Renal morphological changes after sinoaortic denervation in dogs.

The present study investigates morphological renal lesions in sinoaortic-denervated dogs 1 (n = 6) and 18 (n = 5) months after sinoaortic denervation compared with sham-operated controls (n = 8). After 1 month, a marked hyalinization and moderate thickening of the media of arterioles and small interlobular arteries were observed. These changes associated with edema and intimal thickening led to a narrowing of the lumen. In glomeruli, increase of mesangial matrix was focally present in all cases and associated with mesangial proliferation. In four of six cases, some glomeruli appeared retracted, with a large urinary space. A focal area of interstitial fibrosis occurred in just one case. After 18 months, similar but more pronounced vascular lesions were present, with marked hyperplasia of the media. Glomerular changes were characterized by mesangial lesions associated with focal glomerular sclerosis and thickening of Bowman's capsule. Tubulointerstitial lesions were more prominent in this group, with the presence of tubular epithelial changes and casts. Focal interstitial fibrosis, infiltrates, or both were demonstrated in all cases. These morphological lesions were associated with an increase in arterial blood pressure, proteinuria, and natriuresis and a decrease in urinary kallikrein. These results show that chronic sinoaortic denervation in dogs is associated with renal lesions similar to those observed in other well-established experimental and clinical hypertensive states.

Effect of intracisternal 5,-7-dihydroxytryptamine on the acute antihypertensive action of propranolol in the sino-aortic denervated anaesthetized dog.

1 The anti-hypertensive effects of intravenously and intracisternally administered (+/-)-propranolol were studied in anaesthetized dogs with acute neurogenic (sino-aortic denervation) hypertension. The animals were pretreated 7 days earlier with intracisternally administered 5,7-dihydroxytryptamine (5,7-DHT 200 microgram/kg plus desipramine 5 mg/kg i.v.). 2 5,7-DHT (plus desipramine) failed to decrease both basic blood pressure and heart rate measured before sino-aortic denervation. After 5,7-DHT (plus desipramine) pretreatment, acute sino-aortic denervation induced a rise in blood pressure and stimulated the heart rate, these effects being similar (in intensity and duration) to those observed in control (saline-pre-treated) debuffered dogs during the first hour following the deafferentation. 3 In debuffered dogs, (+/-)-propranolol given by intracisternal (50 microgram/kg) or intravenous (300 microgram/kg) routes decreased both blood pressure and heart rate. 4 5,-DHT (plus desipramine) pretreatment abolished the antihypertensive effect of intracisternal propranolol whereas the action of intravenous propranolol was only delayed. In contrast, this pretreatment failed to reduce and even sometimes enhanced the negative chronotropic response induced by propranolol. 5 These results suggest that central 5-hydroxytryptaminergic pathways play an important role in the acute hypotension elicited by intracisternal (+/-)-propranolol in debuffered hypertensive anaesthetized dogs, but little, if any in propranolol-induced bradycardia.

Effects of lysine-vasopressin and oxytocin on central cardiovascular control.

1 The cardiovascular effects of intravenous and intracisternal administration of neurohypophysial peptides were compared in dogs anaesthetized with chloralose. 2 Intravenous lysine-vasopressin (0.1 to 100 mu/kg) induced a dose-dependent increase in blood pressure and a decrease in heart rate. In contrast, intracisternal lysine-vasopressin (0.01 to 10 mu/kg induced a dose-related decrease in blood pressure and did not change heart rate. 3 Intracisternal oxytocin (1 and 10 mu/kg) increased blood pressure and did not change heart rate, whereas the same doses injected intravenously were inactive. 4 Pretreatment with guanethidine (15 mg/kg i.v. 24 h beforehand) abolished the hypotensive responses to intracisternal vasopressin but not the pressor action of intravenous vasopressin. 5 The pressor responses to central injections of oxytocin were not modified by guanethidine. 6 Hypotension elicited by intracisternal vasopressin was probably due to a decrease in sympathetic tone whereas the hypertension induced by intracisternal oxytocin was independent of variations in sympathetic tone.

Naloxone reduces diuretic responses induced by water, alcohol or congenital lack of vasopressin in rats.

