John A. Quest

Effect of Digitalis on Carotid Sinus Baroreceptor Activity

The effect of intracarotid injections of ouabain (25.0 μg) or acetylstrophanthidin (1.56 μg) on feline carotid sinus baroreceptors was evaluated using an isolated perfused carotid sinus preparation. The effects of the drugs on baroreceptor activity were determined by monitoring carotid sinus nerve activity and systemic arterial blood pressure. Administration of either drug to the isolated carotid sinus region altered the relationship between the change in carotid sinus pressure and the fall in systemic arterial blood pressure. Raising the carotid sinus pressure produced a greater depressor response when digitalis was present (−29.6 ± 3.8 mm Hg) than it did when digitalis was absent (−15.3 ± 2.6 mm Hg). Digitalis administration also resulted in a greater increase in carotid sinus nerve discharge when carotid sinus pressure was increased. At a constant carotid sinus pressure, digitalis increased the spontaneous firing of the carotid sinus nerve; the drug-induced augmentation in nerve firing was identical to that produced by raising carotid sinus pressure. These changes in baroreceptor activity in the presence of digitalis occurred without drug-induced changes in the pressure in the isolated carotid sinus region. The results demonstrate that the digitalis preparations studied can directly alter the sensitivity of baroreceptors and produce significant changes in carotid sinus nerve activity and cardiovascular function.

Experimental Studies on the Neurocardiovascular Effects of Urapidil

SummaryThe major purpose of our study was to determine whether urapidil acts in the central nervous system (CNS) to lower arterial blood pressure. Once demonstrating a CNS antihypertensive action of urapidil we further set out to determine: (1) the relative role of a CNS antihypertensive action to the total antihypertensive effect of urapidil; (2) the brain site of action for the antihypertensive effect of urapidil; and, (3) the receptor mechanism whereby urapidil acts in the CNS to lower arterial blood pressure. Studies were conducted in chloralose-anaesthetised cats, and arterial blood pressure and heart rate were monitored. Drugs were administered intravenously (IV), into the cerebral ventricles (ICV), topically by application to the ventral surface of the medulla and by microinjection into specific nuclei. Receptor binding studies were also conducted using rat cerebral cortex homogenates. We found that injection of urapidil into the fourth ventricle decreased arterial pressure. Local application of urapidil to the ventral medullary surface also decreased arterial blood pressure. Microinjection of urapidil into one of the nuclei associated with the ventral surface of the medulla, the rostral part of the nucleus reticularis lateralis (rLRN), produced a similar degree of antihypertensive effect. The effect of urapidil was not altered by α1-receptor blockade. Instead, the urapidil effect resembled that produced by drugs that stimulate serotonin (5-hydroxytryptamine)-1A receptors (B695-40 and 8-OH-DPAT). Furthermore, urapidil was found to have the highest potency for binding to serotonin-1A receptor sites (as compared to α1- and α2receptor sites). Urapidil administered IV was shown to lower arterial blood pressure in part by blocking peripheral α1-adrenoceptors but also, in high doses, by acting in the CNS to decrease central sympathetic outflow. These data indicate that urapidil is a unique drug, possessing both peripheral and CNS actions which contribute to its antihypertensive effect. Urapidil may also be unique in that its central action may involve activation of serotonin-1A receptors.

Hypotensive effect of urapidil: CNS site and relative contribution.

Summary: The purposes of our study were to determine the contribution of the CNS to the hypotensive effect of urapidil in the cat and the specific brain site of action of this agent. For the first purpose, urapidil was studied on preganglionic sympathetic nerve activity, arterial pressure, and heart rate. Three systemic bolus doses of urapidil were administered (0.22, 0.44, and 1.3 mg/kg). All three doses lowered arterial pressure, and the highest dose produced a significant decrease in sympathetic nerve discharge in five of six animals studied. The lower two doses had no significant effect on sympathetic activity, and none of the doses altered heart rate. These results suggest that a high i.v. dose of urapidil is required to evoke hypotension by an action in the central nervous system (CNS). For the second purpose, urapidil was applied bilaterally to the intermediate area of the ventral surface of the medulla in doses of 25 and 50 µg. These doses caused decreases in arterial pressure of −6.1 ± 2.2 (p < 0.05) and −21.0 ± 5.9 (p<0.05) mm Hg, respectively, but no change in heart rate. In addition, respiratory stimulation also occurred with the higher dose as respiratory minute volume increased by 81 ± 14 ml/min (p < 0.05). The highest dose of urapidil had no effect on arterial pressure when applied to other chemosensitive areas of the ventral surface of the brain. Comparative studies with prazosin (10 µg applied bilaterally to the intermediate area) indicated no hypotensive effect of this α1-adrenoceptor blocking agent. These results suggest that the central hypotensive effect of urapidil occurs at the intermediate area and does not involve blockade of α1-adrenoceptors.

