Histological and in vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators

Danielsson, Bengt; Danielson, M. K.; Reiland, Sven; Rundqvist, Eva; Dencker, Lennart; Regård, Carl-Gunnar

doi:10.1002/tera.1420410210

Cited by 43 publications

(12 citation statements)

References 20 publications

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“…It must be added, however, that administration of a drug with a different mechanism of action and different targets (i.e., hydralazine that blocks voltage-gated potassium channels) resulted in the same outcome, indicating that the effect of nifedipine on digit formation in the foetuses was not specific. Indeed, decreased utero-placental blood flow caused by excessive hypotension, rather than a direct blockade of the voltage-dependent ion channel, was implicated as the most probable mechanism underlying the observed defects in a follow-up study [21]. No apparent disturbance of chondrogenesis was observed in embryonic chick limb bud-derived micromass cultures at concentrations of nifedipine below 3 × 10 5 μM.…”

Section: Vdccs and The Effects Of Nifedipine/verapamil On Chondrocytesmentioning

confidence: 86%

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

2015

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Chondrocytes, the single cell type in adult articular cartilage, have conventionally been considered to be non-excitable cells. However, recent evidence suggests that their resting membrane potential (RMP) is less negative than that of excitable cells, and they are fully equipped with channels that control ion, water, and osmolyte movement across the chondrocyte membrane. Among calcium-specific ion channels, members of the voltage-dependent calcium channel (VDCC) family are expressed in chondrocytes where they are functionally active. Ltype VDCC inhibitors such as nifedipine and verapamil have contributed to our understanding of the roles of these ion channels in chondrogenesis, chondrocyte signalling, and mechanotransduction. In this narrative review, we discuss published data indicating that VDCC function is vital for chondrocyte health, especially in regulating proliferation and maturation.We also highlight the fact that activation of VDCC function appears to accompany various inflammatory aspects of osteoarthritis (OA) and, based on in vitro data, the application of nifedipine and/or verapamil may be a promising approach for ameliorating OA severity.However, very few studies on clinical outcomes are available regarding the influence of calcium antagonists, which are used primarily for treating cardiovascular conditions in OA patients. This review is intended to stimulate further research on the chondrocyte 'channelome', contribute to the development of novel therapeutic strategies, and facilitate the retargeting and repositioning of existing pharmacological agents currently used for other comorbidities for the treatment of OA.

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Section: Vdccs and The Effects Of Nifedipine/verapamil On Chondrocytesmentioning

confidence: 86%

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

2015

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“…In keeping with this hypothesis, it is worth remembering that, as shown in studies carried out in sheep and humans, maternal hyperoxia can significantly increase fetal oxygen tension (22,23). Coherently with a mechanistic involvement of hypoxia, hemorrhagic limb defects have been produced by subjecting fetal rats to a hypoxic environment (24) and, as pointed out in previous investigations (3)(4)(5)(6)(7)(8), by exposing fetuses to vasoactive agents capable of uteroplacental perfusion reduction, including epinephrine (25,26), cocaine (27), calcium-channel blockers (28,29), phenytoin (30), and uterine vascular clamping (31,32). Limb defects were also produced by multiple brief exposures of cultured rat embryos to hypoxia (33).…”