The effects of naloxone (2 and 10 mg kg-1 s.c.) were compared in several kinds of experimental polyuria: alcohol- or water-loaded rats and Brattleboro rats (i.e. animals with congenital lack of vasopressin). In normal rats, both water and alcohol increased urine flow and decreased urinary osmolality. Alcohol induced a more marked diuretic response than water. In normally hydrated rats, naloxone (2 and 10 mg kg-1 s.c.) failed to modify urine flow, urinary osmolality, Na+ and K+ urinary excretion, and urine creatinine concentration. The two doses of naloxone decreased urine flow and increased osmolality in both water- and alcohol-loaded rats. In Brattleboro rats, naloxone (10 mg kg-1 s.c.) reduced urine flow and urinary creatine whereas the low dose (2 mg kg-1 s.c.) was without effect. Since it is well known that the mechanism of water- or alcohol-induced diuresis is an inhibition of vasopressin release, the present results suggest that naloxone could prevent this inhibition. They indicate that endogenous opioid peptides may exert an inhibitory control on vasopressin release.

Potentiation by naloxone of pressor reflexes.

1 The effect of intravenous naloxone, and opiate antagonist, was studied on the pressor responses elicited by stimulation of afferent nerves (vagus and laryngeal superior nerves) in anaesthetized dogs. 2 Although naloxone (0.1 mg/kg i.v.) alone failed to modify basic blood pressure, the pressor responses induced by stimulation of either the vagus or laryngeal nerve were potentiated by naloxone. 3 Morphine (0.2 mg/kg i.v.) suppressed these two cardiovascular responses. These depressor effects of morphine were reversed by subsequent injection of naloxone (0.1 mg/kg i.v.). 4 The results suggest the involvement of endogenous opiate peptides in pressor reflexes elicited by stimulation of the afferent nerves.

Effects of yohimbine on submaxillary salivation in dogs.

1. The effects of yohimbine (0.5 mg kg-1 i.v.) on both resting and parasympathetic and sympathetic stimulation-induced submaxillary salivary responses were investigated in the anaesthetized dog. 2. Salivary secretion was increased significantly for a period of 45 min following an injection of yohimbine. 3. Sectioning of the chorda tympani (but not the cervical sympathetic) nerve abolished the yohimbine-induced increase in resting salivary secretion and potentiated that elicited by electrical stimulation of the chorda tympani nerve. 4. These results show that yohimbine increases submaxillary secretion by inhibition of presynaptic alpha 2-adrenoceptors located on the chorda tympani, which inhibit cholinergic transmission.

Thermogenic and lipolytic effect of yohimbine in the dog.

1. Lipid mobilization during a hypocaloric diet may be enhanced by a pharmacological approach using alpha 2-adrenoceptor antagonists since these drugs are known to increase sympathetic tone and stimulate lipolysis. Studies were undertaken in the dog in order to evaluate the effects of oral yohimbine administration (alpha 2-adrenoceptor antagonist) on heat production, metabolic, endocrinological and cardiovascular parameters. 2. Acute oral yohimbine (0.25 or 0.40 mg kg-1) provoked an increase in plasma non-esterified fatty acids. The drug increased sympathetic nervous system activity as indicated by the increased level of plasma noradrenaline. These effects persisted during the entire experimental period (4 h). The increase in plasma noradrenaline level was two fold higher with the higher dose of yohimbine (0.4 mg kg-1). The plasma adrenaline level was increased only with the higher dose. 3. Yohimbine transiently increased plasma insulin and the effect was dose-dependent. 4. Yohimbine (0.25 mg kg-1) enhanced heart rate and arterial blood pressure. 5. The effect of yohimbine on oxygen consumption, carbon dioxide and heat production was determined by indirect calorimetry. The drug (0.25 mg kg-1) increased O2 consumption and CO2 and heat production 30 min after its administration and the effect persisted over the experimental period. The respiratory quotient, rather low in the fasting animals, remained unchanged. 6. The present work indicates that thermogenesis and lipid mobilization are enhanced during fasting in the dog by alpha 2-adrenoceptor blockade. Yohimbine also induced a transient increase in plasma insulin level and increased heart rate and blood pressure. The lipid mobilization plus the action on thermogenesis observed after yohimbine draw attention to the putative interest of a2-antagonists in the pharmacological treatment of obesity during restricted calorie intake.

Yohimbine increases submaxillary kallikrein release into the saliva in dogs: evidence for alpha 2-adrenoceptor-mediated inhibition of cholinergic pathways.

