Behavioral, autonomic and motor effects of neuroleptic drugs in cats: motor impairment and aggression.

The effects of eight neuroleptic drugs injected into the cerebral ventricles on behavior, autonomic and motor activity of unanesthetized cats have been studied. Chlorpromazine, trifluorpromazine, droperidol, haloperidol, domperidone and spiperone induced emotional behavior (restlessness, miaowing, rage, attack, defense, fighting with paws, biting), autonomic (mydriasis, tachypnoea, dyspnoea, panting, salivation, defecation, urination, licking, vomiting) and motor (ataxia, muscular weakness, adynamia) phenomena. The main and the most consistent effect was the motor impairment, while the aggression was inconsistent and of moderate intensity. Of the neuroleptic drugs injected, only spiperone, domperidone and trifluorpromazine produced a dose-dependent motor impairment. The autonomic effects were also inconsistent and of low intensity. Metoclopramide induced inconsistent autonomic and motor effects, while sulpiride was devoid of any visible behavioral, autonomic and motor activity. It appears, therefore, that the motor impairment as well as the aggression caused by the neuroleptic drugs is perhaps related to central D-1 rather than to central D-2 dopamine receptors, but an effect on central norepinephrine and on central serotonin receptors cannot be excluded.

Differential inhibition by ethanol of norepinephrine- and clonidine-induced emesis in cats.

The effect of acute ethanol administration into the cerebral ventricles on the unanesthetized cat upon emesis produced by norepinephrine and clonidine injected similarly as well as upon emesis evoked by copper sulfate given orally was compared and investigated. Ethanol inhibited the norepinephrine- and clonidine-induced emesis. The inhibitory effect of ethanol occurred after a transient and inconsistent emetic action of the drug. Norepinephrine-induced emesis was about 12 times more sensitive than clonidine-induced emesis to the inhibitory effect of ethanol. In addition, norepinephrine-, but not clonidine-induced emesis was abolished after ablation of the area postrema. On the contrary, intracerebroventricular ethanol had virtually no effect on emesis caused by intragastric copper sulfate. The inhibitory effect of ethanol is ascribed to an action on alpha-2 adrenoceptors within the area postrema and on imidazoline-preferring sites and/or muscarinic cholinoceptors outside the area postrema, but not on the emetic region of the brainstem reticular formation. It follows then that ethanol can differentiate alpha-2 adrenoceptors from imidazoline-preferring sites and/or muscarinic cholinoceptors in the brain of the cat.

[Nervous mechanisms of spontaneous oscillations of systolic blood pressure and heart rate]. / Mécanismes nerveux des oscillations spontanées de la pression artérielle systolique et de la fréquence cardiaque.

The phenomenon of rhythmic fluctuations in cardiovascular variables such as heart rate (HR) or arterial blood pressure (BP) has attracted the attention of workers in both pure and applied research. In recent years, the possibility of quantifying these oscillations by using power spectral analysis has aroused a growing interest. We investigated the fluctuations which underly the spontaneous variability of BP and HR in conscious rats. Intrafemoral pulsatile BP was computed to generate evenly spaced signals (systolic, diastolic, mean BP, HR) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic Blood Pressure (SBP) and HR exhibited low frequency oscillations (Mayer waves, 20-605 mHz) and a high frequency oscillation related to respiration (1,855 mHz). The respiratory fluctuations in HR were almost abolished by vagal blockade (atropine). HR fluctuations in the low frequency regime were diminished by vagal blockade or cardiac sympathetic blockade (atenolol). The respiratory frequency fluctuations in SBP were markedly increased by alpha sympathetic blockade (prazosin). On the contrary the low frequency oscillations in SBP were reduced by alpha sympathetic blockade. These data indicate that in conscious rats: 1) the HR oscillation with respiration is vagally mediated, 2) the HR fluctuation in the low frequency regime is jointly mediated by beta sympathetic and parasympathetic activities, 3) the respiratory oscillation in SBP depends on fluctuations in cardiac output and is normally counteracted by the sympathetic tone, 4) the low frequency oscillations in SBP reflect the sympathetic activity to the resistance vessels.

The potentiation of cardiodepressant and hypotensive effects of bradykinin by enalapril and captopril both in vitro and in vivo.

1. Bradykinin (cumulative concentrations of 0.007-0.09 micrograms ml-1) produced a dose-related, but statistically insignificant depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. The same concentrations of bradykinin did not change the atrial rate, but a tendency to a slight decrease was observed. 2. Enalapril (4.06 or 13.54 mumol l-1), produced a dose-related potentiation of the effect of the highest concentration of bradykinin on the isometric contraction. 3. Captopril (equimolar concentrations) also potentiated the effect of the highest concentration of bradykinin on the isometric contraction. This effect of captopril was not dose-related. 4. Both enalapril and captopril did not change the effect of bradykinin on the heart rate. 5. Bradykinin induced dose-related hypotensive responses in anaesthetized cats (0.03-1.0 microgram/kg b.w., i.v.) with a tendency towards bradycardia. 6. Enalapril (0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. However, the potentiating effect of enalapril was not dose-dependent. 7. Captopril (0.1, 0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. Also, the potentiating effect of captopril was not dose-dependent. 8. The failure of ACE inhibitors to potentiate the cardiodepressant and hypotensive effects of bradykinin in a dose-dependent manner is explained with some other mechanism(s) independent of ACE inhibition.

