Tubuloglomerular feedback responses during peritubular infusions of calcium channel blockers

1990 ◽  
Vol 258 (3) ◽  
pp. F537-F544 ◽  
Author(s):  
K. D. Mitchell ◽  
L. G. Navar
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Macula Densa ◽  
Tubuloglomerular Feedback ◽  
Calcium Flux ◽  
Channel Blockers ◽  
Peritubular Capillary ◽  
Arterial Blood ◽  
Feedback Responses

Experiments were performed in pentobarbital-anesthetized rats to evaluate the dependence of the effector limb of the tubuloglomerular feedback mechanism on transmembrane calcium flux through potential-operated calcium channels. Peritubular capillary infusions of the calcium channel blockers, verapamil and nifedipine, were used to achieve high intrarenal levels without influencing arterial blood pressure. Proximal tubule stop-flow pressure (SFP) and single-nephron glomerular filtration rate (SNGFR) tubuloglomerular feedback responses were obtained during control conditions and during simultaneous peritubular capillary infusion with an isotonic saline solution containing either verapamil or nifedipine. Infusion of either 10(-3) M verapamil or 10(-3) M nifedipine, at a rate of 20 nl/min, increased resting SFP (measured during conditions of zero distal volume delivery) and markedly attenuated both the SFP and SNGFR feedback responses to a late proximal perfusion rate of 30 nl/min. Infusion of verapamil (10(-3) M) also increased the slope of the relationship between SFP and renal arterial perfusion pressure between 80 and 120 mmHg (0.43 +/- 0.03 vs 0.24 +/- 0.02, P less than 0.001, n = 10). These findings support the hypothesis that the preglomerular contractile elements responsive to signals from the macula densa cells are activated by calcium influx through potential-operated calcium channels. Furthermore, the preglomerular contractile elements sensitive to calcium channel blockers can dilate further even when orthograde flow to a single macula densa segment is interrupted.

scholarly journals Voltage-gated calcium channel blockers for psychiatric disorders: genomic reappraisal

2019 ◽  
Vol 216 (5) ◽  
pp. 250-253 ◽  
Author(s):  
Paul J. Harrison ◽  
Elizabeth M. Tunbridge ◽  
Annette C. Dolphin ◽  
Jeremy Hall
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Psychiatric Disorders ◽  
Calcium Channel Blockers ◽  
Channel Blockers ◽  
Risk Genes ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Calcium Channel ◽  
Second Use

SummaryWe reappraise the psychiatric potential of calcium channel blockers (CCBs). First, voltage-gated calcium channels are risk genes for several disorders. Second, use of CCBs is associated with altered psychiatric risks and outcomes. Third, research shows there is an opportunity for brain-selective CCBs, which are better suited to psychiatric indications.

scholarly journals A Systematic Review on 1, 4-Dihydropyridines and its Analogues: An Elite Scaffold

2021 ◽  
Vol 12 (3) ◽  
pp. 3117-3134
Keyword(s):  
Myocardial Infarction ◽  
Systematic Review ◽  
Clinical Trials ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Calcium Influx ◽  
Channel Blockers ◽  
Neuroprotective Effects ◽  
Dihydropyridine Derivatives

1,4-Dihydropyridines are a group of pyridine-based molecules possessing a magnificent set of biological and therapeutic potentials. Belonging to the class of calcium channel blockers, they are known to be effective in the conditions, angina, hypertension, myocardial infarction and show vasodilatory and cardiac depressant effects. Hypotensive, antimicrobial, anticancer, anticoagulant, antioxidant, anticonvulsant, antimalarial, antiulcer, and neuroprotective effects have been reported with their rational use. The effects are precipitated in response to inhibition of calcium channels, gradually restricting calcium influx. Drugs like nifedipine, felodipine, and amlodipine are commonly used clinically. Several other drugs belonging to this class have been under clinical trials. The present review focuses on the various 1,4-dihydropyridine derivatives and their pharmacological actions.

Effects of calcium channel blockers on “dynamic” and “steady-state step” renal autoregulation

2004 ◽  
Vol 286 (6) ◽  
pp. F1136-F1143 ◽  
Author(s):  
Karen A. Griffin ◽  
Rifat Hacioglu ◽  
Isam Abu-Amarah ◽  
Rodger Loutzenhiser ◽  
Geoffrey A. Williamson ◽  
...  
Keyword(s):  
Steady State ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Beat Frequency ◽  
Resonance Peak ◽  
Tubuloglomerular Feedback ◽  
Channel Blockers ◽  
Control Mechanisms ◽  
Sprague Dawley ◽  
Renal Autoregulation

