Effects of four calcium channel blockers on central cardiovascular control.

The cardiovascular effects of intravenous and intracisternal administration of low doses of calcium channel blockers (nicardipine: 0.3 to 10 micrograms/kg; nifedipine: 0.01 to 10 micrograms/kg; verapamil: 0.003 to 0.1 mg/kg and diltiazem: 1 to 300 micrograms/kg) were investigated in pentobarbital-anesthetized dogs. All studied calcium channel blockers induced a decrease in blood pressure and an increase in heart rate after intravenous injection. In contrast, the same doses injected by intracisternal route elicited an increase in both blood pressure and heart rate. These results show that blockade of central calcium channels in dogs increases blood pressure and heart rate and suggest that the pharmacological effects of these drugs are the addition of peripheral and central actions. However, the magnitude of these central properties seems to be higher for dihydropyridine than for phenylalkylamine or benzothiazepine derivatives.

Rilmenidine (S 3341) and the sympathoadrenal system: adrenoreceptors, plasma and adrenal catecholamines in dogs.

1. The effects of rilmenidine, a new alpha 2-adrenoreceptor agonist with antihypertensive properties, were investigated on plasma catecholamines, blood cell adrenoreceptors and adrenal medullary function. 2. In conscious sino-aortic denervated (SAD) dogs, rilmenidine (1 mg kg-1 orally for 2 weeks) significantly reduced both blood pressure and heart rate when compared with placebo treatment. The drug decreased plasma noradrenaline and adrenaline levels and corrected the decrease in leucocyte beta-adrenoreceptors observed in placebo-treated SAD dogs. There was no change in platelet alpha 2-adrenoreceptors. 3. In anaesthetized normotensive dogs, rilmenidine (0.1 and 0.3 mg kg-1 i.v.) induced a dose-dependent decrease in both cardiovascular parameters (blood pressure and heart rate) and catecholamine release from the adrenal medulla. 4. The present study shows that rilmenidine decreases sympathetic tone mainly by an action on the adrenal medulla. In addition, its ability to lower blood pressure in SAD dogs, i.e. a model of hypertension in which high sympathetic tone is present, indicates that rilmenidine may also depress other parts of the sympathetic nervous system.

Involvement of cholinergic mechanisms in the central cardiovascular actions of nicardipine in dogs.

The involvement of cholinergic mechanisms in the central cardiovascular effects of a dihydropyridine, nicardipine, was investigated in pentobarbital-anaesthetized normotensive dogs. Nicardipine (1 microgram/kg) injected intracisternally (i.c.) induced a rise in both blood pressure and heart rate. This induced hypertension was suppressed by pretreatment with intravenous (i.v.) atropine or i.c. methylatropine but not i.v. methylatropine. I.c. methylatropine reduced nicardipine-induced tachycardia. These results demonstrate the involvement of cholinergic pathways in the central cardiovascular effects of i.c. nicardipine in dogs and suggest a functional interaction between dihydropyridine binding sites and cardiovascular cholinergic mechanisms in the brain.

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.

Effects of calcium entry blockers on blood pressure and heart rate in neurogenic hypertensive dogs.

The hypotensive and negative chronotropic effects of 5 calcium entry blockers (verapamil 200 micrograms/kg IV; diltiazem 300 micrograms/kg IV; nifedipine 5 micrograms/kg IV; nicardipine 50 micrograms/kg IV; and bepridil 5 mg/kg IV) were compared in control normotensive and acute neurogenic hypertensive anaesthetized dogs. Acute neurogenic hypertension was induced by sino-aortic denervation (SAD). In control normotensive dogs, all drugs (except bepridil) induced a slight and transient decrease in blood pressure. Nifedipine and nicardipine increased heart rate whereas the three other drugs remained ineffective. SAD caused a 2-2.5-fold increase in the hypotensive properties of the 5 drugs in dogs. Moreover, the duration of this induced hypotension was longer than in control normotensive animals. In SAD dogs, all calcium entry blockers significantly decreased heart rate. This study indicates that the direct cardiac inhibitory action of calcium channel blockers is modulated by baroreceptor activity in intact animals. The mechanism of the selective action of calcium entry blockers in hypertensive SAD in contrast to normotensive dogs is discussed.

Antihypertensive effects of mesulergine: further evidence for a peripheral site of action of dopamine agonists.

