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PubMed1999

The role of calcium in the response of cardiac muscle to stretch.

This review focuses on the complex interactions between two major regulators of cardiac function; Ca2+ and stretch. Initial consideration is given to the effect of stretch on myocardial contractility and details the rapid and slow increases in contractility. These are shown to be related to two diverse changes in Ca2+ handling (enhanced myofilament Ca2+ sensitivity and increased intracellular Ca2+ transient, respectively). Interaction between stretch and Ca2+ is also demonstrated with respect to the rhythm of cardiac contraction. Stretch has been shown to alter action potential configuration, generate stretch-activated arrhythmias, and increase the rate of beating of the sino-atrial node. A variety of Ca(2+)-dependent mechanisms including attenuation of Ca2+ extrusion via Na+/Ca2+ exchange, Ca2+ entry through stretch-activated channels (SACs) and mobilisation of intracellular Ca2+ stores have been proposed to account for the effect of stretch on rhythm. Finally, the interaction between stretch and Ca2+ in the secretion of natriuretic peptides and onset of hypertrophy is discussed. Evidence is presented that Ca2+ (entering through L-type Ca2+ channels or SACs, or released from sarcoplasmic reticular stores) influences secretion of both atrial and B-type natriuretic peptide; there is data to support both positive and negative modulation by Ca2+. Ca2+ also appears to be important in the pathway that leads to expression of precursors of hypertrophic protein synthesis. In conclusion, two of the major regulators of cardiac muscle function, Ca2+ and stretch, interact to produce effects on the heart; in general these effects appear to be additive.

Action Potentials↗
PubMed2000

Suitability of process-based tree growth models for addressing tree response to climate change.

Empirical models of tree growth have been used for many years to predict timber yields and other properties of trees. However, such models rely on measured relationships between tree growth and historic environmental conditions. As anthropogenic actions alter the environment, especially atmospheric composition, empirical models become less reliable and process-based models become more useful. Process-based models are challenged to simulate growth of structurally and physiologically complex organisms using explicit mathematical expressions to capture growth response to environmental conditions. In this review we summarize the physiological requirements of process-based models and examine the capabilities of six published models (CARBON, ECOPHYS, PGSM, TREE-BGC, TREGRO, W91) for simulating tree response to changes in environmental conditions (elevated temperature, increased CO(2) concentration, and enhanced concentrations of tropospheric ozone). These analyses indicate that current models are reliable integrators of environmental effects on individual processes (e.g. photosynthesis), but may be less reliable where physiological acclimation occurs or when extrapolated to growth of specific tree compartments.

Journal Article↗
PubMed1999

[3H]ethylketocyclazocine binding to brain opioid receptor subtypes in alcohol-preferring AA and alcohol-avoiding ANA rats.

We measured brain regional patterns of [3H]ethylketocyclazocine binding to brain opioid receptors in ethanol-naive alcohol-preferring Alko, Alcohol (AA) and alcohol-avoiding Alko, Non-Alcohol (ANA) rats, by using quantitative autoradiography. This agonist ligand labels all opioid receptor subtypes. The proportions of mu- and delta-opioid receptor binding were evaluated by displacing the mu- and delta-opioid receptor components by the peptides Tyr-D-Ala-Gly-N(Me)Phe-Gly-ol (DAMGO, 100 nM) and Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE, 100nM), respectively, the K-component being the naltrexone-sensitive binding left after removal of the above two components. The labeling patterns in the brains of the AA and ANA rats were consistent with the well-known distributions of the opioid receptor subtypes in nonselected rat strains and there was no major difference between the lines. The mu-opioid receptor binding was greater in the AA than ANA rats in several brain regions, most interestingly in the substantia nigra pars reticulata and striatal clusters with elevated shell/core ratios in the nucleus accumbens. The delta-opioid receptor binding did not differ between the lines, whereas the AA rats had more K-opioid receptors than the ANA rats in several brain regions, including limbic areas and basal ganglia. The observed results might indicate altered action of the opioidergic system on dopaminergic pathways in rats with differential alcohol preference.

