Administration Of Verapamil Research Articles

Effects of intracoronary administration of small doses of nicorandil and verapamil on blood pressure and heart rate

BackgroundNicorandil and verapamil can improve coronary blood flow and coronary microcirculation during percutaneous coronary intervention. However, the effects of intracoronary (IC) administration of nicorandil and verapamil on hemodynamics remain unclear. AimsTo clarify the safety and effects of IC administration of nicorandil and verapamil on blood pressure (BP) and heart rate (HR) to provide evidence-based basis for clinical intervention. MethodsThe study cohort included 70 patients with coronary artery stenosis recruited from Zhejiang Provincial Hospital of Traditional Chinese Medicine. The patients were randomly assigned to the intervention group (IC administration of 2 mg/2 ml of nicorandil and 200 μg/2 ml of verapamil) or the control group (IC administration of 2 ml of saline). BP and HR were compared before medication, after medication, and when stabilized. ResultsIC administration of verapamil at 200 μg significantly reduced systolic BP as compared to the control group (113.72 ± 3.40 vs. 123.63 ± 3.33 mmHg, respectively, p < 0.05) for a short period of time, and returned to baseline within 2 min, but had no effect on diastolic BP and HR. IC administration injection of nicorandil at 2 mg had no effect on BP or HR. There were no instances of major cardiovascular events. ConclusionIC administration of nicorandil at 2 mg is safe as an adjunctive medication during interventional angiography. Verapamil can also be used as an IC adjuvant, although BP and HR must be monitored for patients with low basal BP, especially systolic BP.

Radial Artery Spasm-A Review on Incidence, Prevention and Treatment.

Radial artery spasm (RAS) is a common complication associated with transradial access (TRA) for coronary interventions, particularly affecting elderly patients in whom radial access is preferred due to its benefits in reducing bleeding complications, improving clinical outcomes, and lowering long-term costs. This review examines the incidence, prevention, and treatment of RAS. Methods included an online search of PubMed and other databases in early 2024, analyzing meta-analyses, reviews, studies, and case reports. RAS is characterized by a sudden narrowing of the radial artery due to psychological and mechanical factors with incidence reports varying up to 51.3%. Key risk factors include patient characteristics like female sex, age, and small body size as well as procedural factors such as emergency procedures and the use of multiple catheters. Preventive measures include using distal radial access, hydrophilic sheaths, and appropriate catheter sizes. Treatments involve the intraarterial administration of nitroglycerine and verapamil as well as mechanical methods like balloon-assisted tracking. This review underscores the need for standardizing RAS definitions and emphasizes the importance of operator experience and patient management in reducing RAS incidence and improving procedural success.

Intra-arterial nicardipine versus verapamil during transradial access coronary catheterization

IntroductionIntra-arterial (IA) vasodilators are recommended during transradial access (TRA) to prevent radial artery spasm (RAS). The American Heart Association (AHA) recommends either IA verapamil, diltiazem, nicardipine, or nitroglycerin to prevent RAS. To our knowledge, the efficacy of RAS prevention and patient tolerability of verapamil and nicardipine has not been directly compared in a randomized fashion. MethodsWe conducted a prospective, single-blinded randomized clinical trial comparing the discomfort experienced by patients receiving either 400 μg of IA nicardipine (n = 26) or 5 mg of IA verapamil (n = 29). Patient discomfort and/or pain was assessed using the Visual Analogue Scale (VAS) both before and after IA administration of nicardipine or verapamil. ResultsThere was a statistically significant difference in mean change in VAS scores between the 2 groups, with an average increase in VAS score of 0.88 in the nicardipine group and 4.81 in the verapamil group (p < 0.0001). The overall rate of RAS was low in our study (5.5 %) with no significant difference in RAS incidence between the 2 groups (p = 0.465). The nicardipine group had 2 RAS cases (7.7 %), with 1 requiring a change in strategy (3.8 %). The verapamil group had 1 RAS case (3.4 %) that did not require a change in strategy. ConclusionIn this trial, we showed that nicardipine causes significantly less discomfort and pain compared to verapamil during IA administration for TRA cardiac catheterization.

