Inhibition of the centrally induced increases in myocardial oxygen demand in rabbits by chronic treatment with baclofen, a selective GABA_B agonist

Abstract

1 A previous study from our group demonstrated that neurones of the paraventricular nucleus of the hypothalamus (PVN) are selectively involved in the central control of the cardiac function. Moreover, in that study, it was shown that baclofen, a selective GABAB receptor agonist, is capable of modulating the increases in myocardial contractility and oxygen demand evoked by electrical or pharmacological stimulation of the PVN. Nevertheless, the acute administration of this compound was frequently accompanied by a cardiodepressant effect. 2 In the present study, the effects of a long term treatment (14 days) with baclofen (3 or 10 mg kg-', i.p.) have been examined on the excitatory haemodynamic responses evoked by central pharmacological stimulation in anaesthetized rabbits.3 The i.c.v. injection of L-glutamate (3 mg kg-') induced marked increases in dP/dt,,ma (32%), mean arterial pressure (39%) and on two indices of myocardial oxygen consumption: the rate-pressure product (34%) and the triple product (78%). 4 Baclofen blunted the positive inotropic response and the increases in myocardial oxygen consumption induced by L-glutamate in a dose-related manner. The higher dose of baclofen (10 mg kg-', i.p.), reduced by more than 50% these excitatory effects of L-glutamate without eliciting any significant negative effect on basal haemodynamics. The same doses of baclofen were not able to blunt the hypertensive response induced by central stimulation. 5 These results confirm and extend our previous findings suggesting that it is possible to discriminate the central control of vasomotor tone from that of cardiac function and also that baclofen can modulate the latter. It is concluded that when given chronically, baclofen modulates the increases in myocardial oxygen demand induced by activation of the central nervous system in doses which do not depress the resting cardiac function.

Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits

“…We have shown previously that the pharmacological stimulation of the central nervous system with L-glutamate injected into the lateral ventricle of rabbits markedly increases the sympathetic outflow to the periphery, resulting in important increases in myocardial oxygen consumption (8,25). It is noteworthy that successive stimulations are not possible in this experimental model since repeated injections of L-glutamate in the same animal lead to tachyphylaxis.…”

Pyridostigmine blunts the increases in myocardial oxygen demand elicited by the stimulation of the central nervous system in anesthetized rats

“…In this context, previous studies showed that electrical or pharmacological stimulation of the hypothalamus [14] or intracerebroventricular (icv) injection of glutamic acid [15] in rabbits caused an increase in blood pressure, cardiac contractility, and myocardial oxygen demand, reproducing the hemodynamic effects of a stressful situation or physical effort.…”

Cardioprotective Effects of Remifentanil in a Sympathetic Hyperactivity Model in Rabbits

“…Administration of the excitatory L-glutamate via ICV injection has been shown to increase cardiac contractility and myocardial oxygen consumption by stimulating the hypothalamus (16). Tibirica et al (16) found that ICV injection of 3 µg kg −1 of L-glutamate was able to raise MAP and increase myocardial oxygen consumption without inducing myocardial ischemia in rabbits. L-NAME is a type of L-arginine, which is known to competitively inhibit NO synthesis.…”

“…The central control of human cardiac functions is situated in the paraventricular nuclei of the hypothalamus (16). Administration of the excitatory L-glutamate via ICV injection has been shown to increase cardiac contractility and myocardial oxygen consumption by stimulating the hypothalamus (16).…”