Alcohol Drinking↗
PubMed1997

Magnesium: effects on reperfusion arrhythmias and membrane potential in isolated rat hearts.

The effects of Mg2+ concentration (Mg2+o, 0, 1.2, 2.4, and 4.8 mM) on the incidence of reperfusion arrhythmias and on the cellular electrical activity were studied in spontaneously beating rat hearts. The surface electrogram and the membrane potential were recorded in control conditions, during 10 min of regional ischemia (ligature of the left anterior descending coronary artery), and on reflow. Changes in Mg2+o did not alter action potential morphology but the depolarization induced by ischemia decreased with increasing Mg2+o. In hearts perfused with Mg2+ free solution or 1.2 mM subthreshold delayed afterdepolarizations (DADs) were often detected during ischemia. Moreover, DADs could be identified as initial events in the production of extrabeats or tachycardia appearing on reperfusion under these conditions. Chaotic electrical activity during fibrillation precluded the observation of DADs. The overall incidence (100%) and severity of ventricular tachyarrhythmias (80% tachycardia and fibrillation) was similar in both groups. At high Mg2+o, subthreshold DADs were occasionally observed during ischemia and often on reperfusion where they did not lead to the development of overt arrhythmias. Consequently, the incidence, severity, and duration of arrhythmic episodes on reflow was markedly reduced. Raising Mg2+ only on reperfusion did not prevent the development of arrhythmias, whose morphology in the intracellular recordings was similar to that found in hearts perfused without Mg2+ or with 1.2 mM. The recovery of sinus rhythm after 10 min of reperfusion was linearly related to Mg2+o. Our data strengthen the view that reperfusion arrhythmias belong to the Ca2+ mediated non reentrant type and suggest that Mg2+ counteracts these arrhythmias by depressing cytosolic Ca2+ oscillations. Besides, it appears that raising Mg2+o reduces ischemic K+o accumulation. The resulting changes in resting potential could contribute to lower DADs amplitude and thus decrease the arrhythmogenic potential of the Ca2+i oscillations induced by reperfusion.

Animals↗
PubMed1994

"If only I weren't" versus "if only I hadn't": distinguishing shame and guilt in counterfactual thinking.

The role of counterfactual thinking in 2 emotions--shame and guilt--was examined. In 1 series of studies, Ss read about situations evocative of shame and guilt or described personal experiences of guilt or shame. They then generated counterfactual alternatives to "undo" the distressing outcomes. Consistent with predictions derived from Tangney (1991), Ss tended to undo shame situations by altering qualities of the self and to undo guilt situations by altering actions. In a 2nd series of studies, Ss imagined themselves in a situation that could evoke either guilt or shame. Ss were then led to mutate the self or behavior to undo the situation. Mutation manipulations amplified shame and guilt such that the former Ss anticipated feeling greater shame, whereas the latter anticipated feeling greater guilt. The role of counterfactual thinking in specific emotions and in differentiating shame- and guilt-prone personalities is discussed.

Adaptation, Psychological↗
PubMed2003

Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents.

The neuroactive steroid allopregnanolone is a potent gamma-aminobutyric acid type A (GABA(A)) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.

Adrenalectomy↗
PubMed2005

Topography of methylphenidate (ritalin)-induced gene regulation in the striatum: differential effects on c-fos, substance P and opioid peptides.