Preventing Sheep Carotid Artery Spasm for Vascular Graft Surgery and Computed Tomography Angiography.

The development of small-diameter vascular grafts requires testing in large animal models before advancing to clinical trials. Vascular graft interposition implantation in sheep carotid arteries (CAs) is the most widely used model, but ovine CAs are prone to severe spasm following surgical manipulation, potentially impairing graft performance assessment. There is paucity in the literature on reducing sheep CA spasm using effective vasodilator therapeutic protocols. In this study, four healthy Merino cross White Suffolk wethers (1-2 years, 52.1 ± 0.8 kg) underwent CT angiography and CA graft surgery. CT angiography using iodinated contrast agent was performed with innominate artery access through the CA or ascending aortic arch access through the femoral artery. Sheep then underwent right CA sham surgery or left CA vascular graft implantation. A variety of vasodilators, including papaverine, sodium nitroprusside, verapamil, and their combination, were tested for preventing or treating CA spasms intraoperatively. Blood flow was reassessed immediately after CA surgery using CT angiography. The results showed that innominate artery access through the CA for CT angiography in sheep induced presurgical CA spasm with reduced arterial flow. Conversely, ascending aortic arch access through the femoral artery for CT angiography did not cause CA spasm and maintained arterial flow. During CA graft surgery, surgical trauma induced CA spasm, which was prevented by localized intra-arterial administration of vasodilators papaverine hydrochloride and verapamil before significant surgical manipulation.

Machine learning predicts cerebral vasospasm in patients with subarachnoid haemorrhage

Cerebral vasospasm (CV) is a feared complication which occurs after 20-40% of subarachnoid haemorrhage (SAH). It is standard practice to admit patients with SAH to intensive care for an extended period of resource-intensive monitoring. We used machine learning to predict CV requiring verapamil (CVRV) in the largest and only multi-center study to date. Patients with SAH admitted to UCLA from 2013 to 2022 and a validation cohort from VUMC from 2018 to 2023 were included. For each patient, 172 unique intensive care unit (ICU) variables were extracted through the primary endpoint, namely first verapamil administration or no verapamil. At each institution, a light gradient boosting machine (LightGBM) was trained using five-fold cross validation to predict the primary endpoint at various hospitalization timepoints. A total of 1750 patients were included from UCLA, 125 receiving verapamil. LightGBM achieved an area under the ROC (AUC) of 0.88>1 week in advance and ruled out 8% of non-verapamil patients with zero false negatives. Our models predicted "no CVRV" vs "CVRV within three days" vs "CVRV after three days" with AUCs=0.88, 0.83, and 0.88, respectively. From VUMC, 1654 patients were included, 75 receiving verapamil. VUMC predictions averaged within 0.01 AUC points of UCLA predictions. We present an accurate and early predictor of CVRV using machine learning with multi-center validation. This represents a significant step towards optimized clinical management and resource allocation in patients with SAH. Robert E. Freundlich is supported by National Center for Advancing Translational Sciences federal grant UL1TR002243 and National Heart, Lung, and Blood Institute federal grant K23HL148640; these funders did not play any role in this study. The National Institutes of Health supports Vanderbilt University Medical Center which indirectly supported these research efforts. Neither this study nor any other authors personally received financial support for the research presented in this manuscript. No support from pharmaceutical companies was received.

Verapamil Attenuates the Severity of Tendinopathy by Mitigating Mitochondrial Dysfunction through the Activation of the Nrf2/HO-1 Pathway.