The cardiovascular effects of mesulergine were studied in anesthetized dogs. Intravenous (IV) administration (0.3 mg/kg) significantly decreased blood pressure in neurogenic hypertensive dogs without any change in heart rate. This effect was completely antagonized by IV administration of domperidone (0.5 mg/kg). Intracisternal administration of mesulergine (0.03, 0.3 and 3 mg/kg) did not produce any change in blood pressure. However, with the highest dose we observed a significant rise in heart rate during the first 2 min (which was probably nonspecific). These results suggest that mesulergine lowers blood pressure in sinoaortic-denervated dogs by means of a peripheral mechanism probably involving DA2 receptors. The findings confirm the potential interest of dopamine-receptor agonists as future antihypertensive agents.

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.

Reduction of vagal pressor reflexes by neurohypophyseal peptides and related compounds.

The effects of intracisternal injections of [Lys8]vasopressin and [Arg8]vasopressin (25, 50, 100, 200 mU/kg) and related compounds oxytocin (25, 50, 100, 200 mU/kg), felypressin (25, 50, 100, 200 mU/kg) and vasotocin (100, 200, 400, 800 ng/kg) on the acute neurogenic pressor responses to afferent vagal stimulation (5, 10, 20 and 30 Hz) were studied in urethane-anaesthetized dogs. [Arg8]vasopressin and [Lys8]vasopressin (50, 100, 200 mU/kg) elicited a significant decrease in the pressor responses. The depressor effects of oxytocin (50, 100, 200 mU/kg) were less marked and felypressin or vasotocin remained inactive. These results suggest that vasopressin, and oxytocin, containing neurons may be modulators involved in central cardiovascular regulation. Since these cardiovascular reflexes are related to an increase in sympathetic tone, the present work suggests that neurohypophyseal peptides could play an inhibitory role in the regulation of blood pressure through a central inhibition of sympathetic tone. In term of structure-activity relationships the present work suggests that under our experimental conditions the sequence 1-5 of amino acids in vasopressin is important for the depressor action.

The role of adrenal medulla and neurohypophysis in the central and peripheral cardiovascular effects of neurohypophysial peptides.

The cardiovascular effects of intravenous and intracisternal administration of neurohypophysial peptides were compared in normal, diabetes insipidus and adrenal demedullated chloralose anaesthetized dogs. In normal dogs, intravenous lysine vasopressin (0.1 to 100 mU/kg) induced a dose-dependent increase in blood pressure with bradycardia whereas intracisternal injection (0.01 to 10 mU/kg) elicited a dose-related decrease in blood pressure but no change in heart rate. Intracisternally injected oxytocin (1 and 10 mU/kg) increased blood pressure. The central hypotensive effects of vasopressin were not observed in diabetes insipidus or adrenal demedullated dogs. In contrast, the central pressor properties of oxytocin were still observed in these two groups of animals. These results show that the central cardiovascular properties of vasopressin (but not those of oxytocin) may vary according to the hormonal state of the animals. Intracisternal vasopressin induces an hypotensive response due to a decrease in sympathetic tone and dependent on the integrity of the neurohypophysial tractus.

Neurohypophysial peptides and central cardiovascular control.

The cardiovascular effects of intravenous and intracisternal administration of neurohypophysial peptides were studied in anaesthetized dogs. Intracisternal oxytocin (1 and 10 mU kg-1) increased blood pressure. Intravenous lysine vasopressin (0.1 to 100 mU kg-1) induced a dose-dependent increase in blood pressure with bradycardia. Intracisternal lysine vasopressin (0.01 to 10 mU kg-1) elicited a dose-related decrease in blood pressure but no change in heart rate. These central hypotensive effects of vasopressin were suppressed by intravenous guanethidine, dl-propranolol, prazosin or atropine and were not observed in diabetes insipidus dogs with surgical lesion of the supra-opticohypophysial tract. Hypotension elicited by intracisternal vasopressin was due to a decrease in sympathetic tone and simultaneous activation of parasympathetic tone. These results suggest the involvement of these peptides in central control of blood pressure.

Alpha-2 adrenergic antilipolytic effect in dog fat cells: incidence of obesity and adipose tissue localization.