Dopamine action alters gene regulation in striatal neurons. Methylphenidate increases extracellular levels of dopamine. We investigated the effects of acute methylphenidate treatment on gene expression in the striatum of adult rats. Molecular changes were mapped in 23 striatal sectors mostly defined by their predominant cortical inputs in order to determine the functional domains affected. Acute administration of 5 and 10 mg/kg (i.p.) of methylphenidate produced robust increases in the expression of the transcription factor c-fos and the neuropeptide substance P. Borderline effects were found with 2 mg/kg, but not with 0.5 mg/kg. For 5 mg/kg, c-fos mRNA levels peaked at 40 min and returned to baseline by 3 h after injection, while substance P mRNA levels peaked at 40-60 min and were back near control levels by 24 h. These molecular changes occurred in most sectors of the caudate-putamen, but were maximal in dorsal sectors that receive sensorimotor and medial agranular cortical inputs, on middle to caudal levels. In rostral and ventral striatal sectors, changes in c-fos and substance P expression were weaker or absent. No effects were seen in the nucleus accumbens, with the exception of c-fos induction in the lateral part of the shell. In contrast to c-fos and substance P, acute methylphenidate treatment had minimal effects on the opioid peptides dynorphin and enkephalin. These results demonstrate that acute methylphenidate alters the expression of c-fos and substance P preferentially in the sensorimotor striatum. These molecular changes are similar, but not identical, to those produced by other psychostimulants.

Animals↗
PubMed2025

Next-generation sequencing in breast cancer: current clinical applications and future directions.

INTRODUCTION: Breast cancer is a heterogeneous disease that claims 670,000 lives by 2022. Omic technologies, particularly next generation sequencing (NGS) offers promising avenues for precision medicine. American Society of Clinical Oncology (ASCO) outlines genomic testing's utility, emphasizing prognostic and diagnostic potential. OBJECTIVES: This review succinctly explores NGS's evolution and clinical applications of NGS in breast cancer, thereby guiding future research to enhance patient care. METHODS: Comprehensive literature searches were conducted using databases such as PubMed, Google Scholar, and ResearchGate, focusing on keywords including breast cancer, HER-2 low breast cancer, circulating tumour DNA, single-cell RNA sequencing, and next-generation sequencing. Peer-reviewed, high-quality articles published in English were selected for inclusion. RESULTS: Previous studies have explored the evolution of NGS technology and its clinical applications in breast cancer, including genomic and transcriptomic characterization, treatment guidance, and resistance prediction. Molecular profiling of challenging entities such as early-onset breast cancer and HER-2 low tumours was summarized, with key findings highlighted. This review also discusses emerging technologies, including circulating DNA and single-cell sequencing, as promising avenues for discovery. CONCLUSION: NGS has revealed the genomic and transcriptomic diversity of breast cancer, identifying actionable alterations associated with chemotherapy response and resistance to therapies such as trastuzumab, TKIs, and CDK4/6 inhibitors. Circulating tumour DNA (ctDNA) shows potential for diagnosis, prediction, prognosis, and monitoring, despite tumour heterogeneity. Single-cell analysis enables exploration of individual cell transcriptomes, though high costs and low throughput remain barriers to widespread adoption. HER2-low tumours continue to pose significant research challenges.

Humans↗
PubMed2026

Liquid biopsy for biliary tract cancer: available evidence and future research directions.

INTRODUCTION: Biliary tract cancers (BTCs) are molecularly heterogeneous, and early genomic profiling is becoming increasingly important for treatment decisions. Because tissue sampling is often limited or inadequate, there is a clear need for minimally invasive biomarkers that can support treatment selection and longitudinal disease assessment. AREAS COVERED: This narrative review summarizes current and emerging liquid-biopsy (LB) applications in BTC, with a primary focus on plasma circulating tumor DNA (ctDNA). The evidence base was assembled through targeted searches of PubMed/MEDLINE and Embase up to 1 February 2026, supported by selective ClinicalTrials.gov searches for ongoing biomarker-driven studies. We discuss ctDNA-based molecular profiling for actionable alterations, its prognostic role including minimal residual disease assessment, and its use in serial monitoring of treatment response and acquired resistance. We also consider how LB may support clinical-trial enrichment and biomarker-guided endpoints, and briefly review complementary approaches using bile and other analytes, while highlighting current evidence gaps. EXPERT OPINION: In BTC, ctDNA is best viewed as a complement to tissue-based profiling, especially when tissue is inadequate or when rapid genotyping is needed. Its broader clinical impact will depend on assay standardization, clearer interpretation frameworks for low-shedding disease, and prospective studies showing that ctDNA-guided decisions improve patient outcomes.