Tendinopathy is a prevalent condition in orthopedics patients, exerting a profound impact on tendon functionality. However, its underlying mechanism remains elusive and the efficacy of pharmacological interventions continues to be suboptimal. Verapamil is a clinically used medicine with anti-inflammation and antioxidant functions. This investigation aimed to elucidate the impact of verapamil in tendinopathy and the underlying mechanisms through which verapamil ameliorates the severity of tendinopathy. In in vitro experiments, primary tenocytes were exposed to interleukin-1 beta (IL-1β) along with verapamil at a concentration of 5 μM. In addition, an in vivo rat tendinopathy model was induced through the localized injection of collagenase into the Achilles tendons of rats, and verapamil was injected into these tendons at a concentration of 5 μM. The in vitro findings highlighted the remarkable ability of verapamil to attenuate extracellular matrix degradation and apoptosis triggered by inflammation in tenocytes stimulated by IL-1β. Furthermore, verapamil was observed to significantly suppress the inflammation-related MAPK/NFκB pathway. Subsequent investigations revealed that verapamil exerts a remediating effect on mitochondrial dysfunction, which was achieved through activation of the Nrf2/HO-1 pathway. Nevertheless, the protective effect of verapamil was nullified with the utilization of the Nrf2 inhibitor ML385. In summary, the in vivo and in vitro results indicate that the administration of verapamil profoundly mitigates the severity of tendinopathy through suppression of inflammation and activation of the Nrf2/HO-1 pathway. These findings suggest that verapamil is a promising therapeutic agent for the treatment of tendinopathy, deserving further and expanded research.

Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model.

Myotonic dystrophy type 1 (DM1) involves misregulated alternative splicing for specific genes. We used exon or nucleotide deletion to mimic altered splicing of genes central to muscle excitation-contraction coupling in mice. Mice with forced skipping of exon 29 in the CaV1.1 calcium channel combined with loss of ClC-1 chloride channel function displayed markedly reduced lifespan, whereas other combinations of splicing mimics did not affect survival. The Ca2+/Cl- bi-channelopathy mice exhibited myotonia, weakness, and impairment of mobility and respiration. Chronic administration of the calcium channel blocker verapamil rescued survival and improved force generation, myotonia, and respiratory function. These results suggest that Ca2+/Cl- bi-channelopathy contributes to muscle impairment in DM1 and is potentially mitigated by common clinically available calcium channel blockers.

Huoxin pill protects verapamil-induced zebrafish heart failure through inhibition of oxidative stress-triggered inflammation and apoptosis

Heart failure (HF) is a major and growing public health concern. Although advances in medical and surgical therapies have been achieved over the last decades, there is still no firmly evidence-based treatment with many traditional Chinese medicines (TCMs) for HF. Huoxin Pill (HXP), a TCM, has been widely used to treat patients with coronary heart disease and angina pectoris. However, the underlying molecular mechanism is poorly understood. In this study, using a verapamil-induced zebrafish HF model, we validated the efficacy and revealed the underlying mechanism of HXP in the treatment of HF. Zebrafish embryos were pretreated with different concentrations of HXP followed by verapamil administration, and we found that HXP significantly improved cardiac function in HF zebrafish, such as by effectively alleviating venous congestion and increasing heart rates. Mechanistically, HXP evidently inhibited verapamil-induced ROS and H2O2 production and upregulated CAT activity in HF zebrafish. Moreover, transgenic lines Tg(mpx:EGFP) and Tg(nfkb:EGFP) were administered for inflammation evaluation, and we found that neutrophil infiltration in HF zebrafish hearts and the activated NF-kB level could be reduced by HXP. Furthermore, HXP significantly downregulated the level of cell apoptosis in HF zebrafish hearts, as assessed by AO staining. Molecularly, RT‒qPCR results showed that pretreatment with HXP upregulated antioxidant-related genes such as gpx-1a and gss and downregulated the expression of the stress-related gene hsp70, proinflammatory genes such as tnf-α, il-6 and lck, and apoptosis-related indicators such as apaf1, puma and caspase9. In conclusion, HXP exerts a protective effect on verapamil-induced zebrafish HF through inhibition of oxidative stress-triggered inflammation and apoptosis.

The impact of Verapamil for radial access in diagnostic cerebrovascular angiograms: A retrospective case-control study.

