Concept: Calcium channel blocker
Although loss of functional β-cell mass is a hallmark of diabetes, no treatment approaches that halt this process are currently available. We recently identified thioredoxin-interacting protein (TXNIP) as an attractive target in this regard. Glucose and diabetes upregulate β-cell TXNIP expression, and TXNIP overexpression induces β-cell apoptosis. In contrast, genetic ablation of TXNIP promotes endogenous β-cell survival and prevents streptozotocin (STZ)- and obesity-induced diabetes. Finding an oral medication that could inhibit β-cell TXNIP expression would therefore represent a major breakthrough. We were surprised to discover that calcium channel blockers inhibited TXNIP expression in INS-1 cells and human islets and that orally administered verapamil reduced TXNIP expression and β-cell apoptosis, enhanced endogenous insulin levels, and rescued mice from STZ-induced diabetes. Verapamil also promoted β-cell survival and improved glucose homeostasis and insulin sensitivity in BTBR ob/ob mice. Our data further suggest that this verapamil-mediated TXNIP repression is conferred by reduction of intracellular calcium, inhibition of calcineurin signaling, and nuclear exclusion and decreased binding of carbohydrate response element-binding protein to the E-box repeat in the TXNIP promoter. Thus, for the first time, we have identified an oral medication that can inhibit proapoptotic β-cell TXNIP expression, enhance β-cell survival and function, and prevent and even improve overt diabetes.
Non-thermal microwave/lower frequency electromagnetic fields (EMFs) act via voltage-gated calcium channel (VGCC) activation. Calcium channel blockers block EMF effects and several types of additional evidence confirm this mechanism. Low intensity microwave EMFs have been proposed to produce neuropsychiatric effects, sometimes called microwave syndrome, and the focus of this review is whether these are indeed well documented and consistent with the known mechanism(s) of action of such EMFs. VGCCs occur in very high densities throughout the nervous system and have near universal roles in release of neurotransmitters and neuroendocrine hormones. Soviet and Western literature shows that much of the impact of non-thermal microwave exposures in experimental animals occurs in the brain and peripheral nervous system, such that nervous system histology and function show diverse and substantial changes. These may be generated through roles of VGCC activation, producing excessive neurotransmitter/neuroendocrine release as well as oxidative/nitrosative stress and other responses. Excessive VGCC activity has been shown from genetic polymorphism studies to have roles in producing neuropsychiatric changes in humans. Two U.S. government reports from the 1970’s-80’s provide evidence for many neuropsychiatric effects of non-thermal microwave EMFs, based on occupational exposure studies. 18 more recent epidemiological studies, provide substantial evidence that microwave EMFs from cell/mobile phone base stations, excessive cell/mobile phone usage and from wireless smart meters can each produce similar patterns of neuropsychiatric effects, with several of these studies showing clear dose-response relationships. Lesser evidence from 6 additional studies suggests that short wave, radio station, occupational and digital TV antenna exposures may produce similar neuropsychiatric effects. Among the more commonly reported changes are sleep disturbance/insomnia, headache, depression/depressive symptoms, fatigue/tiredness,dysesthesia, concentration/attention dysfunction, memory changes, dizziness, irritability, loss of appetite/body weight, restlessness/anxiety, nausea, skin burning/tingling/dermographism and EEG changes. In summary, then, the mechanism of action of microwave EMFs, the role of the VGCCs in the brain, the impact of non-thermal EMFs on the brain, extensive epidemiological studies performed over the past 50 years, and five criteria testing for causality, all collectively show that various non-thermal microwave EMF exposures produce diverse neuropsychiatric effects.
