Blockade of peripheral α2-adrenoceptors by L-659,066 enhances glucose tolerance and insulin release in mice

The purpose of this study was to compare the effects of a peripherally selective (L-659,066) vs. a centrally and peripherally active (L-657,743; MK-912) α₂-adrenergic antagonist on murine plasma glucose and insulin levels following fasting or administration of hyperglycemic agents (α₂-adrenergic agonists, glucose). The intravenous administration of L-657,743 or L-659,066 alone did not cause major alterations in plasma glucose or insulin levels. Pretreatment of mice with either of these agents, however, at selective α₂-adrenoceptor blocking doses (0.3–3 mg/kg) prevented the elevations of plasma glucose levels induced by the α₂-adrenoceptor agonists clonidine or 3,4-dihydroxyphenylimino-2-imidazoline (DPl). Prazosin, an α₁-adrenergic antagonist, did not alter clonidine-induced elevations of plasma glucose levels. Pretreatment of fasted mice with L-657,743 or L-659,066 (1 mg/kg) 5 min before receiving intravenous glucose resulted in higher plasma insulin levels and improved glucose tolerance compared to saline-pretreated animals. Moreover, both α₂-adrenergic antagonists enhanced the acute insulin response to glucose. These findings indicate that, under conditions of hyperglycemia, insulin release is enhanced by the blockade of peripheral α₂-adrenoceptors α₂-Adrenoceptor antagonists, such as L-657,743 or the peripherally selective agent L-659,066, may prove effective in treating noninsulin-dependent diabetes mellitus.     

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on urine output in the rat.

1. In normally-hydrated Wistar rats the alpha 2-adrenoceptor antagonist, idazoxan (1, 3, 10 mg kg-1 i.p.), increased urine output during the 6 h following injection. 2. The more selective and specific alpha 2-adrenoceptor antagonist, RX811059 (0.3, 1, 3 mg kg-1 i.p.), and the peripherally-acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1 i.p.), had no effect on urine output in normally-hydrated animals. 3. In rats given a 25 ml kg-1 water-load orally, idazoxan (10 mg kg-1, i.p.) produced an initial antidiuretic response which was followed by an increase in urine output which was apparent 4 and 6 h after drug administration. 4. RX811059 (1, 3 mg kg-1 i.p.) and L-659,066 (3, 10 mg kg-1 i.p.) significantly decreased urine output in water-loaded rats in the 2 h after injection. 5. The antidiuretic effects of L-659,066 were attenuated in Brattleboro rats which are deficient in vasopressin; only the highest dose (10 mg kg-1 i.p.) decreased urine output, and this was only a small response in comparison with its virtual abolition of urine output in water-loaded Wistar rats. 6. The results with the selective alpha 2-adrenoceptor antagonists in Wistar and Brattleboro rats suggest that alpha 2-adrenoceptors in the periphery may play a physiological role in the control of water balance through a mechanism which involves vasopressin. 7. The paradoxical diuretic effects of idazoxan contrast with the effects of the other alpha 2-adrenoceptor antagonists and therefore may be attributed to a property of this compound unrelated to alpha 2-adrenoceptor blockade.     

Effects of a peripherally acting alpha 2-adrenoceptor antagonist (L-659,066) on hemodynamics and plasma levels of catechols in conscious rats

L-659,066 is a new alpha 2-adrenoceptor antagonist which does not enter the central nervous system after systemic administration and therefore can be used to examine effects of blockade of peripheral alpha 2-receptors on hemodynamics and plasma levels of catechols. After i.v. administration to conscious rats, L-659,066 produced dose-related, small decreases in mean arterial pressure (MAP) and large increases in heart rate (HR), arterial plasma levels of norepinephrine (NE), and levels of the intraneuronal NE metabolite, dihydroxyphenylglycol (DHPG). After administration of L-659,066, HR, but not MAP, was strongly correlated with NE levels (r = 0.93, P less than 0.001). Levels of DHPG and dihydroxyphenylalanine (DOPA) also were strongly correlated with NE levels (r = 098 and r = 0.71). After comparison with responses during hypotension induced by the vasodilator, nitroprusside, the results indicated that L-659,066 increases sympathetically mediated NE release and catecholamine turnover due to inhibition of presynaptic alpha 2-receptors as well as due to reflexive sympathetic activation related to blockade of alpha 2-receptors on arterial smooth muscle cells.     

Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: I. Effects on blood pressure, heart rate and pressor responsiveness in normotensive subjects.

1. Abanoquil (UK 52,046) is a novel, quinoline-derivative, alpha 1-adrenoceptor antagonist which, on the basis of animal studies, possesses antiarrhythmic activity at doses which have little or no effect on blood pressure. 2. In two placebo-controlled, double-blind, crossover studies the alpha 1-adrenoceptor antagonist activity (phenylephrine pressor responses) and the effects on blood pressure and heart rate (in the presence and absence of concomitant beta-adrenoceptor blockade) have been investigated in healthy, normotensive subjects following the intravenous administration (i.v.) of abanoquil. 3. In the first study, abanoquil at a dose of 0.4 micrograms kg-1 i.v. (as a bolus or by increments) produced significant alpha 1-adrenoceptor antagonism (with rightward shifts of more than two-fold in the phenylephrine pressor dose-response curves) but no significant effects on supine or erect blood pressure and heart rate. 4. In the second study, a dose of 0.5 micrograms kg-1 i.v. had no significant effect on supine or erect blood pressure but pre-treatment with atenolol promoted a small fall in erect blood pressure without causing significant orthostatic hypotension. 5. In conclusion, significant alpha 1-adrenoceptor antagonism without marked reflex tachycardia or profound postural hypotension suggest that abanoquil has a different haemodynamic profile from that of 'classical' peripheral alpha 1-adrenoceptor antagonists.     

Modulation of the hypothermic and hyperglycaemic effects of 8-OH-DPAT by alpha 2-adrenoceptor antagonists.

1. The effects of pretreatment with two novel and relatively specific alpha 2-adrenoceptor antagonists on the hypothermic and hyperglycaemic responses induced by the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were investigated in mice. The alpha 2-adrenoceptor antagonists used were, atipamezole, which occupies both central and peripheral receptors, and L 659,066, which poorly penetrates the blood brain barrier. 2. Atipamezole (1 and 3 mg kg-1) alone had no effect on body temperature but significantly attenuated the 8-OH-DPAT-induced hypothermic response. The hyperglycaemic effect of 8-OH-DPAT was also attenuated by pretreatment with atipamezole; however, 3 mg kg-1 atipamezole did cause some hypoglycaemia when administered alone. 3. Pretreatment with L 659,066 (3-30 mg kg-1) failed to alter the hypothermic effects of 8-OH-DPAT. All doses of L 659,066 tested attenuated 8-OH-DPAT-induced hyperglycaemia, but the highest dose (30 mg kg-1) produced hypoglycaemia when administered alone. 4. The results suggest that the attenuation of 8-OH-DPAT-induced hypothermia by alpha 2-adrenoceptor antagonist may be centrally mediated whereas the blockade of 8-OH-DPAT-induced hyperglycaemia may involve peripheral mechanisms.     

Selective alpha 2-adrenoceptor blockade does not enhance glucose-evoked insulin release

An investigation has been made of the effects of the selective alpha 2-adrenoceptor antagonist, idazoxan, on the plasma immunoreactive insulin and glucose responses following a glucose stimulus in conscious euglycaemic rats. UK 14304 (100 micrograms/kg), a selective alpha 2-adrenoceptor agonist, reduced the insulin response and potentiated the hyperglycaemia elicited by an intra-arterial glucose load (0.25 g/kg), thereby confirming previous findings that alpha 2-adrenoceptors can influence pancreatic insulin secretion and glycaemia. The effects of UK 14304 were totally abolished by idazoxan (1.0 mg/kg), indicating that idazoxan, at the dose studied, effectively antagonized alpha 2-adrenoceptor-mediated responses. However, idazoxan (1.0 mg/kg) by itself did not significantly affect the plasma glucose and insulin responses to glucose challenge. The data indicate that selective alpha 2-adrenoceptor blockade per se does not potentiate glucose-evoked insulin secretion.     

alpha 1-Adrenoceptor agonist activity of alpha 2-adrenoceptor antagonists in the pithed rat preparation.