Mechanism of the antihypertensive effect of alpha 2-agonists.

Drugs such as clonidine. methyldopa. guana-benz, guanfacine. and lofexidine have their primary site of antihypertensive action in the central nervous system (CNS) to activate alpha2-adrenergic receptors and lower arterial pressure. The most probable CNS site of action of these drugs is the medulla oblongata at a post-synaptic location. Current evidence indicates that within the medulla. the prototype drug, clonidinc. most likely acts at the lateral reticular nucleus. I his site is the most sensitive in terms of hypotension occurring alter microinjection of clonidinc. In addition, lesion of this nucleus abolishes the hypotensive effect of systemically administered clonidinc. Recently, a clonidine-displacing endogenous brain substance has been isolated and partially purified from calf brain. Know ledge of where clonidinc acts to lower blood pressure should help in assessing the role of an endogenous clonidine-displacing substance in CNS control of cardiovascular function

Comparative Effects of Urapidil, Prazosin, and Clonidine on Ligand Binding to Central Nervous System Receptors, Arterial Pressure, and Heart Rate in Experimental Animals

We studied the effects of urapidil, clonidine, and prazosin on ligand binding to central nervous system receptors in rats and on arterial pressure and heart rate in chloralose-anesthetized cats. Ligand binding studies indicated that urapidil had 90 times greater affinity for alpha 1 than for alpha 2 adrenergic receptors. Administration of urapidil (129 micrograms) into the cerebroventricles of cats revealed no effect after lateral ventricle injection, a decrease of 9.7 +/- 3.0 mm Hg after fourth ventricle injection, and an increase of 10.8 +/- 2.2 mm Hg after restriction of the drug in the forebrain ventricles. Clonidine (30 micrograms) produced hypotension and bradycardia after injection into the lateral ventricle. Prazosin was ineffective after cerebroventricular injection. Intravenous administration of 0.22, 0.67, and 2.00 mg/kg urapidil produced dose-dependent decreases in arterial pressure that were associated with blockade of alpha 1 adrenergic receptors. Intravenous administration of prazosin elicited the same response. Clonidine (10 micrograms/kg, intravenously produced an initial increase in arterial pressure that was unaffected by pretreatment with urapidil or prazosin. These results suggest that urapidil produces hypotension by an action on the peripheral vasculature and in the hindbrain. The peripheral effect involves blockade of alpha 1 adrenoceptors.

Chemical stimulation of the area postrema induces cardiorespiratory changes in the cat

The purpose of our study was to determine the cardiorespiratory effects of exciting cell bodies of the area postrema of the cat. This was accomplished by local application of L-glutamic acid (bilateral application of 5 microliter of a 250-1000 mM solution) and kainic acid (bilateral application of 5 microliter of a 40 mM solution) to the area postrema of chloralose-anesthetized cats while monitoring arterial pressure, heart rate, tidal volume and respiratory rate. These excitatory amino acids activate neuronal cell bodies but not axons of passage. L-Glutamic acid produced a dose-dependent increase in arterial pressure, decreases in respiratory rate and minute volume and, occasionally, ventricular tachyarrhythmias. Kainic acid produced effects similar to those seen with L-glutamic acid except the changes in respiratory activity were more pronounced with each animal exhibiting respiratory arrest. In artificially respired animals, kainic acid produced similar cardiovascular changes as those occurring in spontaneously breathing animals (i.e. increases in arterial pressure of 61 +/- 5.7 mm Hg, and in heart rate of 32 +/- 8.3 beats/min). Finally, application of kainic acid to the area postrema abolished the pressor and tachycardic responses to bilateral occlusion of the carotid arteries. These results suggest that activation of cell bodies in the area postrema can result in pronounced cardiorespiratory changes.

Central nervous system site of action for the respiratory depressant effect of diacetylmorphine (heroin) in the cat.