- Proceedings. Biological sciences / The Royal Society
- Published over 4 years ago
Evidence is accumulating that commonly used pesticides are linked to decline of pollinator populations; adverse effects of three neonicotinoids on bees have led to bans on their use across the European Union. Developing insecticides that pose negligible risks to beneficial organisms such as honeybees is desirable and timely. One strategy is to use recombinant fusion proteins containing neuroactive peptides/proteins linked to a ‘carrier’ protein that confers oral toxicity. Hv1a/GNA (Galanthus nivalis agglutinin), containing an insect-specific spider venom calcium channel blocker (ω-hexatoxin-Hv1a) linked to snowdrop lectin (GNA) as a ‘carrier’, is an effective oral biopesticide towards various insect pests. Effects of Hv1a/GNA towards a non-target species, Apis mellifera, were assessed through a thorough early-tier risk assessment. Following feeding, honeybees internalized Hv1a/GNA, which reached the brain within 1 h after exposure. However, survival was only slightly affected by ingestion (LD50>100 µg bee(-1)) or injection of fusion protein. Bees fed acute (100 µg bee(-1)) or chronic (0.35 mg ml(-1)) doses of Hv1a/GNA and trained in an olfactory learning task had similar rates of learning and memory to no-pesticide controls. Larvae were unaffected, being able to degrade Hv1a/GNA. These tests suggest that Hv1a/GNA is unlikely to cause detrimental effects on honeybees, indicating that atracotoxins targeting calcium channels are potential alternatives to conventional pesticides.
L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a Ca(V)1.2 pore-forming subunit. L-type calcium channels with a Ca(V)1.3 pore-forming subunit are much less abundant, but have been implicated in the generation of mitochondrial oxidant stress underlying pathogenesis in Parkinson’s disease. Thus, selectively antagonizing Ca(V)1.3 L-type calcium channels could provide a means of diminishing cell loss in Parkinson’s disease without producing side effects accompanying general antagonism of L-type calcium channels. However, there are no known selective antagonists of Ca(V)1.3 L-type calcium channel. Here we report high-throughput screening of commercial and ‘in-house’ chemical libraries and modification of promising hits. Pyrimidine-2,4,6-triones were identified as a potential scaffold; structure-activity relationship-based modification of this scaffold led to 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (8), a potent and highly selective Ca(V)1.3 L-type calcium channel antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology. These studies describe the first highly selective Ca(V)1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson’s disease.
(-)-Carvone is a monoterpene ketone found in spearmint (Mentha spicata var. crispa) essential oil that is widely used as an odor and flavor additive. An intestinal antispasmodic effect was recently reported for (-)-carvone, and it has been shown to be more potent than its (+)-antipode. The mechanism of (-)-carvone action in the intestines has not been investigated. To gain a better understanding of the (-)-carvone antispasmodic effect, we investigated its pharmacological effects in the guinea pig ileum. Terminal portions of the ileum were mounted for isotonic contraction recordings. The effect of (-)-carvone was compared with that of the classical calcium channel blocker (CCB) verapamil. In isolated ileal smooth muscle, (-)-carvone did not produce direct contractile or relaxation responses and did not modify electrically elicited contractions or low K-evoked contractions. The submaximal contractions induced by histamine (p<0.001), BaCl (p<0.05), and carbachol (p<0.01) were significantly reduced by (-)-carvone. The contractile response elicited by high concentrations of carbachol was reduced but not abolished by (-)-carvone. No additive action was detected with co-incubation of (-)-carvone and verapamil on carbachol-induced contraction. (-)-Carvone reduced the contraction induced by high K and was almost 100 times more potent than verapamil. Thus, (-)-carvone showed a typical and potent CCB-like action. Many effects described for both (-)-carvone and spearmint oil can be explained as a CCB-like mode of action.
Introduction: There are few clinical trials that provide evidence to support the hypothesis that combined therapies offer a favorable risk-benefit ratio in the reduction of cardiovascular mortality and morbidity. Combined therapies containing an angiotensin-converting enzyme inhibitor (ACEI) with a calcium channel blocker (CCB) is one of the recommended combinations in the reappraisal of the European Society of Hypertension. Areas covered: The authors have performed a systematic review of the available clinical evidence on the use of combined therapies containing an ACEI with a CCB versus other combinations in the management of arterial hypertension (HT) and in the reduction of cardiovascular morbidity/mortality, according to recommendations of The Cochrane Handbook for Systematic Reviews of Interventions. They identified 122 potentially relevant studies. Of these, 38 included combined therapies in one or both treatment arms. Overall, a total of 12 publications were retrieved from the search and provided data on the effects of the combined therapy with an ACEI and a CCB on cardiovascular mortality/morbidity in patients with HT. Clinical evidence corresponds to three double-blind clinical trials: ASCOT-BPLA, ACCOMPLISH and Syst-EUR. Expert opinion: The analysis demonstrates the superiority of the combined therapy with ACEI/CCB not only in the overall population included in the studies but also in subsets of patients with a high cardiovascular risk such as diabetes and chronic kidney disease.