Humans↗
PubMed2005

Effects of caloric restriction and growth hormone resistance on the expression level of peroxisome proliferator-activated receptors superfamily in liver of normal and long-lived growth hormone receptor/binding protein knockout mice.

Growth hormone receptor/binding protein knockout (GHR-KO) mice live approximately 40% longer than their normal siblings do. These mice have dramatically reduced plasma levels of insulin-like growth factor 1 (IGF1) and enhanced insulin sensitivity. We examined the expression level of peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors family genes in the livers of normal and GHR-KO mice fed ad libitum or subjected to long-term 30% caloric restriction (CR). The levels of PPARgamma and PPARalpha messenger RNA and proteins and the levels of retinoid X receptors messenger RNA were elevated in long-lived GHR-KO mice as compared to normal mice with no major effect of CR in either genotype. These findings suggest that enhanced insulin sensitivity of GHR-KO mice may be related to the altered actions of PPARs family members in the liver. The results also indicate that CR may increase insulin sensitivity through a different mechanism.

Animals↗
PubMed2026

Matched targeted therapy use after broad genomic profiling in advanced Non-Small cell lung cancer.

INTRODUCTION: While broad genomic profiling is increasingly used in advanced NSCLC (aNSCLC), the impact of test results on subsequent guideline-concordant targeted therapy selection remains incompletely understood. METHODS: Using a merged dataset of two large, nationwide, patient-level databases, we identified patients who were diagnosed with aNSCLC 2017-2023, had potentially actionable genomic profiling findings, and initiated systemic therapy. Patients were categorized into actionability subgroups based on contemporaneous regulatory approvals and NCCN guideline recommendations. Within each subgroup, we assessed receipt of guideline-concordant targeted therapy within 24 months, including potential underuse (non-receipt of recommended treatment) and overuse (receipt of non-recommended treatment). RESULTS: Among 6620 patients (67.4% ≥65 years, 54.6% female, 68.9% White), guideline-concordant targeted therapy use varied substantially by actionability category: 2313 (89.6%) of 2582 patients with available 1st-line on-label options received them (10.4% underuse), while 212 (67.3%) of 315 patients with available later-line on-label options received them after 1st-line (32.7% underuse). Among 441 patients with available guideline-concordant off-label options, only 122 (27.7%) received them (72.3% underuse). Conversely, 238 (8.6%) of 3282 patients received matched but guideline-discordant off-label options, representing overuse of ineffective or unestablished therapies. Smoking history, squamous histology, and high PD-L1 expression were associated with lower targeted therapy receipt. CONCLUSIONS: In this cohort study of aNSCLC care, the guideline concordance of targeted therapy use varied by clinical actionability of molecular testing results. Underuse was more common in patients with later-line and off-label targeted therapy options. Patients with classical smoking-related risk profiles were substantially less likely to receive targeted therapy even when actionable alterations were identified.

Journal Article↗
PubMedDate not supplied

Electrophysiological and antiarrhythmic properties of propafenon in isolated cardiac preparations.

