Effects of L-type Ca2+ channel modulation on direct myocardial effects of diazepam and midazolam in adult rat ventricular myocytes

Dysrhythmias, although common in overdose situations, are not often seen after benzodiazepine exposures. We report two cases of transient atrioventricular block after benzodiazepine misuse. Case 1 is a 4-year-old boy who was found unresponsive after an ingestion of clonazepam. An electrocardiogram (EKG) performed on emergency department presentation demonstrated first-degree atrioventricular block (PR 206 ms). After flumazenil administration, he developed second-degree atrioventricular block (Mobitz Type 1). EKG abnormalities resolved by morning. Serum clonazepam was 478 ng/mL (laboratory clonazepam reference range, 10-75 ng/mL with a dose of up to 6 mg/day) 5 hours after being found unresponsive. Case 2 is a 23-year-old man who presented to the emergency department after ingesting risperidone, combination hydrocodone/acetaminophen, and alprazolam. On arrival, his EKG demonstrated sinus bradycardia with a PR interval of 182 msec. He subsequently developed second-degree atrioventricular block (Mobitz Type I). Sinus bradycardia with resolution of his atrioventricular block (PR 200 ms) was seen on a third EKG performed 5 hours after presentation. These two patients demonstrated transient first- and second-degree atrioventricular block after benzodiazepine exposure. Benzodiazepines have been shown to alter L-type Ca2+ channel function. This alteration in function may account for the dysrhythmias seen in our patients. Together, these cases serve to remind clinicians of this rare but potentially serious complication associated with benzodiazepine exposure.

show abstract

“…[8][9][10][11] Flumazenil inconsistently reverses this decrease. [8][9][10][11] Flumazenil inconsistently reverses this decrease.…”

Section: Discussionmentioning

confidence: 94%

Benzodiazepine-Associated Atrioventricular Block

Arroyo-Plasencia

Ballentine

Mowry

et al. 2012

American Journal of Therapeutics

View full text Add to dashboard Cite

show abstract

“…The findings reflect the increase in averaged force and thus, an index of energy consumption rate and pH i transients. In contrast, Ca 2+ channel blocker, verapamil, has negative inotropic effects on cardiac contractions ( Bell and McDermott, 1995 ; Kanaya et al., 2006 ). We further tested the effects of verapamil on cardiac contractions and pH i transients.…”

Section: Resultsmentioning

confidence: 99%

Beat-to-beat dynamic regulation of intracellular pH in cardiomyocytes

et al. 2022

View full text Add to dashboard Cite

Summary The mammalian heart beats incessantly with rhythmic mechanical activities generating acids that need to be buffered to maintain a stable intracellular pH (pH i ) for normal cardiac function. Even though spatial pH i non-uniformity in cardiomyocytes has been documented, it remains unknown how pH i is regulated to match the dynamic cardiac contractions. Here, we demonstrated beat-to-beat intracellular acidification, termed pH i transients, in synchrony with cardiomyocyte contractions. The pH i transients are regulated by pacing rate, Cl − /HCO 3 - transporters, pH i buffering capacity, and β-adrenergic signaling. Mitochondrial electron-transport chain inhibition attenuates the pH i transients, implicating mitochondrial activity in sculpting the pH i regulation. The pH i transients provide dynamic alterations of H + transport required for ATP synthesis, and a decrease in pH i may serve as a negative feedback to cardiac contractions. Current findings dovetail with the prevailing three known dynamic systems, namely electrical, Ca 2+ , and mechanical systems, and may reveal broader features of pH i handling in excitable cells.

show abstract

“…On the other hand, several studies have shown that diazepam was able to affect cells by mechanisms related or unrelated to PBRs (24,26). For example, diazepam decreased the Ca 2+ transient and the L-type Ca 2+ channel, which are both important in the negative inotropism and chronotropism caused by this drug (27)(28)(29). In the same line, another study on guinea pigs' hearts indicated that the negative inotropic effect of diazepam referred to its calcium channel blocking effect (15).…”

Section: Discussionmentioning

confidence: 98%

The Effect of Diazepam on the Function of Hypertrophied Rats’ Hearts in Ischemia-Reperfusion Conditions

Shackebaei¹,

Feizollahi²,

Hesari³

et al. 2016

Int Cardiovasc Res J

View full text Add to dashboard Cite

A B S T R A C TBackground: Hypertrophied hearts are susceptible to ischemic injury. Besides, cardiac vulnerability could be changed in the presence of diazepam. Objectives: The current study aimed to investigate the effect of diazepam on hypertrophied rats' hearts in ischemia-reperfusion conditions. Materials and Methods: Male Wistar rats (body weight 210 -270 gr) were administered with isoproterenol (4 mg/kg body weight, intraperitoneally for 7 days) alone or along with diazepam (1 and 5 mg/kg body weight, intraperitoneally for 5 days). The control rats received normal saline intraperitoneally. The animal s' hearts were isolated according to langendorff setup and were passed through baseline, ischemia, and reperfusion stages. Then, cardiac mass index (ratio of heart weight to body weight) was measured. Cardiac functional parameters, including left ventricular developed pressure and rate pressure product, were also assessed at baseline and following ischemia. The data were analyzed using ANOVA and P < 0.05 was considered to be statistically significant. Results: Isoproterenol-induced cardiac hypertrophy was significantly reduced by both doses of diazepam compared to the group only treated with isoproterenol (P < 0.05) although it did not reach the control level. However, diazepam administration (1 and 5 mg/kg) did not change isoproterenol-induced exacerbated ischemia-reperfusion injury compared to the control group (P = 0.001 and P = 0.013, respectively). Conclusions: Diazepam relatively prevented the isoproterenol-induced cardiac hypertrophy in the animal model. This effect could be probably explained by the modification of oxidative stress and preservation of intracellular calcium concentration. Considering the common clinical usage of diazepam, as a peripheral benzodiazepine ligand, antihypertrophic effects of diazepam are recommended to be investigated in clinical trials.

show abstract

Effects of L-type Ca2+ channel modulation on direct myocardial effects of diazepam and midazolam in adult rat ventricular myocytes

Abstract: Midazolam and diazepam have differential effects on cardiac E-C coupling. Diazepam, but not midazolam, enhances cardiac E-C coupling independent of L-type Ca2+ channel modulation.

Cited by 7 publications

References 22 publications

Benzodiazepine-Associated Atrioventricular Block

Benzodiazepine-Associated Atrioventricular Block

Beat-to-beat dynamic regulation of intracellular pH in cardiomyocytes

The Effect of Diazepam on the Function of Hypertrophied Rats’ Hearts in Ischemia-Reperfusion Conditions

Contact Info

Product

Resources

About