Negative Inotropic Effect of Diazepam in Isolated Guinea Pig Heart.

Abstract

ABSTRACT. The inotropic effect of diazepam, a benzodiazepine derivative, and its mechanism of action were examined using guinea pig heart and single ventricular cell preparations. In Langendorff hearts and right ventricular free-wall preparations, diazepam (10 to 100 µM) produced a monophasic negative inotropic effect in a concentration dependent manner. Neither a central type (flumazenil 1 µM) nor a peripheral type (PK11195 10 µM) of benzodiazepine receptor antagonist antagonized the monophasic negative inotropic effects of diazepam. Diazepam (10 to 100 µM) shortened action potential duration of papillary muscle in a concentration dependent manner. In isolated single ventricular cells, diazepam (30 and 100 µM) inhibited the calcium current (I Ca ) in a concentration dependent manner. Diazepam produced a significant decrease in I Ca elicited by first depolarizing pulses, however, the decrease of I Ca was not augmented during a train of depolarizing pulses. Thus, diazepam appears to produce a tonic block of cardiac calcium channels and the mode of inhibition is clearly different from the use-dependent block of verapamil. From these results, it was concluded that diazepam produces a monophasic negative inotropic effect that is independent of the benzodiazepine receptor, and is probably mediated through an inhibition of I Ca in guinea pig heart preparations.KEY WORDS: calcium current, diazepam, heart, negative inotropic effect, patch clamp method.

Part 8: Advanced Life Support

“…521 Four studies indicated that flumazenil is unlikely to improve hemodynamic function in the setting of benzodiazepine overdose and may complicate other therapy (LOE 5). 518,[522][523][524] Two studies described serious adverse effects such as seizure, arrhythmia, hypotension, and withdrawal syndrome after flumazenil was given to patients presenting with decreased level of consciousness attributed to either benzodiazepine toxicity or an unknown cause (LOE 5). 518,525 These side effects were more common with coingestants (such as tricyclic antidepressant and opioids), chronic benzodiazepine use or abuse, and known seizure disorder.…”

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

“…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). Ca 2+ , as a second messenger and a regulatory factor, plays a pivotal role in progression of cardiac hypertrophy (30).…”

“…Peripheral Benzodiazepine Receptors (PBRs), also known as 18kDa translocator proteins, are expressed in various tissues, including the heart, and play an important role in regulation of cardiac hypertrophy and IschemiaReperfusion (I/R) injury (3,(14)(15)(16)(17). Hence, they represent a novel therapeutic target in cardiovascular diseases (18).…”

“…Repeated administration of diazepam can change the density of PBRs in peripheral tissues and organs (14,15,17). Its administration can also affect myocardial susceptibility to ischemic injury (7,18).…”

Benzodiazepines Inhibit the Acetylcholine Receptor-Operated Potassium Current (I_K.ACh) by Different Mechanisms in Guinea-pig Atrial Myocytes

“…For example, both positive and negative inotropic actions, biphasic inotropic action, and no effect of diazepam have been reported in different species of animals using various ranges of concentrations [1,5,8,23]. Our previous studies have provided one explanation for this contradiction, i.e., diazepam produced the negative inotropic effect in isolated guinea pig heart through inhibition of the calcium current [15], while at the same time, it increased calcium sensitivity of the cardiac muscle fiber in the same concentration ranges [13]. From these reports about diazepam, benzodiazepine derivatives are presumed to affect the ionic currents in the heart.…”