Isradipine

Brogden, Rex N.; Sorkin, Eugene M.

doi:10.2165/00003495-199549040-00009

Cited by 35 publications

(3 citation statements)

References 147 publications

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“…Human hypertension is treated with dihydropyridine calcium channel blockers, which preferentially inhibit Ca V 1.2 channels in vascular smooth muscle cells in vivo (27,28). The calcium channel antagonist isradipine (1 and 3 mg/kg) reduced the heart to body weight ratio significantly and increased survival of DCT Ϫ/Ϫ embryos assayed at E18 (Fig.…”

Section: Functions Of the Distal C Terminus Of Ca V 12 Channels In Vivomentioning

confidence: 99%

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Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of β-Adrenergic Regulation and Heart Failure in Vivo

Westenbroek

et al. 2011

Journal of Biological Chemistry

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L-type calcium currents conducted by Ca V 1.2 channels initiate excitation-contraction coupling in cardiac and vascular smooth muscle. In the heart, the distal portion of the C terminus (DCT) is proteolytically processed in vivo and serves as a noncovalently associated autoinhibitor of Ca V 1.2 channel activity. This autoinhibitory complex, with A-kinase anchoring protein-15 (AKAP15) bound to the DCT, is hypothesized to serve as the substrate for ␤-adrenergic regulation in the fight-or-flight response. Mice expressing Ca V 1.2 channels with the distal C terminus deleted (DCT ) current in cardiomyocytes, where Ca 2ϩ enters through the channel and initiates excitation-contraction coupling via Ca 2ϩ -induced Ca 2ϩ release (1). Normal expression of Ca V 1.2 channels is required for cardiac contractile function and for survival beyond embryonic day 14 (2). Lack of the Ca V 1.2 channel also abolishes the development of myogenic tone and disrupts hormonal regulation of blood pressure (3). In contrast, deletion of Ca V 1.3, which also conducts L-type Ca 2ϩ currents, causes sinoatrial nodal dysfunction and cardiac arrhythmias but does not impair contractility or cause premature death (4). Overall, these gene deletion studies illustrate that L-type Ca 2ϩ currents are essential for normal cardiovascular function and for normal development.Ca V 1 channels are multisubunit complexes composed of a pore-forming ␣1 subunit and auxiliary ␤, ␣2␦, and in some cases ␥ subunits (5-7). They are a primary target for regulation by numerous hormones, protein kinases, and phosphoprotein phosphatases (5-7). In the "fight-or-flight" response, increased force of contraction is achieved largely through regulation of Ca V 1.2 channels in the heart by the sympathetic nervous system through activation of ␤-adrenergic receptors, adenylyl cyclase, and cyclic AMP-dependent protein kinase (PKA) and resulting phosphorylation of Ca V 1.2 channels (1,5,6,8). ␤-Adrenergic regulation of Ca V 1.2 channels requires A-kinase anchoring protein 15 (AKAP15), 2 which anchors the kinase to the distal C terminus of Ca V 1.2 via a modified leucine zipper (LZ) motif (9 -11).The C terminus of Ca V 1 channels undergoes proteolytic processing in vivo in skeletal and cardiac muscle (12-15). In cardiac muscle, the ␣1 subunit of Ca V 1.2 channels is present in two size forms of ϳ240 and 210 kDa, which differ by truncation of the distal C terminus (DCT) (15). This truncation leads to enhanced activity of Ca V 1.2 channels expressed in Xenopus oocytes and mammalian cell lines (16,17). Single channel conductance, modulation by ␤ and ␣2␦ subunits, and sensitivity to Ca 2ϩ channel agonists such as Bay K8644 remain unchanged (16, 17). The proteolytically cleaved DCT binds to the truncated channel and acts as potent autoinhibitor (18). Mutations of key charged residues at the interface between distal and proximal C-terminal domains of Ca V 1.2 relieves autoinhibition (18). Moreover, recent studies indicate that regulation of Ca V 1.2 channels can be reconstituted in transfect...