The main intention of this study was to characterize the alpha-adrenoceptor responsible for the inhibition of lipolysis in dog fat cell and to define circumstances that may be associated to a modification of the alpha-mediated antilipolytic effect. Isolated fat cells from omental and subcutaneous adipose tissue from normal and obese dogs were used. Basal and theophylline stimulated lipolysis was studied in the presence of selected alpha-adrenergic agonists and antagonists. The antilipolytic effect of catecholamines is mediated by alpha 2-type adrenoceptors in dog fat cell. The alpha-adrenergic responsiveness is enhanced (or unmasked) in large fat cells of obese dogs and depends on the site from which the adipose tissue sample is taken. The alpha-response is stronger in subcutaneous than in omental adipocytes. In conclusion, the weakened lipolytic responsiveness to epinephrine of obese dog fat cells seems related to an increased alpha-adrenergic response rather than a decreased beta-lipolytic effect. Obesity is a circumstance characterized in the dog fat cell by a modification of the balance between alpha-2 and beta receptors.

Clonidine inhibits diuresis caused by negative pressure breathing and left atrial distension: role of central adrenergic alpha 2 receptors.

1. Intravenous (10 micrograms/kg) or intracisternal (1 microgram/kg) clonidine inhibited the diuretic response elicited by negative pressure breathing (NPB) or left atrial distension (LAD) in chloralose anaesthetized dogs. The drug reduced the induced tachycardia, but not the increase in respiratory rate elicited by NPB. Blood pressure was unchanged. 2. Propranolol (1 mg/kg IV) did not change NPB-induced diuresis. 3. Intravenous yohimbine (1 mg/kg IV) restored these two diuresis inhibited by intravenous or intracisternal clonidine, whereas prazosin (0.05 mg/kg IV) was without effect. 4. These results show that the adrenergic receptor implicated in the volumetric control of vasopressin secretion could be of the alpha 2 subtype. This alpha 2 adrenoceptor could be localized at a central level. 5. The possible clinical consequences (hydrosaline retention and antihypertensive drugs; use of clonidine in aerospace medicine) of these data are discussed.

Clonidine-induced lipolysis in dog adipocytes by stimulation of histamine (H2)-receptors.

The effect of the alpha-adrenergic agonist clonidine on lipolysis was investigated in omental dog fat cells. In presence of theophylline, clonidine markedly enhanced lipolysis. This effect was competitively inhibited by the (H2)-receptor blocking agent cimetidine while the H1-histamine receptor antagonist (mepyramine) was without any significant effect. This result suggests that clonidine stimulates dog adipocyte lipolysis through histamine (H2)-receptor activation. Histamine and clonidine stimulated dog fat cell adenylate cyclase; the stimulation was suppressed by cimetidine.

Influence of hypocaloric diet on alpha-adrenergic responsiveness of obese human subcutaneous adipocytes.

Spontaneous and stimulated lipolytic activity of subcutaneous abdominal adipocytes from obese subjects treated by a hypocaloric diet (800-1000 kcal/d) for 13-15 d were studied. A strong increase in basal lipolytic activity of the adipocytes occurred after the restrictive diet treatment. Linked to this phenomenon, an important alpha-adrenergic antilipolytic effect of adrenaline appeared whereas, the beta-stimulating effect of isoproterenol (beta-adrenomimetic drug) was not affected. The increased alpha-inhibitory effect of adrenaline was shown to theophylline-stimulated adipocytes of energy-restricted subjects. It is concluded that after a period of hypocaloric diet, the adrenaline-dependent lipolysis of subcutaneous abdominal fat cells of obese subjects is reversed. The lipolytic response induced by adrenaline, described in the adipocytes of obese controls, develop towards an alpha-adrenergic antilipolytic response after the hypocaloric treatment. Our data suggest that, in states with increased rate of lipolysis, there is an increased readiness for alpha-adrenergic response.

[Adrenergic lipolysis in human fat cells: properties and physiological role of alpha-adrenergic receptors (author's transl)]. / La lipolyse adrénergique du tissu adipeux humain: propriétés et rôle physiologique des alpha récepteurs.

