia. The SFR was impaired in the PKGi group. *p<0.05 vs. control. AT: active tension.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1217 "Ancho" => 1390 "Tamanyo" => 44306 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Modulation of the SFR by ischemia. In the Isch group, muscles did not display SFR; instead, they exhibited a significant and progressive decrease in contractility during the 15 min after stretch. *p<0.05 vs. control. AT: active tension.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1663 "Ancho" => 2897 "Tamanyo" => 184113 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Contractile response to acute myocardial stretch under ischemic conditions. Isch-PDE5i demonstrated a significantly attenuated AT decline after stretch. *p<0.05 vs. Isch. AT: active tension.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1371 "Ancho" => 1664 "Tamanyo" => 102606 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Role of the PKG signaling pathway in the normal SFR. The pathway appears to have a permissive role in the SFR, probably through phosphorylation of TnI at serine 23/24 and through inhibition of PDE3.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The influence of variations in temperature and blood-pressure on the performance of the isolated mammalian heart" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F.P. Knowlton" 1 => "E.H. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 9 | 9 | 18 |
| 2024 Outubro | 50 | 31 | 81 |
| 2024 Setembro | 57 | 23 | 80 |
| 2024 Agosto | 55 | 30 | 85 |
| 2024 Julho | 55 | 41 | 96 |
| 2024 Junho | 45 | 29 | 74 |
| 2024 Maio | 55 | 27 | 82 |
| 2024 Abril | 51 | 29 | 80 |
| 2024 Maro | 60 | 21 | 81 |
| 2024 Fevereiro | 48 | 39 | 87 |
| 2024 Janeiro | 41 | 31 | 72 |
| 2023 Dezembro | 36 | 21 | 57 |
| 2023 Novembro | 29 | 20 | 49 |
| 2023 Outubro | 34 | 15 | 49 |
| 2023 Setembro | 32 | 21 | 53 |
| 2023 Agosto | 25 | 20 | 45 |
| 2023 Julho | 29 | 10 | 39 |
| 2023 Junho | 33 | 15 | 48 |
| 2023 Maio | 51 | 16 | 67 |
| 2023 Abril | 29 | 4 | 33 |
| 2023 Maro | 51 | 31 | 82 |
| 2023 Fevereiro | 39 | 16 | 55 |
| 2023 Janeiro | 36 | 10 | 46 |
| 2022 Dezembro | 31 | 41 | 72 |
| 2022 Novembro | 44 | 22 | 66 |
| 2022 Outubro | 28 | 18 | 46 |
| 2022 Setembro | 39 | 37 | 76 |
| 2022 Agosto | 42 | 64 | 106 |
| 2022 Julho | 44 | 28 | 72 |
| 2022 Junho | 39 | 22 | 61 |
| 2022 Maio | 54 | 43 | 97 |
| 2022 Abril | 41 | 22 | 63 |
| 2022 Maro | 33 | 32 | 65 |
| 2022 Fevereiro | 36 | 18 | 54 |
| 2022 Janeiro | 35 | 34 | 69 |
| 2021 Dezembro | 29 | 37 | 66 |
| 2021 Novembro | 47 | 38 | 85 |
| 2021 Outubro | 43 | 42 | 85 |
| 2021 Setembro | 40 | 37 | 77 |