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Section: Functions Of the Distal C Terminus Of Ca V 12 Channels In Vivomentioning

confidence: 99%

“…Hypertension in humans is effectively treated with the calcium channel blocker isradipine and the angiotensin-converting enzyme inhibitor captopril (27,28,47). In addition, pulmonary hypertension in humans is effectively treated with tadalafil (48).…”

Section: Functional Roles Of the Dct Of Ca V 12 Channels In Vivo-mentioning

confidence: 99%

Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of β-Adrenergic Regulation and Heart Failure in Vivo

Westenbroek

et al. 2011

Journal of Biological Chemistry

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“…Delzicol has its effects on the GI tract. In patients with IBD, mucosal product of arachidonic acid metabolites is increased and mesalazine is thought to reduce inflammation by blocking specific pathways like the cyclooxygenase pathway and reducing prostaglandin production [16]. The basic side effects of Delzicol are nausea, constipation, and an upset stomach.…”

Section: Approved Drug-mesalazinementioning

confidence: 99%

An Analysis of Metabolic Conditions and Current Therapeutic Approaches: A Systematic Review

Trivedi,

Fayaz,

Korban

et al. 2024

Preprint

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This review rigorously investigates the evolving pharmacological landscape for metabolic disorders, focusing on Phenylketonuria (PKU), Inflammatory Bowel Disease (IBD), Galactosemia, Medium Chain Acyl CoA Dehydrogenase Deficiency (MCADD), and Prader-Willi Syndrome (PWS). Adhering to PRISMA guidelines, we meticulously searched databases such as NHS, Rare Diseases, Pubchem, Clinical Trials, DrugBank, PubMed, and Mayo Clinic, spanning from January 2000 to December 2023. Our objective was to evaluate the efficacy and potential of both FDA-approved drugs and those in clinical trials. The review revealed significant advancements in the treatment of disorders like PKU, with drugs like Kuvan facilitating improved metabolic functioning. In IBD, treatments have progressed to specifically target inflammatory pathways using drugs like Azathioprine and Mesalazine, shifting away from broader immunosuppressants. Galactosemia and MCADD, disorders without definitive cures, have shown potential in clinical trials with investigational drugs like AT-007 and Triheptanoin. Particularly intriguing are the ongoing trials for PWS, a complex syndrome, where Oral NNZ-2591 and Oxytocin demonstrate promising potential. These findings highlight the critical importance of specialized treatment strategies, tailored to address the unique metabolic challenges posed by each disorder. The diverse nature of these disorders necessitates a multifaceted approach, combining current scientific knowledge with innovative drug development. This study not only contributes to a better understanding of existing treatments but also emphasizes the need for continued research and development to uncover more effective and personalized therapeutic options for managing these varied metabolic disorders.

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Effects of isradipine on intravenous cocaine-induced cardiovascular response: a pilot study

Johnson

Wells

Kenny

et al. 1999

Hum. Psychopharmacol. Clin. Exp.

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We examined the eects of isradipine, a dihydropyridine-class calcium channel antagonist, and eective antihypertensive medication on the pressor eects of cocaine on cardiac function. Using continuous non-invasive cardiovascular monitoring of heart rate, blood pressure, electrocardiographic recordings, and peripheral oxygen saturation, six healthy cocaine addicts received the following treatments in blinded, crossover fashion: (a) placebo; (b) intravenous cocaine (0 . 325 mg/kg iv), and (c) isradipine (10 mg pXoX cocaine. While cocaine-taking was associated with a small increase in blood pressure, this eect was not signi®cantly aected by isradipine. Isradipine pretreatment was, however, associated with a signi®cant re¯ex rise in heart rate following cocaine. Cocaine administration with or without isradipine produced no clinically signi®cant abnormalities of rhythm or conduction on the electrocardiogram and on peripheral oxygen saturation. While these results should be considered preliminary, they do suggest that this isradipine dose and/or dosing strategy does not have a clinically signi®cant cardioprotective eect during cocaine-taking.

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Isradipine

Cited by 35 publications

References 147 publications

Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of β-Adrenergic Regulation and Heart Failure in Vivo

Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of β-Adrenergic Regulation and Heart Failure in Vivo

An Analysis of Metabolic Conditions and Current Therapeutic Approaches: A Systematic Review

Effects of isradipine on intravenous cocaine-induced cardiovascular response: a pilot study

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