Age-related pacemaker deterioration is due to impaired intracellular and membrane mechanisms: Insights from numerical modeling

Age-related deterioration of pacemaker function has been documented in mammals, including humans. In aged isolated sinoatrial node tissues and cells, reduction in the spontaneous action potential (AP) firing rate was associated with deterioration of intracellular and membrane mechanisms; however, their relative contribution to age-associated deficient pacemaker function is not known. Interestingly, pharmacological interventions that increase posttranslation modification signaling activities can restore the basal and maximal AP firing rate, but the identities of the protein targets responsible for AP firing rate restoration are not known. Here, we developed a numerical model that simulates the function of a single mouse pacemaker cell. In addition to describing membrane and intracellular mechanisms, the model includes descriptions of autonomic receptor activation pathways and posttranslation modification signaling cascades. The numerical model shows that age-related deterioration of pacemaker function is related to impaired intracellular and membrane mechanisms: HCN4, T-type channels, and phospholamban functions, as well as the node connecting these mechanisms, i.e., intracellular Ca2+ and posttranslation modification signaling. To explain the restored maximal beating rate in response to maximal phosphodiesterase (PDE) inhibition, autonomic receptor stimulation, or infused cyclic adenosine monophosphate (cAMP), the model predicts that phospholamban phosphorylation by protein kinase A (PKA) and HCN4 sensitivity to cAMP are altered in advanced age. Moreover, alteration in PKA and cAMP sensitivity can also explain age-reduced sensitivity to PDE inhibition and autonomic receptor stimulation. Finally, the numerical model suggests two pharmacological approaches and one gene manipulation method to restore the basal beating rate of aged pacemaker cells to that of normal adult cells. In conclusion, our numerical model shows that impaired membrane and intracellular mechanisms and the nodes that couple them can lead to deteriorated pacemaker function. By increasing posttranslation modification signaling, the deteriorated basal and maximal age-associated beating rate can be restored to adult levels.

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Age-related vulnerability to nigral dopaminergic degeneration in rats via Zn2+-permeable GluR2-lacking AMPA receptor activation

NeuroToxicology ◽

10.1016/j.neuro.2020.12.014 ◽

2021 ◽

Vol 83 ◽

pp. 69-76

Author(s):

Satoko Nakajima ◽

Nana Saeki ◽

Haruna Tamano ◽

Ryusuke Nishio ◽

Misa Katahira ◽

...

Keyword(s):

Ampa Receptor ◽

Receptor Activation ◽

Age Related ◽

Dopaminergic Degeneration

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ANG II AT2 receptor modulates AT1receptor-mediated descending vasa recta endothelial Ca2+ signaling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00317.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. H779-H789 ◽

Cited By ~ 23

Author(s):

Kristie Rhinehart ◽

Corey A. Handelsman ◽

Erik P. Silldorff ◽

Thomas L. Pallone

Keyword(s):

Receptor Agonist ◽

Calcium Concentration ◽

Cyclopiazonic Acid ◽

Receptor Activation ◽

Receptor Subtype ◽

Ang Ii ◽

Receptor Stimulation ◽

Vasa Recta ◽

Stimulation Of

We tested whether the respective angiotensin type 1 (AT1) and 2 (AT2) receptor subtype antagonists losartan and PD-123319 could block the descending vasa recta (DVR) endothelial intracellular calcium concentration ([Ca2+]i) suppression induced by ANG II. ANG II partially reversed the increase in [Ca2+]igenerated by cyclopiazonic acid (CPA; 10−5 M), acetylcholine (ACh; 10−5 M), or bradykinin (BK; 10−7 M). Losartan (10−5 M) blocked that effect. When vessels were treated with ANG II before stimulation with BK and ACh, concomitant AT2 receptor blockade with PD-123319 (10−8 M) augmented the suppression of endothelial [Ca2+]i responses. Similarly, preactivation with the AT2 receptor agonist CGP-42112A (10−8 M) prevented AT1 receptor stimulation with ANG II + PD-123319 from suppressing endothelial [Ca2+]i. In contrast to endothelial [Ca2+]i suppression by ANG II, pericyte [Ca2+]i exhibited typical peak and plateau [Ca2+]i responses that were blocked by losartan but not PD-123319. DVR vasoconstriction by ANG II was augmented when AT2 receptors were blocked with PD-123319. Similarly, AT2 receptor stimulation with CGP-42112A delayed the onset of ANG II-induced constriction. PD-123319 alone (10−5 M) showed no AT1-like action to constrict microperfused DVR or increase pericyte [Ca2+]i. We conclude that ANG II suppression of endothelial [Ca2+]i and stimulation of pericyte [Ca2+]i is mediated by AT1 or AT1-like receptors. Furthermore, AT2 receptor activation opposes ANG II-induced endothelial [Ca2+]i suppression and abrogates ANG II-induced DVR vasoconstriction.