Propafenon, a new antiarrhythmic drug, caused a 30% decrease in maximal driving frequency and a 65 ms net increase in functional refractory period of isolated guinea pig atria at a concentration as low as 0.5 microgram/ml. The spontaneous rate of isolated atria and the contractility of electrically driven ventricular strips were reduced after treatment with propafenon 1 microgram/ml. Propafenon 0.5 microgram/ml also altered action potentials of sheep Purkinje fiber. It reduced the action potential and overshoot amplitudes, decreased the maximum rate of depolarization of the action potential upstroke in a frequency-dependent fashion, shortened the action potential and effective refractory period, and depressed the membrane responsiveness. Moreover, propafenon antagonized the chronotropic and inotropic effects of isoprenaline in isolated guinea pig heart preparations; the pA2 value was about 6.4. Finally, propafenon possessed very weak calcium antagonist properties, being about 100 times less potent than verapamil in this respect. We conclude that propafenon is an antiarrhythmic drug with beta-adrenoceptor blocking and "membrane stabilizing" activities in the same range of concentrations and that it has a calcium antagonistic activity only at much higher concentrations.

Action Potentials↗
PubMed1991

Troponin I is encoded in the haplolethal region of the Shaker gene complex of Drosophila.

We have analyzed one of the nine complementation groups that constitute the haplolethal (HL) region of the Shaker gene complex (ShC). Five mutations, including a dominant lethal, define this complementation group: HL I. Mutant phenotypes show abnormal embryogenesis with structural defects in the nervous system and aberrant degeneration of specific adult muscles in addition to altered action potentials. HL I encodes a family of proteins with extensive homology to invertebrate troponin I (TnI). Members of this family are brought about by two alternative and two mutually exclusive exons in conjunction with two differential polyadenylation sites. Transcription analysis indicates that some isoforms are adult specific and others are synthesized throughout development, except during early metamorphosis. Certain isoforms of Drosophila TnI are expressed in specific muscles. The specificity of mutant phenotypes suggests a functional role of particular TnI isoforms in the development and the mature activity of muscle and nervous systems.

Amino Acid Sequence↗
PubMed1990

The 'calcium sensitising' effects of ORG30029 in saponin- or Triton-skinned rat cardiac muscle.

1. The effects of a range of concentrations of ORG30029 (1 microM to 1 mM) were investigated on fully (Triton-treated) or selectively (saponin-treated) 'skinned' ventricle trabeculae from rat. The Ca-sensitivity was increased by 100 microM and amounted to a mean reduction in the Ca2+ necessary for half-maximal activation (1/Kapp) of 0.174 +/- 0.053 (mean +/- s.e.mean) pCa units. ORG30029 (50 microM) gave a smaller mean shift of 0.05 +/- 0.016 pCa units. A slight shallowing of the relationship between -log[Ca2+] (pCa) and steady-state tension was also generally found (mean Hill exponent reduction 0.37 +/- 0.28 at 100 microM). 2. The Ca-sensitizing action altered in a dose-dependent fashion. Judged by the ability to enhance force from an initial level of activation of 10-20% of maximum Ca-activated force (Cmax), the first significant effects occurred near 10 microM and continued to increase at 1 mM. 3. A small (3.7 +/- 1.1%) but consistent increase in Cmax was produced by ORG30029 at 100 microM. Much larger increases were produced by the drug at higher concentrations (up to 20-50% at 1 mM). 4. The consequence of these changes is that at levels of activation likely to occur in the heart, the absolute increase in force by 100 microM ORG30029 was considerable: it amounted to a 150-200% increase at a [Ca2+] producing 20% at Cmax. At this drug concentration virtually all the effect was due to Ca-sensitizing rather than increasing Cmax. 5. In the saponin-treated preparations, at concentrations up to 1 mM, ORG30029 did not release Ca from the sarcoplasmic reticulum, as indicated by the failure to evoke contracture under conditions where caffeine induced large responses. 6. At 100 microM, ORG30029 potentiated the transient, caffeine-induced contracture (saponin-treated preparation) to an extent consistent with the Ca-sensitizing effect seen under conditions of steady-state tension development.

Animals↗
PubMed2000

PACAP peptides modulate guinea pig cardiac neuron membrane excitability and neuropeptide expression.