Different combinations of medications are utilized during wrist access for radial artery (RA) or ulnar artery (UA) catheterization in neuroendovascular procedures to preclude vasospasm. These "cocktails" commonly include the calcium channel blocker Verapamil, without established benefit. We analyze outcomes in patients with and without Verapamil in their "cocktail" by using a case-control cohort of our single-center experience. A prospective log of consecutive patients who underwent diagnostic cerebral angiograms using RA/UA access was retrospectively reviewed, and patients were grouped into Verapamil and non-Verapamil cohorts. The primary outcomes assessed were the presence of forearm skin rashes (hives) and RA/UA spasms. Our initial management included Verapamil (5 mg) in the cocktail, but Verapamil was removed after we noticed the development of hives in multiple patients immediately following its injection. A total of 221 patients underwent 241 RA/UA diagnostic cerebral angiograms and were included in our analysis. One hundred and forty-nine patients (61.8%) underwent catheterization with Verapamil and 92 (38.2%) were catheterized without it. Four of the 149 patients in the Verapamil group (2.7%) developed hives during the procedure and were treated with Benadryl (25 mg). Of the 92 patients who did not receive Verapamil, there were zero (0%) cases of hives and one (1.1%) case of vasospasm. Verapamil in the "cocktail" for wrist access diagnostic cerebral angiograms was associated with periprocedural hives, but not associated with a significant reduction in spasm compared to the non-Verapamil group. Our findings suggest that the administration of prophylactic Verapamil for these procedures may not be necessary.

Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro

Low back pain is usually caused by intervertebral disc degeneration (IVDD), during which the involvement of oxidation system imbalance and inflammasome activation cannot be neglected. In this study, we aimed to validate the expression level of TXNIP in IVDD and investigate the function and potential mechanism of action of verapamil. TXNIP is upregulated in the degenerate nucleus pulposus in both humans and rats, as well as in tert-butyl hydroperoxide (TBHP)-stimulated nucleus pulposus cells. Administration of verapamil, a classic clinical drug, mitigated the TBHP-induced overproduction of reactive oxygen species and activation of the NLRP3 inflammasome, thus protecting cells from pyroptosis, apoptosis, and extracellular matrix degradation. The Nrf2/TXNIP/NLRP3 axis plays a major role in verapamail-mediated protection. In vivo, a puncture-induced IVDD rat model was constructed, and we found that verapamil delayed the development of IVDD at both the imaging and histological levels. In summary, our results indicate the potential therapeutic effects and mechanisms of action of verapamil in the treatment of IVDD.

1762-P: Increased Glucose Sensing and Insulin Secretion Induced by Verapamil Is Associated with Enhanced Oxygen Consumption Rate in MIN6 ß-Cells

It has been shown recently that oral administration of verapamil in persons with type 1 diabetes (T1D) decreased the dependency on exogenous insulin and improved the β cell function. Additionally, it decreased the frequency of hypoglycemic events. This finding encouraged us to test the effect of verapamil on the function of MIN6 mouse β cell-line. Glucose-Stimulated Insulin Secretion (GSIS) assay was performed using static incubation method. MIN6 cells were pre-treated with 50 μM verapamil for 24 hours, then the levels of total insulin content and secreted insulin were measured before and after GSIS assay using highly sensitive mouse insulin ELISA kit. Glucose sensing was estimated by the percentage of secreted insulin over total insulin content for each concentration of glucose. The measured insulin levels were normalized by the level of total protein. Oxygen consumption rate (OCR) was measured using Seahorse system and metabolic stress kit. MIN6 cells were seeded in Agilent Seahorse XF96 cell culture microplate at a cell density of 4×104 cells/well, under normal (5.6 mM) and high (25.2 mM) glucose concentrations for 24 hours, after which, cells were treated with verapamil (50 μM) or left untreated and incubated for 24 hours. Our results show no significant difference between total insulin content of treated vs. untreated cells. GSIS data show that insulin secretion was significantly higher in verapamil-treated cells at 8.4, 11.2, and 16.8 mM, but not at 2.8 and 5.6 mM glucose. The results suggest that β cells were hypersensitized to glucose when treated with verapamil. In metabolic flux analysis for mitochondrial respiration, treatment with verapamil increased basal and maximal respiration. Taken together, our study showed that verapamil increased the level of glucose sensing and oxidative respiration under conditions of high glucose, which may explain its effect on lowering the frequency of hypoglycemic events in clinical studies. Disclosure H.Arefanian: None. S.E.John: None. M.Alhusayan: None. S.J.Kurian: None. N.A.Abukhalaf: None. S.Shenouda: None. H.Alsaeed: None. S.P.Kochumon: None. M.Abu-farha: None. J.Abubaker: None. A.T.Thangavel: None. F.Bahman: None. R.Ahmad: None. F.Almulla: None. A.Al madhoun: None. F.Alzaid: None. S.T.Sindhu: None. M.R.Williams: None. F.Alrashed: None. R.Nizam: None. S.Jacob: None. Funding Kuwait Foundation for the Advancement of Sciences (RACB-2019-001)

