Arie Zeegers

PK 11195 antagonizes the positive inotropic response of the isolated rat heart to diazepam but not the negative inotropic response

The influence of the ligand PK 11195 (1-(2-chlorophenyl)-N-methyl-N-(1- methylpropyl)-3-isoquinolinecarboxamide), antagonist of the peripheral-type benzodiazepine receptor, on the inotropic response of the perfused rat heart to diazepam (7-chloro-5-phenyl-methyl- 1,3-dihydro-2H-1,4-benzodiazepin-2-one) was studied. Diazepam induced a positive inotropic response which was preceded by a transient negative inotropic response. Concentrations of 10(-7) M PK 11195 were ineffective, whereas concentrations of 10(-6) and 10(-5) M PK 11195 reduced the positive inotropic response significantly. At 5 x 10(-5) M PK 11195 the response was completely abolished. The negative inotropic response was not changed by either concentration of PK 11195 used. It is concluded that the positive inotropic response of the isolated rat heart to diazepam may well be mediated through peripheral-type benzodiazepine receptors; the negative inotropic response must be related to other (more complex) mechanisms.

Modification of cardiac actions of Ro 05-4864 by PK 11195 and flumazenil in the perfused rat heart

The benzodiazepine analogue Ro 05-4864 [chlorodiazepam] (2.10[-5] to 4.10[-4] M) induced a concentration-dependent increase of coronary flow rate (Emax 82.4% [+/- 2.2 SEM]) and an increase of contraction force (Emax 68.3% [+/- 4.7 SEM]) of the retrograde perfused, isolated Langendorff rat heart. The influence of PK 11195, antagonist of the peripheral type benzodiazepine receptor, and flumazenil (Anexate), antagonist of the central type benzodiazepine receptor, on these responses to Ro 5-4864 was studied. In concentrations of 10(-7) to 5.10(-5) M, PK 11195 significantly reduced both the increase of coronary flow rate and of contraction force, without affecting these functions by itself; the positive inotropic response produced by Ro 05-4864 was even abolished in the presence of 5.10(-5) M PK 11195. The Emax values of Ro 05-4864 on both coronary flow and inotropy were reduced significantly by PK 11195. In the presence of flumazenil, 10(-7) to 10(-5) M, both the vasodilatory and the positive inotropic response induced by Ro 05-4864 were significantly counteracted as well. The Emax values of Ro 05-4864 were reduced significantly. In conclusion, the results support earlier suggestions that it is tempting to involve peripheral type benzodiazepine receptors in cardiac actions of benzodiazepines. The finding that the centrally acting benzodiazepine antagonist flumazenil reduced the cardiac actions of Ro 05-4864 is as yet difficult to explain. On the other hand concentrations of both agonist and antagonist employed are so-much high that interference of other receptors than benzodiazepine receptors must be considered as well.

Flunarizine but not theophylline modulates inotropic responses of the isolated rat heart to diazepam

Diazepam (2 x 10(-5)-6 x 10(-4) M) induced a concentration-dependent positive inotropic effect on the perfused rat heart which was preceded by a transient concentration-dependent negative inotropic response. The influence of the Ca(2+)-entry blocking drug, flunarizine, and the adenosine receptor blocking drug, theophylline on these inotropic responses was studied. Flunarizine in concentrations of 10(-9)-10(-6) M antagonized the positive inotropic response to diazepam significantly; the negative inotropic response was reduced as well. At the lower concentrations of diazepam the negative inotropic response was completely abolished in the presence of flunarizine. The actions of the Ca(2+)-entry blocker were related to the concentrations used. Theophylline in concentrations up to 5 x 10(-5) M did not interfere with either inotropic response to diazepam. The results suggest that Ca2+ currents in the myocardium are involved with the response of the isolated heart to diazepam. It is concluded that the finding that the negative inotropic effect of diazepam was almost abolished by flunarizine suggests that the site of this response most be associated with Ca(2+)-current mechanisms.

Cardiac effects of benzodiazepine receptor agonists and antagonists in the isolated rat heart: A comparative study

Effects of PK 11195 and flumazenil on cardiac responses to diazepam, clonazepam and zolpidem were compared. Coronary flow rate was increased at relatively low doses of diazepam and decreased at higher doses. Clonazepam induced a dose-dependent increase, and zolpidem a decrease of coronary flow rate. PK 11195 reduced the diazepam-induced increase of coronary flow rate, and flumazenil was ineffective. Neither antagonist evoked substantial changes in the decrease of coronary flow rate. PK 11195, and less so flumazenil, antagonized the clonazepam-induced increase. PK 11195 and flumazenil only in their highest doses suppressed and respectively potentiated the zolpidem-induced decrease. Inotropy showed a biphasic response in the presence of diazepam, i.e. an initial transient decrease, followed by a dose-dependent increase in two steps. Clonazepam induced a similar response. Zolpidem increased the inotropy. The negative inotropic response induced by diazepam did not change significantly in the presence of PK 11195 or flumazenil. The positive inotropic response was suppressed by PK 11195, and less so by flumazenil. The negative response to clonazepam was antagonized by both PK 11195 and flumazenil; the positive response was not significantly changed. In the presence of lower doses of PK 11195, the zolpidem-induced response was potentiated, whereas higher doses produced reversal; flumazenil potentiated the response. In conclusion, the results support earlier suggestions, involving receptor mechanisms with cardiac effects of benzodiazepines. Both agonists and antagonists (inter)act in a different manner, suggesting that rather ambiguous receptor mechanisms are involved in benzodiazepine effects in the heart.

Alterations in high affinity choline accumulation rate in rat cerebral cortex during anaesthesia with ketamine and pentobarbital

After i.p. injection of ketamine (75 mg/kg) or pentobarbital-Na (40 mg/kg) to rats, there was a rapid, then a steady decrease of the sodium-dependent high affinity choline (HAC) accumulation rate to a minimum. This minimum was followed by a rapid increase (ketamine) or a gradual rise (pentobarbital-Na). Immediately after the rats came out of anaesthesia, the accumulation rate had not yet completely recovered. We suggest the ketamine or pentobarbital-Na induce alterations in central cholinergic systems, i.e. changes in choline uptake and incorporation into acetylcholine. It is conceivable that interactions of cholinesterase inhibitors or corticosteroids with the anaesthetics are based upon some modification of these changes.