Lipolytic activity of human isolated fat cells from different fat deposits was studied. The purpose of the present investigations was to determine the epinephrine responsiveness, with regard to alpha- and beta-adrenergic receptor site activity, of omental and subcutaneous adipocytes (abdominal or from the lateral part of the thigh). Adipocytes were obtained from normal subjects or from obese subjects on iso- or hypocaloric diets. The lipolytic effect of epinephrine varied according to the fat deposits, while the beta-lipolytic effect of isoproterenol was more stable (Fig. 1). We explored the possible involvement of adrenergic alpha-receptors, in order to explain these results. The potentiating action of phentolamine on epinephrine-induced lipolysis, and the antilipolytic effect of alpha-agonists on basal or theophylline--induced lipolysis, were found to be a good indication of alpha-adrenergic activity. The alpha-adrenergic antilipolytic effect was most prominent in adipose tissue from the lateral part of the thigh, and less noticeable in omental adipocytes. In conclusion, the inability of epinephrine to induce lipolysis, and the epinephrine-induced inhibition of lipolysis observed when the basal rate of FFA release was spontaneously increased in subcutaneous fat-cells of the thigh, could be explained by an increased alpha adrenergic responsiveness (Fig. 2). Moreover, various alpha-adrenergic agonists (phenylephrine, noradrenaline and adrenaline) showed a clear inhibiting effect on theophylline-stimulated adipocytes from the thigh. The pharmacological study of the antilipolytic effect of epinephrine on theophylline-induced lipolysis showed that the inhibition was linked to a specific stimulation of the alpha-receptors of the subcutaneous adipocytes (Fig. 4). From the different sets of experiments, it is shown that the modifications in the lipolytic effect of epinephrine on adipocytes of different areas could be explained by the occurrence of a variable alpha-adrenergic effect initiated by catecholamine. Furthermore, theophylline stimulation of lipolysis provides an accurate system to investigate the alpha-inhibiting effect of catecholamines. Our study was completed by the investigation of the lipolytic activity of subcutaneous fat cells from obese subjects submitted to a hypocaloric diet (800-1 000 Cal/day). An increased alpha-inhibitory effect of epinephrine was shown on the increased basal lipolytic activity observed in the fat cells of obese subjects on a hypocaloric diet (Fig. 5); a similar effect was observed when these adipocytes were stimulated by theophylline. To conclude, these investigations allow the alpha-adrenergic effect to be considered as a regulator mechanism of the in vitro lipolytic activity in human adipose tissue, since the antilipolytic effect is operative whenever the basal rate of lipolysis is increased (spontaneously, after caloric restriction, or with a lipolytic agent such as theophylline).

[The role of beta and alpha adrenergic receptors in the lipolytic effect of catecholamines on dog adipocytes (author's transl)]. / Intervention de récepteurs adrénergiques alpha et bêta dans l'effet des catécholamines sur la lipolyse d'adipocytes de chien.

Pharmacological properties of adrenergic receptors have been investigated in fat cells isolated from omental adipose tissue of the Dog. From the results, the following points can be stated. 1. Lipolysis is markedly enhanced by isoproterenol. This effect is competitively inhibited by propranolol (a beta-adrenoceptor blocking agent). (Fig 1). 2. The beta 2-sympathomimetic salbutamol is found to have only a slight effect on lipolysis rate (Fig. 2). 3. The epinephrine-induced lipolysis is potentiated by phentolamine (an alpha-adrenoceptor blocking agent) only on large sized adipose cells (mean fat cell size 96.7 +/- 5.3 micrometer; Fig. 5). 4. The isoproterenol-induced lipolysis is partially inhibited by phenylephrine (an alpha-adrenomimetic drug) (Table I). These findings show that beta 1 nature of the receptors involved in the adrenergic control of lipolysis in Dog adipose tissue. Moreover an antilipolytic effect of epinephrine, via alpha-adrenergic receptors, is observed, especially in large adipose cells.

[Reduction of adrenaline-dependent lipolysis in the adipose tissue of adrenalectomized dogs by an alpha adrenergic effect]. / Réduction de la lipolyse adrénalino-dépendante du tissue adipeux de chien surrénalectomisé par effet alpha adrénergique.

In dog, surrenalectomy reduces isoprenalino-depending lipolysis but still more adrenalino-depending lipolysis. Phentolamine potentializes the response to adrenaline but does not that observed with isoprenaline. Surrenalectomy unmasks an alpha adrenergical effect of adrenaline on adipocytes of dog adipose tissue.