[Spectrum analysis of blood pressure and cardiac rate in the conscious rat]. / Analyse spectrale de la pression artérielle et de la fréquence cardiaque du rat conscient.

Intrafemoral pulsatile blood pressure of conscious rats was computed to generate evenly spaced signals (systolic, diastolic, mean blood pressure, heart rate) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic blood pressure and heart rate exhibited low frequency oscillations (Mayer waves, 20-605 mHz) and a high frequency peak related to respiration (1,765 mHz). The diastolic blood pressure and the mean blood pressure only exhibited low frequency oscillations. This procedure could be useful to analyze the various components of blood pressure variability.

The area postrema and the hypertensive effect of angiotensin.

The intracerebroventricular administration of angiotensin II in pentobarbital-anesthetized cats produced dose-dependent increases in the arterial blood pressure without significant changes in the heart rate. The ablation of the area postrema significantly reduced, but did not abolish, the pressor effect of angiotensin injected into the cerebral ventricles. It follows, then, that the central pressor effect of angiotensin is dependent on the integrity of the area postrema and that this central site, at least in part, contributes to the pressor action of endogenous angiotensin.

Clonidine reduces blood pressure and heart rate oscillations in the conscious rat.

We investigated the effects of clonidine on the fluctuations that underlie the spontaneous variability of blood pressure (BP) and heart rate (HR) in conscious rats. Analog-to-digital conversion of the intrafemoral BP was used to determine systolic, diastolic, and mean BP and HR every 200 ms. The equidistant sampling allowed a direct spectral analysis using a fast Fourier transform algorithm. An i.v. dose of 10 micrograms/kg of clonidine markedly reduced the variability of BP and HR after 20 min as indicated by a reduction in the variances by approximately one-half of the control value for BP and to one-third of the control value for HR. At this time, clonidine had not significantly altered BP or HR. Spectral profiles of systolic BP and HR illustrated the alterations in the spontaneous oscillations underlying these variance changes. Clonidine dramatically reduced the amplitude of BP and HR oscillations in the frequency region of 195-605 mHZ, which depends on the activity of the autonomic nervous system. We suggest that an increased sensitivity of the baroreflex is responsible for the apparent better control of BP and HR with clonidine.

Spectral analysis of blood pressure and heart rate in conscious rats: effects of autonomic blockers.

We investigated the fluctuations which underly the spontaneous variability of blood pressure and heart rate in conscious rats. Intrafemoral blood pressure was computed to generate evenly spaced signals (systolic, diastolic, mean blood pressure, heart rate) at 200 ms intervals. This equidistant sampling allowed a direct spectral analysis using a Fast Fourier Transform algorithm. Systolic blood pressure and heart rate exhibited low-frequency oscillations (Mayer waves, 20-605 mHz) and a high- frequency oscillation related to respiration (1855 mHz). The respiratory fluctuations in heart rate were almost abolished by vagal blockade (atropine). Heart rate fluctuations in the low-frequency regime were diminished by vagal blockade or cardiac sympathetic blockade (atenolol). The respiratory frequency fluctuations in systolic blood pressure were markedly increased by alpha-sympathetic blockade (prazosin). In contrast, the low-frequency oscillations in systolic blood pressure were reduced by alpha-sympathetic blockade. These data indicate that in conscious rats: (1) the heart rate oscillation with respiration is vagally mediated; (2) the heart rate fluctuation in the low-frequency range is jointly mediated by beta-sympathetic and parasympathetic activities; (3) the respiratory oscillation in systolic blood pressure depends on fluctuations in cardiac output and is normally counteracted by the sympathetic tone; (4) the low-frequency oscillations in systolic blood pressure reflect the sympathetic activity to the resistance vessels.

Ablation of the area postrema and emesis.

The emetic action of dopamine, norepinephrine, epinephrine, nicotine, dimethylphenyl-piperazinium (DMPP), and 4-m-chlorophenylcarbamoyloxy-2-butynyltrimethylammonium (McN-A-343) injected intracerebroventricularly (i.c.v.) to the unanesthetized cat was investigated and compared. ED50 values (mg) were as follows: nicotine, 0.011; epinephrine, 0.047; norepinephrine, 0.57; DMPP, 0.9; dopamine, 1.66; and McN-A-343, 4.42. The most potent was nicotine, whereas the least active McN-A-343. On the other hand, DMPP produced the longest emetic response, about 30 min, while McN-A-343-induced emesis lasted up to 1 min. The ablation of the area postrema abolished the emetic response to i.c.v. dopamine, norepinephrine, epinephrine, nicotine, and DMPP. However, the emetic response to i.c.v. McN-A-343 was significantly reduced in cats with an ablated area postrema. Taken together, the results obtained show that the area postrema is almost always involved in the central regulation of emesis and that the area postrema represents, in most cats, a common site of confluence of different inputs subserving the emesis.