Contribution analysis of metabolic tissues on systemic exposure of an active metabolite after oral administration of verapamil using a stable isotope-labeled compound

The present study illustrates the advantage of an isotope-IV study for the contribution analysis of metabolic tissues on systemic exposure of metabolites. A model parent drug, verapamil (VER), and its metabolite, norverapamil (Nor-VER), were used. This isotope-IV study used rats with and without the pre-treatment of the CYP inhibitor 1-aminobenzotriazole (ABT), was performed by the oral administration of VER (1 mg/kg) combined with the intravenous administration of stable isotope-labeled VER (VER-d6, 0.005 mg/kg). Plasma concentration profiles of both compounds and respective metabolites (Nor-VER, Nor-VER-d6) were then evaluated by LC-MSMS. VER oral availability was increased, and the systemic clearance decreased, in addition, the relative systemic exposure of Nor-VER and Nor-VER-d6 was increased by ABT pre-treatment. PK analyses revealed that, in ABT untreated rats, most Nor-VER in systemic circulation originated from the intestinal absorption process. ABT pre-treatment increased the contribution ratio to the systemic exposure of Nor-VER from the hepatic metabolism of systemically circulated VER, and decreased the contribution ratio of intestinal metabolism. These findings indicated that the isotope-IV study may be useful for considering the PK profile of metabolites.

Topical Administration of Verapamil in Poly(ethylene glycol)-Modified Liposomes for Enhanced Sinonasal Tissue Residence in Chronic Rhinosinusitis: Ex Vivo and In Vivo Evaluations.

Verapamil is a calcium channel blocker that holds promise for the therapy of chronic rhinosinusitis (CRS) with and without nasal polyps. The verapamil-induced side effects limit its tolerated dose via the oral route, underscoring the usefulness of localized intranasal administration. However, the challenge to intranasal administration is mucociliary clearance, which diminishes localized dose availability. To overcome this challenge, verapamil was loaded into a mucoadhesive cationic poly(ethylene glycol)-modified (PEGylated) liposomal carrier. Organotypic nasal explants were exposed to verapamil liposomes under flow conditions to mimic mucociliary clearance. The liposomes resulted in significantly higher tissue residence compared with the free verapamil control. These findings were further confirmed in vivo in C57BL/6 mice following intranasal administration. Liposomes significantly increased the accumulation of verapamil in nasal tissues compared with the control group. The developed tissue-retentive verapamil liposomal formulation is considered a promising intranasal delivery system for CRS therapy.

Evaluation of the Effect of Isobutyl Paraben and 2-ethyl Hexyl Paraben on P-glycoprotein Functional Expression in Rats: A Pharmacokinetic Study.