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Intracellular mechanisms coupled to NPY Y2 and Y5 receptor activation and lipid accumulation in murine adipocytes

Neuropeptides ◽

10.1016/j.npep.2012.08.006 ◽

2012 ◽

Vol 46 (6) ◽

pp. 359-366 ◽

Cited By ~ 21

Author(s):

Joana Rosmaninho-Salgado ◽

Vera Cortez ◽

Marta Estrada ◽

Magda M. Santana ◽

Alexandra Gonçalves ◽

...

Keyword(s):

Lipid Accumulation ◽

Receptor Activation ◽

Intracellular Mechanisms

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Reversal of age-related oxidative stress prevents hippocampal synaptic plasticity deficits by protecting d-serine-dependent NMDA receptor activation

Aging Cell ◽

10.1111/j.1474-9726.2012.00792.x ◽

2012 ◽

Vol 11 (2) ◽

pp. 336-344 ◽

Cited By ~ 56

Author(s):

Coline Haxaire ◽

Fabrice R Turpin ◽

Brigitte Potier ◽

Myriam Kervern ◽

Pierre-Marie Sinet ◽

...

Keyword(s):

Oxidative Stress ◽

Synaptic Plasticity ◽

Nmda Receptor ◽

Receptor Activation ◽

Hippocampal Synaptic Plasticity ◽

Age Related ◽

Nmda Receptor Activation

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Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+signaling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00088.2014 ◽

2014 ◽

Vol 306 (10) ◽

pp. H1385-H1397 ◽

Cited By ~ 16

Author(s):

Jie Liu ◽

Syevda Sirenko ◽

Magdalena Juhaszova ◽

Steven J. Sollott ◽

Shweta Shukla ◽

...

Keyword(s):

Heart Rate ◽

Cell Function ◽

Ryanodine Receptors ◽

Phosphodiesterase Inhibitor ◽

Receptor Activation ◽

Functional Changes ◽

Adult Mice ◽

Size Number ◽

Pathway Activation ◽

Beating Rate

A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca2+clock, and the electrogenic-sarcolemmal membrane clock. Ca2+-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca2+signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na+/Ca2+exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20–24 mo) vs. adult (3–4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca2+load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca2+-cycling proteins, including SR Ca2+-ATPase pump, ryanodine receptors, and Na+/Ca2+exchanger. Thus a deterioration in intrinsic Ca2+clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca2+cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.

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Adrenergic activation of glycogen phosphorylase in primary culture diabetic cardiomyocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.262.3.h649 ◽

1992 ◽

Vol 262 (3) ◽

pp. H649-H653 ◽

Cited By ~ 3

Author(s):

J. A. Buczek-Thomas ◽

S. R. Jaspers ◽

T. B. Miller

Keyword(s):

Hypersensitive Response ◽

Adrenergic Receptor ◽

Glycogen Phosphorylase ◽

Receptor Activation ◽

Receptor Stimulation ◽

Beta Adrenergic ◽

Rat Cardiomyocytes ◽

Adult Rat ◽

Adrenergic Activation

The basis of catecholamine-induced activation of glycogen phosphorylase was investigated in adult rat cardiomyocytes isolated from normal and alloxan-diabetic animals. Cells derived from diabetic animals exhibited a hypersensitive response to epinephrine stimulation that was apparent 3 h after cell isolation and was further enhanced on maintenance of the myocytes in culture for 24 h. Normal cells initially lacked the hypersensitive response to epinephrine stimulation, although on maintenance of these cells in culture for 24 h, the hypersensitive response was acquired in vitro. To assess alpha- and beta-adrenergic mediation of the response, normal and diabetic cardiomyocytes were incubated with propranolol, a beta-blocker, before direct alpha 1-receptor stimulation with phenylephrine. Both normal and diabetic myocytes failed to undergo activation of phosphorylase in 3- or 24-h cell cultures. In addition, the effects of epinephrine on phosphorylase activation were completely inhibited by propranolol, whereas prazosin, an alpha-blocker, was unsuccessful. The present data suggest that the hypersensitive response of glycogen phosphorylase in normal and diabetic cardiomyocytes is solely mediated through beta-adrenergic receptor activation.