The Comparative Effects of Valsartan and Amlodipine on Vascular Microinflammation in Newly Diagnosed Hypertensive Patients.
- Clinical and experimental hypertension (New York, N.Y. : 1993)
- Published over 6 years ago
Pentraxin 3 (PTX3) is a new candidate immunoinflammatory marker that has been reported to be associated with cardiometabolic risk factors. We aimed to investigate the effects of valsartan and amlodipine on the PTX3 and C-reactive protein (CRP) levels in patients with essential hypertension. Patients with a newly diagnosed essential hypertension were admitted to our internal medicine outpatient clinic. Patients were randomized to one of the following intervention protocols: calcium channel blocker (amlodipine, 5-10 mg/day) as group A (n = 22; mean age ± standard deviation [SD]: 52 ± 11 year) and angiotensine II receptor blocker (valsartan, 80-320 mg/day) as group B (n = 28; mean age ± SD: 50 ± 14 year). Endothelial dysfunction and systemic inflammation were evaluated with PTX3 and CRP. There was a significant decrease in the level of PTX3 after treatment in two groups (P < .05). Although there was a significant decrease in the level of CRP after treatment in amlodipine group, there was no significant decrease in the levels of PTX3 and CRP after treatment in two groups. There were no significant differences in the systolic and diastolic blood pressure reduction between the two treatment groups. In the treatment of hypertension, prior knowledge of the level of plasma PTX3 could be important in antihypertensive drug choice. C-reactive protein and PTX3 are the markers that have role in vascular inflammation and are found associated with the prognosis of cardiovascular outcomes in many trials. In our study, PTX and CRP levels were decreased when compared to baseline levels.
This study sought to evaluate the clinical relevance of potential clopidogrel drug-drug interactions.
Abstract BACKGROUND: Vascular dementia (VaD) - a severe form of vascular cognitive impairment - and cognitive decline are associated with hypertension and therefore it seems logical to consider that reducing BP with anti-hypertensive therapy may protect against the development/onset of cognitive function impairment or dementia. SCOPE: This narrative, non-systematic review discusses the available evidence on the potential correlation between the use of anti-hypertensive agents and the risk of VaD and cognitive decline. METHODS: MEDLINE was searched for inclusion of relevant studies. No limitations in time were considered. RESULTS: A consensus on the potential effects of anti-hypertensive treatment in the reduction of VaD and associated cognitive decline has not been reached. A protective effect of anti-hypertensive agents has been observed in a number of studies although it is still unclear if different classes of anti-hypertensive agents have a different effect on the development of VaD. CONCLUSIONS: The protective effect of anti-hypertensive agents appears to depend on the specific drug used - positive effects have been observed with calcium channel blockers (CCBs), such as lercanidipine and nitrenidipine, the combination perindopril-indapamide and telmisartan.
Exposure to lead (Pb) can induce kidney damage, which is related to induction of oxidative damage and disturbance of intracellular calcium homeostasis. Pb can readily permeate through dihydropyridine-sensitive L-type calcium channels and accumulate within cells. The objective of this study was to investigate protective effects of calcium channel blockers (CCBs) verapamil and nimodipine on nephrotoxicity induced by Pb acetate in mice. One hundred twenty male mice were randomly divided into 6 groups: control, Pb, low-dose verapamil, high-dose verapamil, low-dose nimodipine and high-dose nimodipine (n=20 per group). Pb acetate was injected intraperitoneally (i.p.) at 40mg/kg body weight/day for 10 days to establish the Pb toxicity model. While control mice received saline, mice of the treated groups simultaneously received i.p. injections of verapamil or nimodipine daily for 10 days. Both verapamil and nimodipine showed protection against Pb-induced kidney injury, including alleviation of renal pathological damage and decreasing the level of Pb in kidney homogenate and extent of apoptosis in nephrocytes. Moreover, verapamil and nimodipine significantly down-regulated levels of blood urea nitrogen and creatinine in the serum. In addition, verapamil and nimodipine administration decreased malondialdehyde content and increased activities of super oxide dismutase activity and glutathione peroxidase in the kidney homogenate. The findings in the present study implicate the therapeutic potential of CCBs for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb uptake and inhibition of lipid peroxidation.