| 2021 Agosto | 30 | 31 | 61 |
| 2021 Julho | 31 | 28 | 59 |
| 2021 Junho | 34 | 19 | 53 |
| 2021 Maio | 47 | 37 | 84 |
| 2021 Abril | 42 | 32 | 74 |
| 2021 Maro | 79 | 23 | 102 |
| 2021 Fevereiro | 86 | 14 | 100 |
| 2021 Janeiro | 125 | 17 | 142 |
| 2020 Dezembro | 52 | 5 | 57 |
| 2020 Novembro | 75 | 16 | 91 |
| 2020 Outubro | 48 | 4 | 52 |
| 2020 Setembro | 63 | 14 | 77 |
| 2020 Agosto | 27 | 6 | 33 |
| 2020 Julho | 50 | 9 | 59 |
| 2020 Junho | 39 | 5 | 44 |
| 2020 Maio | 37 | 0 | 37 |
| 2020 Abril | 36 | 8 | 44 |
| 2020 Maro | 41 | 7 | 48 |
| 2020 Fevereiro | 187 | 11 | 198 |
| 2020 Janeiro | 31 | 5 | 36 |
| 2019 Dezembro | 60 | 5 | 65 |
| 2019 Novembro | 31 | 4 | 35 |
| 2019 Outubro | 25 | 4 | 29 |
| 2019 Setembro | 53 | 6 | 59 |
| 2019 Agosto | 37 | 7 | 44 |
| 2019 Julho | 38 | 12 | 50 |
| 2019 Junho | 42 | 9 | 51 |
| 2019 Maio | 46 | 9 | 55 |
| 2019 Abril | 45 | 19 | 64 |
| 2019 Maro | 100 | 12 | 112 |
| 2019 Fevereiro | 108 | 11 | 119 |
| 2019 Janeiro | 77 | 3 | 80 |
| 2018 Dezembro | 72 | 10 | 82 |
| 2018 Novembro | 94 | 12 | 106 |
| 2018 Outubro | 234 | 25 | 259 |
| 2018 Setembro | 54 | 11 | 65 |
| 2018 Agosto | 33 | 15 | 48 |
| 2018 Julho | 23 | 5 | 28 |
| 2018 Junho | 46 | 6 | 52 |
| 2018 Maio | 49 | 10 | 59 |
| 2018 Abril | 62 | 3 | 65 |
| 2018 Maro | 57 | 8 | 65 |
| 2018 Fevereiro | 31 | 7 | 38 |
| 2018 Janeiro | 40 | 8 | 48 |
| 2017 Dezembro | 61 | 16 | 77 |
| 2017 Novembro | 63 | 14 | 77 |
| 2017 Outubro | 44 | 12 | 56 |
| 2017 Setembro | 37 | 14 | 51 |
| 2017 Agosto | 44 | 11 | 55 |
| 2017 Julho | 36 | 9 | 45 |
| 2017 Junho | 63 | 24 | 87 |
| 2017 Maio | 43 | 19 | 62 |
| 2017 Abril | 44 | 3 | 47 |
| 2017 Maro | 29 | 20 | 49 |
| 2017 Fevereiro | 24 | 8 | 32 |
| 2017 Janeiro | 21 | 7 | 28 |
| 2016 Dezembro | 30 | 12 | 42 |
| 2016 Novembro | 46 | 16 | 62 |
| 2016 Outubro | 32 | 11 | 43 |
| 2016 Setembro | 20 | 7 | 27 |
| 2016 Agosto | 20 | 0 | 20 |
| 2016 Julho | 6 | 3 | 9 |
| 2016 Junho | 7 | 5 | 12 |
| 2016 Maio | 18 | 6 | 24 |
| 2016 Abril | 25 | 2 | 27 |
| 2016 Maro | 35 | 10 | 45 |
| 2016 Fevereiro | 43 | 20 | 63 |
| 2016 Janeiro | 43 | 13 | 56 |
| 2015 Dezembro | 48 | 10 | 58 |
| 2015 Novembro | 42 | 16 | 58 |
| 2015 Outubro | 36 | 13 | 49 |
| 2015 Setembro | 42 | 9 | 51 |
| 2015 Agosto | 48 | 13 | 61 |
| 2015 Julho | 23 | 5 | 28 |
| 2015 Junho | 19 | 4 | 23 |
| 2015 Maio | 50 | 15 | 65 |
| 2015 Abril | 43 | 7 | 50 |
| 2015 Maro | 40 | 8 | 48 |
| 2015 Fevereiro | 40 | 6 | 46 |
| 2015 Janeiro | 31 | 13 | 44 |
| 2014 Dezembro | 34 | 9 | 43 |
| 2014 Novembro | 51 | 17 | 68 |
| 2014 Outubro | 132 | 88 | 220 |
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