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Effects of renal receptor stimulation on neurons within the ventrolateral medulla of the cat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.2.r290 ◽

1993 ◽

Vol 265 (2) ◽

pp. R290-R301 ◽

Cited By ~ 2

Author(s):

M. A. Vizzard ◽

A. Standish ◽

W. S. Ammons

Keyword(s):

Renal Artery ◽

Renal Vein ◽

Receptor Activation ◽

Artery Occlusion ◽

Ventrolateral Medulla ◽

Receptor Stimulation ◽

Renal Artery Occlusion ◽

Renal Receptor ◽

Excitatory Responses ◽

Alpha Chloralose

Experiments were performed to determine if activation of renal receptors by occlusion of the renal artery, renal vein, or ureter would alter activity of cells within the ventrolateral medulla of the cat. Extracellular unit recordings were obtained from 195 cells located within the rostral ventrolateral medulla of 90 alpha-chloralose-anesthetized cats. Fifty-five of 195 cells (28.2%) tested for responses to renal receptor activation responded to at least one of the occlusions. Occlusion of the ureter increased the activity of 25 cells from 9.7 +/- 3.7 to 23.0 +/- 6.5 impulses/s and decreased the activity of 5 cells from 11.9 +/- 3.6 to 3.5 +/- 1.2 impulses/s. Occlusion of the renal vein increased the activity of seven cells from 7.5 +/- 3.3 to 22.3 +/- 7.3 impulses/s and decreased the activity of six cells from 13.8 +/- 3.8 to 4.1 +/- 2.0 impulses/s. Renal artery occlusion elicited solely excitatory responses from 43 cells. Thirty-one of the 43 cells increased their activity within 0-3 s of the onset of renal artery occlusion from 4.1 +/- 0.8 to 12.6 +/- 1.2 impulses/s. Renal artery occlusion increased the activity of 10 out of 43 cells with a mean latency of 26.1 +/- 6.5 s from 8.3 +/- 2.5 to 29.6 +/- 9.3 impulses/s. Twenty-four of the 55 (43.6%) responders were responsive to two or more forms of renal receptor activation. These results demonstrate that activation of renal mechanoreceptors and chemoreceptors affects cells within the ventrolateral medulla of the cat.(ABSTRACT TRUNCATED AT 250 WORDS)

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Perivascular Adipose Tissue-Enhanced Vasodilation in Metabolic Syndrome Rats by Apelin and N-Acetyl–l-Cysteine-Sensitive Factor(s)

International Journal of Molecular Sciences ◽

10.3390/ijms20010106 ◽

2018 ◽

Vol 20 (1) ◽

pp. 106 ◽

Cited By ~ 2

Author(s):

Satomi Kagota ◽

Kana Maruyama-Fumoto ◽

Saki Iwata ◽

Miho Shimari ◽

Shiori Koyanagi ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Mrna Level ◽

Receptor Activation ◽

At1 Receptor ◽

Mesenteric Arteries ◽

Mrna Levels ◽

Perivascular Adipose Tissue ◽

Age Related ◽

Sensitive Factor

Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N-acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF.

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Rapid accumulation and sustained turnover of inositol phosphates in cerebral-cortex slices after muscarinic-receptor stimulation

Biochemical Journal ◽

10.1042/bj2600237 ◽

1989 ◽

Vol 260 (1) ◽

pp. 237-241 ◽

Cited By ~ 14

Author(s):

I H Batty ◽

S R Nahorski

Keyword(s):

Cerebral Cortex ◽

Muscarinic Receptor ◽

Metabolic Flux ◽

Inositol Phosphates ◽

Inositol Phosphate ◽

Receptor Activation ◽

Inositol Polyphosphate ◽

Receptor Stimulation ◽

Cortex Slices ◽

Rapid Kinetics

The rapid kinetics of [3H]inositol phosphate accumulation and turnover were examined in rat cerebral-cortex slices after muscarinic-receptor stimulation. Markedly increased [3H]inositol polyphosphate concentrations were observed to precede significant stimulated accumulation of [3H]inositol monophosphate. New steady-state accumulations of several 3H-labelled products were achieved after 5-10 min of continued agonist stimulation, but were rapidly and effectively reversed by subsequent receptor blockade. The results show that muscarinic-receptor activation involves phosphoinositidase C-catalysed hydrolysis initially of polyphosphoinositides rather than of phosphatidylinositol. Furthermore, prolonged carbachol stimulation is shown not to cause receptor desensitization, but to allow persistent hydrolysis of [3H]phosphatidylinositol bisphosphate and permit sustained metabolic flux through the inositol tris-/tetrakis-phosphate pathway.

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