1. The effects of the alpha 2-adrenoceptor antagonist, yohimbine (0.5 mg kg-1, i.v.) on basal, sympathetic and parasympathetic stimulation-induced submaxillary kallikrein release were investigated in the anaesthetized dog. Kallikrein was measured by its kininogenase activity before and after trypsin activation which also allowed a study of the proportion of active to total enzyme. 2. Yohimbine induced a rapid, three fold increase in basal kallikrein release correlated with an increase in salivary flow rate which lasted for 60 min following injection. 3. Sectioning the chorda tympani did not affect basal kallikrein release but abolished yohimbine-induced rise in salivary kallikrein secretion. 4. Parasympathetic stimulation alone induced a 3 to 4 fold increase in basal kallikrein release correlated with an increase in salivary flow rate. Yohimbine induced a significant additional increase in parasympathetic-stimulated kallikrein release. 5. When the cervical sympathetic nerve was sectioned the basal kallikrein release decreased by 30 to 40%. 6. Sympathetic stimulation alone also induced a 3 to 4 fold increase in basal kallikrein. This was not correlated with the salivary flow and unaffected by yohimbine. 7. The results indicate that yohimbine increases submaxillary kallikrein release into the saliva by inhibition of presynaptic alpha 2-adrenoceptors located on the chorda tympani nerve endings.

Lipomobilizing effects of procaterol and yohimbine in the conscious dog: comparison of endocrinological, metabolic and cardiovascular effects.

1. Lipid mobilization during a hypocaloric diet may be enhanced by a pharmacological approach using beta 2-adrenoceptor agonists or alpha 2-adrenoceptor antagonists. Studies were undertaken in the dog, an animal model presenting fat cell antilipolytic alpha 2- and lipolytic beta-adrenoceptors, in order, firstly, to demonstrate the presence of beta 2 subtype adrenoceptors on adipocytes and, secondly, to compare the effects of procaterol (beta 2-adrenoceptor agonist) and of yohimbine (alpha 2-adrenoceptor antagonist) on metabolic, endocrinological and cardiovascular parameters. 2. Procaterol strongly stimulates lipolysis in dog adipocytes in vitro. The utilisation of selective beta 1- and beta 2-adrenoceptor antagonists (bisoprolol and ICI 118,551) in both lipolysis and binding studies (displacement of [3H]-dihydroalprenolol binding) demonstrated the presence of the two beta-adrenoceptor subtypes in dog fat cells. 3. Infusion of either yohimbine or procaterol (10 and 0.4 nmol min-1 kg-1, respectively for 30 min), provoked an equivalent increase in plasma non-esterified fatty acids (+100%). Procaterol, but not yohimbine, induced hyperglycaemia (+120%). Plasma insulin was weakly enhanced by yohimbine (+120%) as compared to the increase given by procaterol (+500%). 4. Both drugs stimulated sympathetic nervous system activity, as indicated by the increased plasma noradrenaline concentration, but only yohimbine increased the plasma adrenaline level. 5. Cardiovascular measurements indicated that procaterol strongly enhances heart rate and transiently decreases mean blood pressure. Yohimbine exhibits a weaker effect on heart rate and slightly increases mean blood pressure. 6. The present work clearly indicates that lipid mobilization is enhanced during fasting in the dog by selective beta 2-adrenoceptor stimulation or by alpha 2-adrenoceptor blockade. This enhanced lipolytic effect may result either from a direct action of the drugs on the adrenoceptors of fat cells or from an activation of the sympathetic nervous system. Procaterol suffers major limitations since it strongly increases heart rate, immunoreactive insulin and glycaemia. On the other hand, yohimbine induces only minor modifications both in cardiovascular and endocrinological parameters.

Effects of pinacidil on the sympatho-adrenal system in dogs.

1. The aim of the present work was to study the antihypertensive effect of pinacidil, a potassium channel opener, in sinoaortic denervated (SAD) conscious dogs and to investigate whether the involvement of the sympathetic nervous system induced by this vasodilator compound is only of baroceptor reflex origin. 2. Pinacidil (0.1, 0.2, 0.4 mg kg-1 i.v.) induced a dose-dependent decrease in blood pressure in normal as well as in SAD dogs. In contrast, the induced-tachycardia observed in normal dogs was not found in SAD animals. 3. Since pinacidil induced an increase in plasma catecholamines, free fatty acids, glucose, plasma renin activity and aldosterone in SAD dogs it is suggested that this sympathetic activation is independent of the baroreceptor reflex pathways. 4. The sympathetic activation is mainly of peripheral origin, since pinacidil (0.7 mg kg-1 i.v.) induced an increase in adrenaline release from the adrenal gland after section of the great splanchnic nerve in anaesthetized dogs. This increase is probably due to an effect that does not involve K+ channel opening. However, this effect of pinacidil was not observed during splanchnic nerve stimulation (in this case, the involvement of K+ channel opening is suggested).