Pharmaceutical excipients have been shown to influence drug disposition through modulating transport protein. This study assessed the effect of single dose administration of parabens on the pharmacokinetics (PK) of digoxin, a probe substrate of p-glycoprotein (p-gp), in vivo. Also, the effect of multiple dosing of parabens on p-gp expression was examined. Rats were randomized into four groups that received either the vehicle, 25 mg/ kg verapamil, 100 mg/ kg isobutyl paraben, or 100 mg/ kg 2-ethyl hexyl paraben, which was followed by giving 0.2 mg/ kg digoxin via oral gavage. Blood samples were collected at different time points, digoxin concentration was measured using LC/MS-MS, and digoxin PK parameters were estimated. Another set of rats received multiple doses of parabens for 14 days, followed by measuring intestinal and hepatic mRNA expression of p-gp using qRT-PCR. Single dose administration of verapamil significantly increased Cmax (by 60.4 %) and AUC0-t (by 61.7 %) of digoxin compared to the control group, while the PK parameters of digoxin in rats exposed to parabens were not significantly different from the control. Consistently, the mRNA expression of p-gp in the intestine and liver was not affected by parabens treatment. The lack of isobutylparaben and 2-ethylhexyl paraben effect on p-gp may suggest the insignificant interaction of parabens with p-gp drug substrates, which could be considered for safety when designing pharmaceutical formulations.

Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy.

Reports indicate that autophagy is essential for maintaining hepatocyte proliferative capacity during liver regeneration. However, the role of autophagy in fibrotic liver regeneration is incompletely elucidated. We investigated the deregulation of autophagic activities in liver regeneration after partial hepatectomy using a CCl4-induced fibrosis mouse model. The baseline autophagic activity was significantly increased in the fibrotic liver. After 50% partial hepatectomy (PHx), liver regeneration was remarkably decreased, accompanied by increased hepatocyte size and binuclearity ratio. Moreover, the expression of autophagy-related proteins was functionally deregulated and resulted in a reduction in the number of autophagosome and autophagosome-lysosome fusions. We further showed upregulation of autophagy activities through verapamil administration, improved hepatocyte proliferation capacity, and restricted cellular hypertrophy and binuclearity ratio. In conclusion, we demonstrated that the impairment of liver regeneration is associated with aberrant autophagy in fibrotic liver and that enhancing autophagy with verapamil may partially restore the impaired liver regeneration following PHx.

Verapamil inhibits TXNIP-NLRP3 inflammasome activation and preserves functional recovery after intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) is the second most common type of stroke with no satisfactory treatment. Recent studies from our group and others indicated a potential positive effect of verapamil, a commonly prescribed calcium channel blocker, with thioredoxin-interacting protein (TXNIP) inhibitor properties, in ischemic stroke and cognitive disorders. It is unclear whether there would be a beneficial effect of verapamil administration in ICH. Therefore, this study was designed to determine the neuroprotective effects of verapamil in a murine ICH model. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum of adult male C57BL/6 mice. Verapamil (0.15 mg/kg) or saline was administered intravenously at 1 h post-ICH followed by oral (1 mg/kg/d) administration in drinking water for 28 days. Motor and cognitive function were assessed using established tests for motor coordination, spatial learning, short- and long-term memory. A subset of animals was sacrificed at 72 h after ICH for molecular analysis. Verapamil treatment reduced expression of TXNIP and NOD-like receptor pyrin domain-containing-3 inflammasome activation in the perihematomal area. These protective effects of verapamil were associated with decreased proinflammatory mediators, microglial activation, and blood-brain barrier permeability markers and paralleled less phosphorylated nuclear factor kappa B level. Our findings also demonstrate that long-term low-dose verapamil effectively attenuated motor and cognitive impairments. Taken together, these data indicate that verapamil has therapeutic potential in improving acute motor function after ICH. Further investigations are needed to confirm whether verapamil treatment could be a promising candidate for clinical trials.

Idiopathic left fascicular ventricular tachycardia in children and adolescents.

Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

Increased Ca2+ influx through CaV1.2 drives aortic valve calcification

Calcific aortic valve disease (CAVD) is heritable, as revealed by recent GWAS. While polymorphisms linked to increased expression of CACNA1C — encoding the CaV1.2 L-type voltage-gated Ca2+ channel — and increased Ca2+ signaling are associated with CAVD, whether increased Ca2+ influx through the druggable CaV1.2 causes CAVD is unknown. We confirmed the association between increased CaV1.2 expression and CAVD in surgically removed aortic valves from patients. We extended our studies with a transgenic mouse model that mimics increased CaV1.2 expression within aortic valve interstitial cells (VICs). In young mice maintained on normal chow, we observed dystrophic valve lesions that mimic changes found in presymptomatic CAVD and showed activation of chondrogenic and osteogenic transcriptional regulators within these valve lesions. Chronic administration of verapamil, a CaV1.2 antagonist used clinically, slowed the progression of lesion development in vivo. Exploiting VIC cultures, we demonstrated that increased Ca2+ influx through CaV1.2 drives signaling programs that lead to myofibroblast activation of VICs and upregulation of genes associated with aortic valve calcification. Our data support a causal role for Ca2+ influx through CaV1.2 in CAVD and suggest that early treatment with Ca2+ channel blockers is an effective therapeutic strategy.

Intracoronary epinephrine and verapamil in the refractory no-reflow phenomenon in patients with acute myocardial infarction

Despite modern advances in performing percutaneous coronary interventions, refractory no-reflow remains a serious problem that worsens in-hospital and long-term prognosis. Low-dose adrenaline may exhibit potent beta-receptor agonist properties that mediate coronary vasodilation.Aim. To evaluate the efficacy and safety of intracoronary administration of epinephrine and verapamil, as well as their combination, compared with standard treatment in patients with ST-segment elevation myocardial infarction (STEMI) and refractory no-reflow during percutaneous coronary interventions.Material and methods. Patients with STEMI and refractory no-reflow will be randomized into 4 groups: standard therapy, intracoronary adrenaline, intracoronary verapamil, intracoronary epinephrine + verapamil. All patients will be assessed for epicardial blood flow using the Thrombolysis in Myocardial Infarction (TIMI) and Myocardial Blush Grade (MBG) scales, peak troponin levels, ST segment changes, echocardiography, magnetic roesnance imaging, and dynamic single photon emission computed tomography.Results. Based on the pharmacodynamic effects of epinephrine and verapamil, their combination is expected to have a more potent vasodilating effect.Conclusion. If the Intracoronary administration of EPInephrine and VERapamil in the refractory no-reflow phenomenon (EPIVER) study will be successful, a novel, more effective method for managing refractory no-reflow phenomenon will appear. This will ensure better preservation of left ventricular systolic function, as well as improve the prognosis and clinical course of the disease.

Intraoperative Verapamil Fails to Reduce Delayed Graft Function in Donation After Circulatory Death Renal Allografts.

Background.The shortage of transplantable organs has led to increased utilization of kidneys that may be particularly vulnerable to ischemia-reperfusion injury (IRI) and delayed graft function (DGF). Kidneys from donation after circulatory death (DCD) donors have additional IRI from donor procurement that results in increased risk of DGF. Verapamil may reduce IRI in kidney allografts when given at the time of organ reperfusion. This study sought to determine if intraoperative administration of verapamil (Ver) could reduce the risk of DGF in DCD kidney transplants.Methods.A single-center retrospective matched cohort study was performed of 93 Ver (–) kidney transplant recipients compared with 93 Ver (+) kidney transplant recipients, matched by donor age, Kidney Donor Profile Index, and DCD status. Covariates that could impact DGF risk were evaluated by univariate and multivariate logistic regression analyses.Results.The Ver (–) and Ver (+) matched cohorts did not have any significant differences in the demographic covariates. There was no difference in DGF rate between the Ver cohorts in either the overall study population or within the DCD subgroup. There was a trend toward reduced DGF in the Ver (+) cohort for cold ischemia time (CIT) ≤24 h, but this failed to achieve statistical significance. On multivariate analysis, only CIT was found to be independently associated with DGF.Conclusions.Intraoperative verapamil failed to reduce DGF risk in DCD kidney allografts. Limitations to this study include nonrandomization for the intraoperative administration of verapamil and the mean CIT >24 h in the study population. Only CIT was an independent prognosticator for DGF on multivariate analysis in a cohort matched for DCD status, consistent with prior studies.