Morphological studies identified PACAP-immunoreactive nerve fibers in dense pericellular arrangements around virtually every cholinergic parasympathetic neuron of guinea pig cardiac ganglia; all postganglionic cardiac neurons expressed membrane-associated PAC1 receptor protein. Characterization of the alternative splice variants established predominant expression of the PAC1(very short) receptor transcript containing neither HIP nor HOP exons. PACAP depolarized cardiac neurons and increased membrane excitability; the excitability resulted from neither altered action potential properties nor inhibition of IM. Treatment of cardiac ganglia explants with PACAP significantly reduced the numbers of cholinergic neurons coexpressing somatostatin immunoreactivity, which did not appear to be correlated with prosomatostatin mRNA expression. The PACAP-mediated decrease in somatostatin immunoreactive neurons required calcium influx through L-type calcium channels and activation of adenylyl cyclase, whereas activation of phospholipase C or protein kinase A was not required. These observations indicate that PACAP through the PAC1 receptors elicits complex actions on guinea pig parasympathetic cardiac ganglia neurons, including modulation of membrane ion conductances and modulation of neuropeptide expression.

Animals↗
PubMed1991

Effects of putative modulators of relaxation microinjected into intact amphibian smooth muscle cells.

1. Single smooth muscle cells were isolated intact from the stomach of the toad Bufo marinus. The relaxation of cells following cessation of electrical stimulation was compared with those relaxed by pressure microinjection of either metal ion chelators or cyclic nucleotides. 2. Injection of either a Ca2+ chelator or 3',5'-cyclic AMP slowed or halted shortening and promoted re-extension of a cell or collapse of membrane evaginations (blebs) in a manner similar to that following cessation of electrical stimulation. Collapse of blebs occurred first and was then followed smoothly by the next stage with cells re-extending at maximum rates in one of three ranges at 22 degrees C. These rates, in order of increasing speed, were 0.005, 0.009 and 0.03 cell lengths s-1 after electrical stimulation, 3',5'-cyclic AMP and EDTA injection, respectively. On the other hand, shortening began at a maximum rate of about 0.1 cell lengths s-1 unless a Ca2+ chelator or 3',5'-cyclic AMP was injected about 30 s or less before electrical stimulation. Injection of these agents reduced the speed of shortening by about half. 3. Injection of a liquid per se (e.g. 140 mM-KCl) neither altered action potentials nor duplicated the changes produced by the aforementioned relaxing agents. Large, sustained injections of substances that were not relaxing agents (e.g. dilute KCl) ruptured the membrane without producing any bleb collapse or re-extension of a contracted cell. Blebs not only collapsed rapidly when a relaxing agent was injected but bleb collapse was a much more sensitive indication of relaxation than cell re-extension; small injections of relaxing agents could clearly collapse blebs with no associated measurable change in cell length. This supports the idea previously inferred from fixed or permeabilized cells, that filaments in smooth muscle are organized to produce force over short distances at points along the cell membrane, in addition to shortening along the long axis. 4. Physiological relaxation of smooth muscle can evidently be mimicked by 3',5'-cyclic AMP elevation. Restoring forces may develop during shortening of isolated smooth muscle cells in elements of their cytoskeleton, surface membrane, or contractile filaments. However, these putative forces may not be able to produce physiological re-extension in the absence of a rise in cyclic AMP and/or a fall in [Ca2+].

Animals↗
PubMed2002

Modulation of noradrenaline-induced vasoconstriction in isolated perfused mesenteric arterial beds from obese Zucker rats in the presence and absence of insulin.