The purpose of our study was to identify central nervous system sites involved in the respiratory depressant effect of drugs that stimulate opioid receptors. Diacetylmorphine (heroin) was administered into several cerebroventricular regions of chloralose-anesthetized cats, while monitoring pulmonary ventilation with a Fleisch pneumotachograph. Administration of heroin (17, 50, 150, and 450 micrograms) into the forebrain ventricles, which was restricted to these ventricles, resulted in no significant respiratory effects. In contrast, administration of heroin into either the fourth ventricle or the cisterna magna resulted in a significant (P less than 0.05) decrease in respiratory minute volume (VE). In the fourth ventricle this was because of a decrease in frequency (f) and in the cisterna magna, to a decrease in tidal volume (VT). Intravenous administration of heroin in the same dose-range produced a decrease in VE, which was primarily due to a decrease in f. Bilateral application of heroin (70 micrograms/side) to each of three ventral medullary surface sites (Mitchells, Schlaefkes, and Loeschckes areas) known to influence respiration elicited a decrease in VE only at Mitchells area. This decrease was due to decreases in f and VT. The role of this site in the action of intravenously administered heroin was tested by topical application of naloxone to this area in animals with respiratory depression evoked by intravenous heroin. Bilateral application of naloxone (15 micrograms/side) to Mitchells area restored breathing to normal. These results lead us to suggest that the site of heroin-induced respiratory depression is a specific area (Mitchells area) on the ventral surface of the medulla.

Effects of serotonin antagonists on digitalis-induced ventricular arrhythmias.

The present study was performed to determine whether pharmacological blockade of serotonin receptors would counteract digitalis-induced ventricular arrhythmias. The effect of the serotonin receptor blocking drugs, methysergide, cinansersin, and cyproheptadine on ventricular arrhythmias produced by ouabain was studied in anesthetized dogs. Each of the three serotonin receptor blocking drugs given as a bolus i.v. injection of 1.5--3.0 mg/kg produced an antiarrhythmic effect. In addition, methysergide administered in the above doses to cats intoxicated with deslanoside, restored an abnormal ventricular arrhythmia to either sinus or junctional rhythm. Methysergide, administered to cats intoxicated with deslanoside but pretreated with p-chlorophenylalanine, exerted an antiarrhythmic effect in less than half of the animals tested. These data indicate that serotonin antagonists are effective in counteracting digitalis-induced ventricular arrhythmias and support the notion that a serotonergic mechanism may be mediating the arrhythmogenic effect of digitalis.

Central cardiovascular effects produced by the GABA receptor agonist drug, THIP☆

In chloralose-anesthetized cats, injection of THIP (30-1000 microgram) into the fourth ventricle produced dose-dependent decreases in blood pressure and heart rate. Administration of similar doses into either the lateral and third ventricle or administration of the largest dose intravenously did not produce these effects. Microinjection of THIP (1.95 microgram) into nucleus ambiguus reversed bradycardia evoked by microinjection of bicuculline methiodide (160 ng) into this nucleus. These results confirm previous findings indicating that activation of GABA receptors in the hindbrain produces hypotension and bradycardia as well as reversal of bicuculline-induced activation of cardiac parasympathetic nerves.

Effect of diazepam on digitalis-induced ventricular arrhythmias in the cat.

Abstract The capacity of diazepam to counteract cardiac arrhythmias was studied in barbiturate-anesthetized cats treated with digitalis (i.e., deslanoside, 25 μg/kg given every 15 min iv). Diazepam dissolved in commercial propylene glycol solvent was administered in repeated doses of 10 mg iv at approximately 45-sec intervals to five animals exhibiting deslanoside-induced ventricular arrhythmias. Conversion of the arrhythmia to sinus rhythm was observed in two animals, while development of more serious rhythm changes was observed in the other three animals. One explanation for the deleterious effect seen with diazepam in the three animals is that the solvent itself may produce significant cardiocirculatory changes. To test this possibility, seven animals were intoxicated with deslanoside and the diazepam solvent was administered in doses of 1.0 ml every 45 sec until a total dose of 5.0 ml was given. In each animal, the administration of the solvent was associated with the development of more serious rhythm changes. Ventricular fibrillation (VF) developed 10.8 ± 1.6 min after the onset of deslanoside-induced ventricular tachycardia (VT). The corresponding time interval between deslanoside-induced VT and VF was 26.7 ± 5.0 min when no solvent was administered. These results indicate that propylene glycol solvent is deleterious to cardiac rhythm and should not be employed as a vehicle for antiarrhythmic drugs.