Section: Tiboni Et Almentioning

confidence: 98%

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

2003

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In the present study the relationship between exposure to the nitric oxide synthesis inhibitor N -nitro-L-arginine methyl ester (L-NAME) and the induction of limb defects, with respect to stage specificity and dose dependency, was investigated in the mouse. ICR (CD-1) mice were dosed s.c with L-NAME at 50 or 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals treated with vehicle on gestation d 14 served as control. Uterine contents were evaluated for teratogenesis on gestation d 18. A treatment-related disruption of limb development was noted. The effect was dose dependent and phase specific. L-NAME became teratogenically operational on gestation d 13 and elicited its maximum effect on gestation d 14, whereas no significant teratogenicity was observed when exposure occurred after gestation d 15. In utero exposure to L-NAME also reduced embryo viability relative to controls. When the higher dose was injected on gestation d 16, a significant number of dams delivered preterm. In a parallel study, the ability of hyperoxia to prevent limb teratogenesis was investigated. To this aim, a group of L-NAMEtreated animals (90 mg/kg s.c. on gestation d 14) were exposed to 98 to 100% O 2 for 12 h. L-NAME-treated mice breathing room air served as positive controls. In response to hyperoxia, a significant decrement of L-NAME-induced limb defects was found. This study characterizes for the first time the teratogenic capacity of L-NAME in the mouse. Results obtained with hyperoxia fit the hypothesis that hypoxic tissue damage may play a contributory role in L-NAME-induced limb defects. NO is a colorless gaseous molecule involved in the regulation of diverse important physiologic processes, including vascular tone, platelet reactivity, smooth muscle contractility, neurotransmission, and the cytotoxic action of immune cells (1). NO is generated endogenously during the conversion of L-arginine to citrulline by a family of enzymes known as NOS. At least three isoforms of NOS have been isolated, including the constitutive eNOS and neuronal NOS isoforms, and the inducible isoform, iNOS (1). Pharmacologic manipulation of NOS activity can be achieved by several classes of NOS inhibitors including L-arginine analogs, which act by denying NOS its substrate in a competitive manner (2).The L-arginine analog L-NAME, a nonselective inhibitor of NOS, has been shown to be teratogenic when administered to rats (3-8). Limb reduction defects with associated characteristic areas of macroscopic hemorrhage were the most common phenotypic alterations noted (3-8). L-NAME is not the only L-arginine analog known to cause dysmelia, as N -nitro-Larginine also induced limb defects (9). Notably, disruptions similar to those induced by L-arginine analogs have been noted in knockout mice lacking eNOS (10, 11). The current state of knowledge on L-NAME teratogenicity also includes the following facts: 1) the period of fetal vulnerability has an onset relatively late in gestation (3-5); 2) both oral (3-6) and parenteral (5) treatments are effective;...

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“…(3f) has been observed [37,38], and (Azarbayjani unpublished). The digital reduction defects were also preceded by hemorrhage and necrosis [39] and were identical with those known to be induced by drugs which cause embryonic hypoxia by severely decreasing uteroplacental blood flow [40][41][42]. The similarities in pathophysiological and morphological alterations underlying orofacial clefts and digital reduction defects give further evidence for a common mechanism after hypoxic episodes due to temporary clamping of uterine vessels and intrauterine exposure to PHT.…”

Section: Pharmacological Effectsmentioning

confidence: 54%

Class III Antiarrhythmics and Phenytoin: Teratogenicity Due to Embryonic Cardiac Dysrhythmia and Reoxygenation Damage

Danielsson¹,

Sköld²,

Azarbayjani³

2001

CPD

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Class III antiarrhythmic drugs, like almokalant, dofetilide and ibutilide, cause a spectrum of malformations in experimental teratology studies. The pattern of developmental toxic effects is very similar to those reported for phenytoin, which is an established human and animal teratogen. The toxic effects are characterised by embryonic death, decreased fetal weights, and stage specific malformations, such as distal digital reductions, orofacial clefts and cardiovascular defects. Class III antiarrhythmics decrease the excitability of cardiac cells by selectively blocking the rapid component of the delayed rectified potassium channel (IKr), resulting in prolongation of the repolarisation phase of the action potential. Phenytoin, which decrease the excitability of neurones, has recently also been shown to block IKr, in addition to its known blockade of sodium channels. Animal studies indicate that IKr is expressed in the embryo and that the embryonic heart is extremely susceptible to IKr-blockers during a restricted period in early development. At concentrations not affecting the maternal heart, the embryonic heart reacts with bradycardia, arrhythmia and cardiac arrest when exposed to such drugs. Available studies strongly support the idea that birth defects after in utero exposure to both selective and non-selective IKr-blockers (like phenytoin) are initiated by concentration dependent embryonic bradycardia/arrhythmia resulting in 1) hypoxia; explaining embryonic death and growth retardation, 2) episodes of severe hypoxia, followed by generation of reactive oxygen species within the embryo during reoxygenation, causing orofacial clefts and distal digital reductions, and 3) alterations in embryonic blood flow and blood pressure, inducing cardiovascular defects.

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Histological and in vitro studies supporting decreased uteroplacental blood flow as explanation for digital defects after administration of vasodilators

Cited by 43 publications

References 20 publications

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

Voltage-Dependent Calcium Channels in Chondrocytes: Roles in Health and Disease

The Nitric Oxide Synthesis Inhibitor Nω-Nitro-L-Arginine Methyl Ester (L-NAME) Causes Limb Defects in Mouse Fetuses: Protective Effect of Acute Hyperoxia

Class III Antiarrhythmics and Phenytoin: Teratogenicity Due to Embryonic Cardiac Dysrhythmia and Reoxygenation Damage

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