Cardiovascular effects of central injection of acetylcholine in anaesthetized dogs: a role for vasopressin release.

1. The effect of an intracisternal injection of 20 micrograms kg-1 of acetylcholine was studied on systolic and diastolic blood pressures, heart rate, and plasma levels of noradrenaline, adrenaline, vasopressin, plasma renin activity and atrial natriuretic factor in chloralose-anaesthetized dogs, 8 of which were normal and 7 with diabetes insipidus (deprived of vasopressin secretion by surgical lesion of the hypothalamoneurohypophysial system). 2. Acetylcholine significantly increased systolic and diastolic blood pressures in both groups of animals. However, the rise in blood pressure was significantly shorter lived in the dogs with diabetes insipidus. 3. Acetylcholine significantly increased plasma levels of noradrenaline but not adrenaline in control animals and in dogs with diabetes insipidus. Noradrenaline and adrenaline responses after acetylcholine were not different in the two groups of animals. 4. Acetylcholine induced a significant increase in vasopressin plasma levels only in control animals while in dogs with diabetes insipidus vasopressin remained at nearly undetectable levels. 5. Acetylcholine significantly increased atrial natriuretic factor plasma levels only in control dogs. 6. Although plasma renin activity increased in both groups of animals after the i.c. injection of acetylcholine, this change was not significant in any group. 7. These results suggest that, in the anaesthetized dog, the central injection of acetylcholine induces a rise in blood pressure through both an increase in sympathetic outflow and a release of vasopressin.

Relationships between kallikrein secretion, kallikrein excretion and beta-adrenoceptors in kidney cortical slices from neurogenic hypertensive dogs.

1. Sinoaortic denervation (SAD) in dogs is characterized by an increase in blood pressure and heart rate as well as the development of renal morphological lesions similar to those observed in essential hypertension in human subjects. To assess the effect of SAD on the secretion of kallikrein kinin systems (KKS), we studied the in vitro secretion of kallikrein by renal cortical slices of normal and neurogenic hypertensive dogs (1 and 18 months after SAD). The method using renal cortical slices allowed the study of secretion of kallikrein independently of renal perfusion pressure. The number of renal beta-adrenoceptors was measured by [125I]-cyanopindolol binding. 2. SAD was associated with a marked increase in urinary kallikrein excretion at one month and a significant decrease at 18 months when compared with controls. Both changes were statistically significant (P < 0.05). Concurrently, a progressive increase in in vitro kallikrein secretion was observed (+80 +/- 10% and +179 +/- 48%, 1 and 18 months after SAD, respectively). Moreover, the cortical slices obtained from sinoaortic denervated dogs contained more kallikrein than the control cortical slices (+32 +/- 16% and +55 +/- 7%, 1 and 18 months after SAD, respectively). 3. Renal beta-adrenoceptor number significantly (P < 0.05) decreased 18 months after SAD from 18 +/- 2 to 8 +/- 3 fmol mg-1 protein without any change in affinity constant. 4. Although there was no test of association, because the number of renal beta-adrenoceptors decreased whereas kallikrein secretion increased, the present data could suggest a beta-adrenoceptor-mediated inhibition of kallikrein secretion. These results show that although the urinary kallikrein is decreased, the tissue secretory capacities are enhanced. This could suggest a renal compensatory mechanism possibly involved in tissue protection in dogs after SAD, although such a mechanism is not sufficient to reverse hypertension.

A study of tolerance to apomorphine.

