L-type Ca2+ channel blockers inhibit the window contraction of mouse aorta segments with high affinity

Michiels, Cédéric F.; Hove, Cor E. Van; Martinet, Wim; Meyer, Guido R.Y. De; Fransen, Paul

doi:10.1016/j.ejphar.2014.05.036

Cited by 15 publications

(14 citation statements)

References 27 publications

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“…The cumulative concentration–response curves to K + ‐induced depolarization (10, 20, 30, 50, 80, 124 mM) were obtained in the presence of 1 μM of the ɑ‐adrenergic receptor antagonist phentolamine to exclude the contribution of NA released from perivascular adrenergic nerves. Functional contribution of the L‐type Ca 2+ channels was tested by preconstriction of arteries with 80 mM K + in the presence of phentolamine followed by relaxation with 0.01–1000 nM nifedipine .…”

Section: Methodsmentioning

confidence: 99%

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Jensen

Joergensen

Dam

et al. 2018

Basic Clin Pharma Tox

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TMEM16A is essential for Ca -activated Cl conductance in vascular smooth muscle. The importance of TMEM16A for agonist-induced vascular constriction and blood pressure control is, however, under debate. Previous studies suggested that TMEM16A might have a complex cellular function beyond being essential for the Ca -activated Cl conductance, for example modulation of Ca channel expression. Mice with constitutive, smooth muscle-specific expression of siRNA directed against Tmem16a (transgenic mice, TG) were generated. Isometric constrictions of isolated aorta, mesenteric, femoral and tail arteries from TG mice were compared with wild-types. Protein expression was analysed by Western blots. Blood pressure and heart rate were studied telemetrically. Significant TMEM16A down-regulation was seen in aorta and tail arteries, while no changes were detected in mesenteric and femoral arteries. Contractile responses of mesenteric and femoral arteries from TG and wild-type mice were not different. Aorta from TG mice showed reduced agonist-induced constriction, while their responses to elevated K were unchanged. Tail arteries from TG mice also constricted less to adrenergic stimulation than wild-types. Surprisingly, tail arteries from TG mice constricted less to elevated K too and were more sensitive to nifedipine-induced relaxation. Consistently, TMEM16A down-regulation in tail arteries was associated with reduction in CACNA1C protein (i.e. vascular L-type Ca channel) expression. No differences in blood pressure and heart rate between the groups were seen. This study suggests a complex contribution of TMEM16A in vascular function. We suggest that TMEM16A modulates arterial contractility, at least in part, indirectly via regulation of CACNA1C expression.

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Section: Methodsmentioning

confidence: 99%

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Jensen

Joergensen

Dam

et al. 2018

Basic Clin Pharma Tox

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“…Amlodipine besylate (AB) is a long-acting dihydropyridine CCB that permanently blocks vascular smooth muscle L-type calcium channels (Michiels, Van Hove, Martinet, De Meyer, & Fransen, 2014). AB also has the function of improving vascular endothelium and antiatherosclerosis (He et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using ¹H‐NMR‐ and MS‐based metabolomics

Li¹,

Zhao²,

Jiang³

et al. 2020

Biomedical Chromatography

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Duzhong Jiangya Tablet (DJT) composed of Eucommia ulmoides Oliv. and several other traditional Chinese medicines is a Chinese herbal compound, which is clinically used to treat hypertension. The aim of this study was to evaluate the antihypertensive effect of DJT and amlodipine besylate (AB) on the synergistic treatment of spontaneously hypertensive rats (SHRs), and to explore its antihypertensive mechanism. The synergistic therapeutic effect of DJT in combination with AB on SHR was studied using two metabolomics methods based on mass spectrum (MS) and nuclear magnetic resonance. Metabolomics analysis of plasma, urine, liver, and kidney and the combination of orthogonal partial least squares discriminant analysis was performed to expose potential biomarkers. Then, the overall metabolic characteristics and related abnormal metabolic pathways in hypertensive rats were constructed. Blood pressure measurements showed that DJT combined with AB has better effects in treating hypertension than it being alone. A total of 30 biomarkers were identified, indicating that hypertension disrupted the balance of multiple metabolic pathways in the body, and that combined administration restored metabolite levels better than their administration alone. The changes of biomarkers revealed the synergistic therapeutic mechanism of DJT combined with AB, which provided a reference for the combination of Chinese and Western medicines.

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“…Segments were depolarized at different preloads by high extracellular K + to study contractions due to Ca 2+ influx via VGCC, which can be inhibited with VGCC blockers such as diltiazem (Michiels et al, 2014). They were also stimulated at different preloads with the α 1 -adrenoceptor agonist phenylephrine (PE) to focus on contractions due to intracellular Ca 2+ release from the IP 3 -sensitive sarcoplasmic reticulum Ca 2+ store and on contractions due to mixed Ca 2+ influx from the extracellular space via VGCC and NSCC (Fransen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

et al. 2017

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Most vaso-reactive studies in mouse aortic segments are performed in isometric conditions and at an optimal preload, which is the preload corresponding to a maximal contraction by non-receptor or receptor-mediated stimulation. In general, this optimal preload ranges from about 1.2 to 8.0 mN/mm, which according to Laplace's law roughly correlates with transmural pressures of 10–65 mmHg. For physiologic transmural pressures around 100 mmHg, preloads of 15.0 mN/mm should be implemented. The present study aimed to compare vascular reactivity of 2 mm mouse (C57Bl6) aortic segments preloaded at optimal (8.0 mN/mm) vs. (patho) physiological (10.0–32.5 mN/mm) preload. Voltage-dependent contractions of aortic segments, induced by increasing extracellular K+, and contractions by α1-adrenergic stimulation with phenylephrine (PE) were studied at these preloads in the absence and presence of L-NAME to inhibit basal release of NO from endothelial cells (EC). In the absence of basal NO release and with higher than optimal preload, contractions evoked by depolarization or PE were attenuated, whereas in the presence of basal release of NO PE-, but not depolarization-induced contractions were preload-independent. Phasic contractions by PE, as measured in the absence of external Ca2+, were decreased at higher than optimal preload suggestive for a lower contractile SR Ca2+ content at physiological preload. Further, in the presence of external Ca2+, contractions by Ca2+ influx via voltage-dependent Ca2+ channels were preload-independent, whereas non-selective cation channel-mediated contractions were increased. The latter contractions were very sensitive to the basal release of NO, which itself seemed to be preload-independent. Relaxation by endogenous NO (acetylcholine) of aortic segments pre-contracted with PE was preload-independent, whereas relaxation by exogenous NO (diethylamine NONOate) displayed higher sensitivity at high preload. Results indicated that stretching aortic segments to higher than optimal preload depolarizes the SMC and causes Ca2+ unloading of the contractile SR, making them extremely sensitive to small changes in the basal release of NO from EC as can occur in hypertension or arterial stiffening.

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L-type Ca2+ channel blockers inhibit the window contraction of mouse aorta segments with high affinity

Cited by 15 publications

References 27 publications

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using ¹H‐NMR‐ and MS‐based metabolomics

Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

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L-type Ca2+ channel blockers inhibit the window contraction of mouse aorta segments with high affinity

Cited by 15 publications

References 27 publications

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Variable Contribution of TMEM16A to Tone in Murine Arterial Vasculature

Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using 1H‐NMR‐ and MS‐based metabolomics

Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

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Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using ¹H‐NMR‐ and MS‐based metabolomics