The genetically obese Zucker rat (fa/fa) is an insulin-resistant animal model with early-onset severe hyperinsulinemia that eventually develops mild hypertension. Thus, it represents a model in which the effect of hyperinsulinemia - insulin resistance associated with hypertension on vascular reactivity can be examined. The purpose of this study was to investigate the contribution of endogenous nitric oxide (NO) and prostaglandins to reactivity to noradrenaline (NA) in the presence and absence of insulin in mesenteric arterial beds (MAB) from 25-week-old obese Zucker rats and their lean, gender-matched littermates. In the absence of insulin, bolus injection of NA (0.9-90 nmol) produced a dose-dependent increase in perfusion pressure in MAB from both lean and obese rats. Although there was no significant difference in NA pD2 (-log ED50) values, the maximum response of MAB from obese rats to NA was slightly but significantly reduced compared with that of MAB from lean rats. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 300 microM) enhanced and indomethacin (20 microM) inhibited pressor responses to NA in MAB from both obese and lean rats. Perfusion with insulin (200 mU/L, a level similar to that in obese rats in vivo) potentiated only the responses of the obese MAB to the two lowest doses of NA tested (0.9 and 3 nmol). In the presence of L-NMMA, insulin further potentiated the NA response in MAB from obese rats. Indomethacin, the prostaglandin H2/thromboxane A2 receptor antagonist SQ 29548 (0.3 microM), and the nonselective endothelin-1 (ET-1) receptor antagonist bosentan (3 microM) all abolished insulin potentiation of the NA response in obese MAB. These data suggest that concurrent release of NO and vasoconstrictor cyclooxygenase product(s) in MAB from both obese and lean Zucker rats normally regulates NA-induced vasoconstrictor responses. Furthermore, insulin increases the release of contracting cyclooxygenase product(s) and enhances reactivity to low doses of NA in MAB from obese rats. The effects of insulin may be partially mediated by ET-1 via ET receptors and are buffered to some extent by concomitant NO release. This altered action of insulin may play a role in hypertension in this hyperinsulinemic - insulin-resistant model.

Animals↗
PubMed1994

Intracellular calcium concentrations during metabolic inhibition in the motoneuron cell line NSC-19.

Changes in the concentrations of intracellular free calcium ([Ca2+]i) and adenine nucleotides were determined in response to metabolic inhibitors in the motoneuron cell line NSC-19. The NADH dehydrogenase inhibitor amobarbital (Amytal) and the mitochondrial uncoupler carbonylcyanide m-chlorophenylhydrazone (CCCP) were used to alter energy metabolism. Exposure of cells to 5 mM Amytal did not significantly change ATP concentrations but produced transient elevations of [Ca2+]i of approximately 80 nM, which were reduced by 32% when cells were studied in Ca(2+)-free solutions. CCCP (10 microM) caused a transient reduction in ATP concentration of 33%. CCCP also produced sustained elevations of [Ca2+]i of about 280 nM, which were reduced by 47% when in Ca(2+)-free solutions. In spite of the sustained elevation of [Ca2+]i induced by CCCP, NSC-19 showed no reduction in cell viability after 48 h compared with controls. Ruthenium red, a blocker of Ca2+ uptake by mitochondria, had little effect on the CCCP-induced [Ca2+]i increment. KCl or glutamate did not produce significant changes in [Ca2+]i, indicating that these cells do not possess significant numbers of voltage-dependent Ca2+ channels or excitatory amino acid receptor-gated channels. [Ca2+]i values in these cells were modified by changes in extracellular Ca2+ concentrations. In Ca(2+)-containing solutions, inhibition of Na+/Ca2+ exchange by amiloride and bepridil led to increased [Ca2+]i, as did blockade of Ca2+ ATPase by vanadate, suggesting that membrane transporters are important in Ca2+ efflux in NSC-19. The present studies indicate that exposure of NSC-19 cells to Amytal and CCCP produces Ca2+ increments by release from internal stores, as well as by transmembrane influx. These results demonstrate that small increments in [Ca2+]i can be produced by metabolic inhibitors or other compounds and that such changes are not associated with immediate cell death. Changes in [Ca2+]i could potentially result in abnormal cell function secondary to altered action of Ca(2+)-dependent enzymes.

Adenine Nucleotides↗