1. The present study was designed to investigate tolerance to several pharmacological effects of apomorphine. 2. Changes in blood pressure, heart rate, plasma noradrenaline levels, rectal temperature, respiratory rate and retching plus vomiting were compared after administration of apomorphine (200 micrograms kg-1, i.v. as a bolus) or saline at different time intervals (30, 120 and 720 min) in four groups of chloralose-anaesthetized dogs. 3. The first administration of apomorphine induced a significant decrease in blood pressure and rectal temperature, a marked rise in heart rate with no change in noradrenaline plasma levels or respiratory rate. Emesis occurred in 71% of the animals. 4. A second administration of apomorphine 30 min later failed to modify blood pressure or heart rate. In contrast, the magnitude of apomorphine-induced changes in blood pressure and heart rate was similar to that observed after the first administration when apomorphine was given 120 or 720 min later. 5. The apomorphine-induced decrease in rectal temperature evoked by a second dose of apomorphine was less marked when given 30 and 120 min after the first dose and unchanged when given 720 min later. 6. The number of animals exhibiting retching and vomiting was lower when apomorphine was reinjected after 30 min than when the time between two successive injections of apomorphine was 120 or 720 min. 7. These results show that tolerance to apomorphine involves its cardiovascular, hypothermic and emetic effects. The time course of tolerance to repeated injections of apomorphine is longer for its hypothermic than for its hypotensive or emetic effects. This suggests a tissue-specific regulation of D2 dopamine receptors to repeated injections of apomorphine.

A study of the action of clonidine on secretion from the adrenal medulla in dogs.

The effects of clonidine on adrenal catecholamine (adrenaline and noradrenaline) secretion were investigated in chloralose-anaesthetized dogs. Intravenous administration of clonidine (10 and 20 micrograms kg-1) induced a decrease in both adrenal catecholamine secretion rates and cardiovascular parameters (blood pressure and heart rate). In contrast, a dose of 5 micrograms kg-1 was ineffective. Intracisternal clonidine (in a lower dose of 3 micrograms kg-1) also decreased adrenaline and noradrenaline release from the adrenal gland. Clonidine failed to modify adrenal catecholamine release evoked by electrical stimulation of the splanchnic nerve. These results demonstrate that clonidine decreases adrenaline release from the adrenal gland through a central and not a peripheral mechanism in dogs. This action might contribute to its antihypertensive effects.

Central cardiovascular effects of acetylcholine in the conscious dog.

1. The effects of central cholinomimetic drugs on cardiovascular and vasoactive hormonal responses (blood pressure, heart rate, catecholamines, vasopressin, atrial natriuretic factor, neuropeptide Y plasma levels and plasma renin activity) were investigated in conscious Beagle dogs. For this purpose a catheter was chronically implanted into each dog's cisterna magna to allow repeated central injections in the awake animals. 2. Intracisternal acetylcholine (20 micrograms kg-1) significantly increased systolic and diastolic blood pressure. These changes were accompanied by an initial short term tachycardia followed by a long lasting bradycardia. Intracisternal acetylcholine also increased noradrenaline, adrenaline and vasopressin plasma levels, decreased plasma renin activity but did not modify plasma levels of neuropeptide Y and atrial natriuretic factor. 3. The effects of acetylcholine were completely abolished by pretreatment with intracisternal injection of the muscarinic antagonist, atropine (5 micrograms kg-1) but not by the intracisternal injection of the nicotinic antagonist, mecamylamine (25 micrograms kg-1). 4. The present results demonstrate that there are qualitative and quantitative differences between the central cardiovascular effects of acetylcholine in conscious dogs compared to what we previously reported, using a comparable protocol, in anaesthetized dogs. Under both conditions, we observed a central cholinergically mediated increase in blood pressure secondary to an increase in sympathetic tone and vasopressin release but these responses were shorter (less than 10 min) in the conscious dogs than in anaesthetized dogs (more than 10 min). Moreover, we detected in the response to the central cholinergic stimulation in the conscious dogs a significant increase in plasma adrenaline levels and biphasic changes in heart rate which were not described previously in the anaesthetized dog.

Changes in plasma catecholamine and neuropeptide Y levels after sympathetic activation in dogs.

1. Plasma levels of noradrenaline (NA) and neuropeptide Y (NPY) were evaluated in two experimental models associated with an increase in sympathetic tone: conscious dogs which were subject to either sinoaortic denervation or acute administration of the alpha 2-adrenoceptor antagonist yohimbine. 2. Dogs that had undergone sinoaortic denervation exhibited a two fold increase in plasma NA without any change in NPY levels. 3. Yohimbine (0.05 mg kg-1 i.v. as a bolus) produced similar effects. A higher dose of yohimbine (0.5 mg kg-1 i.v.) increased both plasma NA (7 fold) and NPY (6.5 fold) levels. 4. The present results indicate that changes in plasma catecholamines and NPY are not always concomitant. They suggest that the simultaneous release of NA and NPY is only observed under in vivo conditions for a marked increase in sympathetic tone.

Lack of haemodynamic effects of nitric oxide on post-capillary pulmonary hypertension induced by acute sino-aortic denervation.