Renal autoregulation (AR) mechanisms provide the primary protection against transmission of systemic pressures and hypertensive renal damage. However, the relative merits of the “step” change vs. “dynamic” methods for the assessment of AR capacity remain controversial. The effects of 48–72 h of orally administered amlodipine (L-type) and mibefradil (T-type) calcium channel blockers (CCBs) on step and dynamic AR in Sprague-Dawley rats were compared. Both CCBs significantly impaired “steady-state step” AR (autoregulatory indexes = ∼0.5 vs. ∼0.1 in controls, P < 0.05; n = 9–10/group). By contrast, dynamic AR compensation in separate conscious rats ( n = 12) was not significantly altered by either amlodipine ( n = 10) or mibefradil ( n = 6; fractional gain in admittance ∼0.4–0.5 in all groups at frequencies in the range of 0.0025–0.025 Hz). However, both CCBs tended to attenuate the myogenic resonance peak along with shifting it to a significantly slower frequency ( P < 0.001) during dynamic AR, but no consistent effects were observed on the tubuloglomerular feedback resonance peak. While the reasons for the insensitivity of dynamic vs. steady-state step AR capacity estimates to CCBs remain to be established, the present data indicate that dynamic AR methods may have a limited utility for assessing AR capacity but may provide potentially important insights into the operational characteristics of AR control mechanisms. A strong correlation was also observed between the average conductance and the admittance gain at the heart beat frequency ( r = 0.77, P < 0.001), suggesting that such parameters may provide additional and possibly more meaningful indexes of BP transmission in conscious animals during dynamic AR.

scholarly journals Metal-Ion Transporter SLC39A14 Is Required for Cardiac Iron Loading in the Hjv Mouse Model of Iron Overload

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 758-758
Author(s):  
Qingli Liu ◽  
Corbin Azucenas ◽  
Bryan Mackenzie ◽  
Mitchell Knutson
Keyword(s):  
Calcium Channels ◽  
Iron Overload ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Knockout Mice ◽  
Iron Uptake ◽  
Nonheme Iron ◽  
Channel Blockers ◽  
Iron Loading ◽  
Cardiac Iron

Abstract Although iron overload-related cardiomyopathy is a leading cause of morbidity and mortality in iron-overload disorders (e.g., thalassemia major and hemochromatosis), the molecular mechanisms that mediate cardiac iron uptake and accumulation are incompletely understood. Previous studies using Slc39a14 knockout mice have revealed that SLC39A14 is required for the uptake of non-transferrin-bound iron (NTBI) by the liver and pancreas and is essential for iron loading of hepatocytes and pancreatic acinar cells. To investigate the requirement for SLC39A14 in cardiac iron accumulation, we generated cardiomyocyte-specific Slc39a14 knockout (Slc39a14 hrt/hrt) mice and crossed them with iron-loading hemojuvelin (Hjv) knockout mice to generate Hjv -/-;Slc39a14 hrt/hrt animals. At 12 and 24 weeks of age, cardiac nonheme iron levels were ~340% higher in Hjv -/- mice than in controls. By contrast, cardiac nonheme iron levels in Hjv -/-;Slc39a14 hrt/hrt mice at these ages were only ~60% higher than those than in controls, and ~65% less than those in Hjv -/- mice. Moreover, cardiac nonheme iron levels in Hjv -/-;Slc39a14 +/hrt (heterozygous conditional Slc39a14 knockout) mice were between those of Hjv -/- and Hjv -/-;Slc39a14 hrt/hrt mice, suggesting a gene-dosage effect of Slc39a14 on cardiac iron accumulation. A role for voltage-dependent calcium channels in mediating the uptake of NTBI into cardiomyocytes has been proposed based on observations of the effects of L-type calcium-channel blockers on iron uptake and accumulation in vitro and in vivo. We considered the possibility that these observations could be explained if SLC39A14 were reactive with calcium-channel blockers. To test this hypothesis, we examined the effects of blockers on the activity of SLC39A14 by using radiotracer assays in RNA-injected Xenopus oocytes expressing mouse SLC39A14. We found that 100 µM amlodipine (Amld), nifedipine, and nicardipine each afforded modest inhibition of SLC39A14-mediated 55Fe 2+. Inhibition of iron transport by Amld was dose-dependent, EC 50 = 167 µM ± (SEM) 30 µM. Our findings implicate SLC39A14 in mediating cardiomyocyte NTBI uptake in the mouse and raise doubts about the relative importance of calcium channels as a mechanism by which NTBI gains entry to the heart. Disclosures No relevant conflicts of interest to declare.

Effects of verapamil and diltiazem on acute stroke in cats

1985 ◽  
Vol 63 (6) ◽  
pp. 929-936 ◽  
Author(s):  
Mark W. Roy ◽  
Robert J. Dempsey ◽  
Kathleen L. Meyer ◽  
David L. Donaldson ◽  
Phillip A. Tibbs ◽  
...  
Keyword(s):  
Blood Flow ◽  
Calcium Channel ◽  
Acute Stroke ◽  
Calcium Channel Blockers ◽  
Intravenous Infusion ◽  
Brain Area ◽  
Channel Blockers ◽  
Arterial Blood ◽  
Mca Occlusion ◽  
India Ink