1. The aims of the present experiments were to define a new experimental model of pulmonary hypertension induced by a post-capillary mechanism and to assess the haemodynamic effects of nitric oxide on post-capillary pulmonary hypertension. 2. Cardiopulmonary variables of 28 male beagle dogs, anaesthetized with chloralose, 16 spontaneous breathing and 12 with assisted ventilation, were studied before and after sino-aortic denervation (SAD). The haemodynamic effects of inhaled nitric oxide (25 p.p.m., 10 min). N(omega)-nitro-L-arginine methyl ester (20 mg kg-1, i.v.), urapidil (0.5 mg kg-1-, i.v.) and propranolol (300 micrograms kg-1, i.v.) were studied after SAD. 3. SAD induced an acute and transient pulmonary hypertension, more marked in spontaneous breathing dogs. This pulmonary hypertension involved a post-capillary mechanism, secondary to the left ventricular haemodynamic effects of the acute increase of left ventricular after-load induced by systemic hypertension. In fact, the increase of mean pulmonary arterial pressure after SAD and the decrease of this parameter after urapidil or propranolol were strongly correlated with the variations of pulmonary capillary wedge pressure. Furthermore, no significant change in pulmonary vascular resistance was found after SAD or administration of alpha or beta-adrenoceptor antagonists. 4. Inhaled nitric oxide did not reverse pulmonary hypertension induced by SAD. N(omega)-nitro-L-arginine methyl ester had no significant haemodynamic effect of pulmonary circulation. 5. In conclusion, the lack of effect of inhaled nitric oxide and nitric synthase inhibitor on pulmonary circulation parameters SAD suggest that endothelium-derived oxide is not involved in the mechanisms leading to post-capillary pulmonary hypertension.

Naloxone reverses the effects of enalapril and enalaprilic acid on the pressor responses to afferent vagal stimulation.

The effects of intracisternal injection of enalapril (MK 421) or its bioactive form enalaprilic acid (MK 422) (0.075 mg/kg) on the pressor responses elicited by afferent stimulation of the vagus were investigated in the urethane-anaesthetized dog. The angiotensin converting enzyme inhibitors (ACEI)-induced decrease in the systolo-diastolic pressor responses to vagal stimulation was reversed by naloxone (0.1 mg/kg iv). These data support evidence for an additional central site of action of These data support evidence for an additional central site of action of ACEI and suggest the involvement of central opioid mechanisms in the hypotensive properties of ACEI.

Effect of intracisternal application of 6-hydroxydopamine on the antihypertensive action of propranolol in the dog.

The antihypertensive effects of intravenous (i.v.) and intracisternal (i.cist.) dl-propranolol were studied in anesthetized hypertensive dogs pretreated with i.cist. administered 6-hydroxydopamine (6-OHDA, 600 micrograms/kg) one week previously. Acute neurogenic hypertension was elicited by sino-aortic denervation (deafferentation). In control (saline-pretreated) dogs, dl-propranolol given i.cist. (50 micrograms/kg) or i.v. (0.3 and 1 mg/kg) decreased both the rise in blood pressure and tachycardia induced by deafferentation. These hypotensive and negative chronotropic actions of i.v. (0.3 mg/kg) propranolol were suppressed by pretreatment with 6-OHDA. At a higher dose (1 mg/kg), i.v. propranolol always corrected hypertension and tachycardia in 6-OHDA-treated dogs as in control animals. After 6-OHDA, i.cist. propranolol (50 micrograms/kg) failed to decrease the rise in blood pressure in debuffered animals. Conversely, the bradycardia induced by i.cist. propranolol was more marked in 6-OHDA-treated dogs than in control animals. These results confirm that the antihypertensive action of propranolol can be partly explained by an action on the central nervous system. They support the hypothesis that the hypotension observed after intracisternal (and also after low does of i.v.) propranolol is dependent on the integrity of central catecholaminergic neurons. These studies suggest that the antihypertensive action of propranolol may be partly due to the blockade of central presynaptic beta-adrenoceptors.

Blockade by clonidine of negative pressure breathing-induced diuresis in the dog.

The effects of clonidine and dl-propranolol on negative pressure breathing-induced diuresis in chloralose-anaesthetized dog were studied. Clonidine (10 microgram/kg i.v.) suppressed the diuretic response, whereas dl-propranolol (1 mg/kg i.v.) was inactive.