✓ To test the effect of verapamil and diltiazem in acute stroke, three groups of mongrel cats of either sex underwent occlusion of the middle cerebral artery (MCA) via a transorbital approach under ketamine anesthesia. The first group served as controls, the second received an intravenous infusion of verapamil (0.1 µg/kg/min), and the third received an intravenous infusion of diltiazem (0.1 to 1.0 µg/kg/min). All drug infusions began 2 hours before MCA occlusion and continued for the remainder of the experiment. Before and for up to 24 hours after MCA occlusion, regional cerebral blood flow (rCBF), somatosensory evoked potentials (SSEP's), arterial blood gases, blood pressure, temperature, and hematocrit were measured at least every 2 hours. At the experiment's end, brains were perfused with India ink, removed, sliced, photographed for determination of nonperfused brain area, and weighed, dried, and reweighed for H2O content determination. In these studies, verapamil was associated with worsening of rCBF in ischemic regions and inappropriate increases in rCBF in nonischemic regions, indicating intracerebral steal. Diltiazem increased rCBF in marginally ischemic regions. Changes in SSEP's paralleled blood flow changes, with verapamil decreasing amplitude and conduction velocity while diltiazem slightly improved conduction in the ischemic brain. Verapamil increased the area of nonperfused brain and the content of cerebral H2O. Diltiazem-treated animals had decreased cerebral H2O content, but had a marked increase in the area of nonperfused brain, a finding associated with the high incidence of transtentorial herniation in the diltiazem-treated animals. These findings agree with in vitro studies demonstrating high sensitivity of cerebral blood vessels to calcium channel blockers. These studies further support the notion that calcium channel blockers probably affect several different classes of calcium channels, at different brain sites.

Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus

1995 ◽  
Vol 74 (1) ◽  
pp. 43-53 ◽  
Author(s):  
V. A. Doze ◽  
G. A. Cohen ◽  
D. V. Madison
Keyword(s):  
Calcium Channels ◽  
Action Potential ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Gabab Receptor ◽  
Gaba Release ◽  
Extracellular Potassium ◽  
Channel Blockers ◽  
Voltage Dependent ◽  
Subtype Selective

1. Experiments were performed in rat hippocampal slices to examine the nature of GABAergic inhibition of inhibitory synaptic transmission. In these experiments the effects of the gamma-aminobutyric acid-B (GABAB) receptor agonist, baclofen, and of subtype-selective calcium channel blockers were tested with the use of intracellular recordings of evoked inhibitory postsynaptic potentials (IPSPs) and whole cell recordings of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs). 2. Baclofen inhibited evoked and spontaneous (action-potential-dependent) monosynaptic GABAA-mediated IPSPs and IPSCs but had no effect on the frequency of tetrodotoxin-resistant (action-potential-independent) miniature IPSCs recorded in CA1 pyramidal neurons. 3. Depolarizing GABAergic synaptic terminals by raising the extracellular potassium concentration caused an increase in action-potential-independent miniature IPSC frequency that could be inhibited by either baclofen or cadmium, a blocker of voltage-dependent calcium channels. In addition, under these depolarizing conditions, cadmium occluded the baclofen inhibition of miniature IPSCs. These data suggest that baclofen reduces only depolarization-induced, not quantal, GABA release and that it does so by decreasing presynaptic voltage-dependent calcium influx. 4. Experiments with subtype-selective calcium channel blockers demonstrate that the presynaptic action of baclofen was mediated through both omega-conotoxin-GVIA-sensitive and omega-agatoxin-IVA-sensitive, but not dihydropyridine-sensitive calcium channels.

scholarly journals Prenylflavanones as Novel T-Type Calcium Channel Blockers Useful for Pain Therapy

2019 ◽  
Vol 14 (9) ◽  
pp. 1934578X1987344
Author(s):  
Huy Du Nguyen ◽  
Takuya Okada ◽  
Fumiko Sekiguchi ◽  
Maho Tsubota ◽  
Hiroyuki Nishikawa ◽  
...  
Keyword(s):  
Side Effects ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Pain Therapy ◽  
Channel Blocker ◽  
Visceral Pain ◽  
Channel Blockers ◽  
Prenylated Flavonoids ◽  
Structure Activity

Prenylated flavonoids have attracted much attention due to their promising and diverse bioactivities on multitarget tissues. To the best of our knowledge, our recent studies demonstrated first that (2 S)-6-prenylnaringenin (6-PNG), a hop component, blocks Cav3.2 T-type calcium channels (T-channels) and alleviates neuropathic and visceral pain with little side effects; it also indicated first that other natural prenylflavanones (PFVNs), such as sophoraflavanone G and (2 S)-8-PNG, or synthetic 6-PFVNs including (2 R/S)-6-PNG and its derivatives are capable of blocking T-channels and useful for pain therapy. Through the structure-activity relationship studies on the synthetic 6-PFVNs, we identified 6-(3-ethylpent-2-enyl)-5,7-dihydroxy-2-(2-hydroxyphenyl)chroman-4-one (8j or KTt-45) as the most potent blocker of Cav3.2 T-channels. It is interesting to recognize a prenylated flavonoid, belonging to other sub-classes, as a novel T-channel blocker. Therefore, this article will review some of our recent studies to introduce a new branch to researchers studying on prenylated flavonoids.

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