The selective alpha 2-adrenoceptor antagonist, RX781094, evoked a dose-related pressor response in the pithed rat preparation when administered in bolus doses by the intravenous route. This response was enhanced following depletion of endogenous amines by reserpine, and inhibited by the selective alpha 1-adrenoceptor antagonist, prazosin. Two other selective alpha 2-adrenoceptor antagonists, Wy26703 and Wy26392, had no marked effect on the blood pressure of this preparation. Pretreatment of the preparation with Wy26703 had no significant effect on the pressor response evoked by RX781094. It is concluded that RX781094 is an alpha 1-adrenoceptor agonist at similar doses to those at which it exhibits alpha 2-adrenoceptor antagonist properties. The agonist activity exhibited by RX781094 is not a general property of all alpha 2-adrenoceptor antagonists and should be considered when this compound is employed as an alpha 2-adrenoceptor antagonist.     

Studies with abanoquil (UK-52,046) a novel quinoline alpha 1-adrenoceptor antagonist: II. Duration of action, pharmacokinetics and concentration-effect relationships in normotensive subjects.

1. This study further examines the quinoline-derivative abanoquil with particular respect to the duration of its alpha 1-adrenoceptor antagonist activity and its concentration-effect relationship following a single intravenous bolus dose of 0.5 micrograms kg-1 in young, normotensive males. 2. alpha 1-adrenoceptor antagonism (as assessed by phenylephrine pressor responses) was detectable for up to 12 h post dosing: at 12 h there was a significant 1.5-fold rightward shift (95% CI: 2.2 to 1.1) of the pressor dose-response curve for diastolic blood pressure. 3. Despite evidence of substantial alpha 1-adrenoceptor antagonism abanoquil had no significant effect on blood pressure, supine and erect, but there were small and statistically significant increments in heart rate. 4. The degree of alpha 1-adrenoceptor antagonism was related to whole blood concentrations abanoquil: the PD-ratios of phenylephrine pressor responses performed at 1, 6, and 12 h post dosing were significantly correlated with log drug concentrations (r = 0.57 for systolic (P less than 0.05) and r = 0.78 for diastolic blood pressure (P less than 0.005). 5. In conclusion, abanoquil produced significant alpha 1-adrenoceptor antagonism which was related to circulating drug concentrations. The absence of other significant cardiovascular effects suggests that abanoquil warrants further clinical study as an antiarrhythmic agent.     

Potentiation of the anti-obesity effect of the selective beta 3-adrenoceptor agonist BRL 35135 in obese Zucker rats by exercise.

1. The effects of chronic treatments with a selective beta 3-adrenoceptor agonist and a selective alpha 2-adrenoceptor antagonist and their interactions with physical exercise training were studied in experimental obesity. 2. BRL 35135 (beta 3-agonist, 0.5 mg kg-1 day-1 p.o.), atipamezole (alpha 2-antagonist, 4.0 mg kg-1 day-1 p.o.) and placebo were given to genetically obese male Zucker rats. Half of the rats were kept sedentary whereas the other half were subjected to moderate treadmill exercise training. Body weight gain, cumulative food intake, the neuropeptide Y content of the hypothalamic paraventricular nucleus, brown adipose tissue thermogenic activity (measured as GDP binding), plasma insulin and glucose levels were measured after 3 weeks' treatment and exercise. 3. Treatment with BRL 35135 reduced weight gain by 19%, increased brown adipose tissue thermogenic activity 45-fold and reduced plasma insulin by 50%. Atipamezole slightly increased food intake and neuropeptide Y content in the paraventricular hypothalamic nucleus but had no effect on the other measured parameters. Exercise alone had no effect on weight gain, food intake or thermogenic activity, whereas it reduced plasma insulin and glucose levels. 4. The effect of BRL 35135 on weight gain and thermogenic activity was significantly potentiated by exercise; the reduction in weight gain was 56% in comparison with 19% in sedentary animals. Food intake was significantly reduced in the BRL 35135-treated-exercise-trained animals, although neither beta 3-agonist nor exercise alone affected it.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered thermoregulatory responses to clonidine in streptozotocin-diabetic rats.

1. The effects of streptozotocin (STZ) treatment on alpha 2-adrenoceptor regulation of body temperature were studied by monitoring the response of colonic temperature to administration of clonidine. 2. A dose-dependent fall in colonic temperature occurred in control rats given clonidine challenge (0.05-2.0 mg kg-1, s.c.); this response was inhibited by prior administration of either yohimbine or idazoxan (2 mg kg-1, s.c.) but not by the peripherally-acting alpha 2-adrenoceptor antagonist L-659,066 (10 mg kg-1, s.c.). 3. In rats treated with STZ (65 mg kg-1, i.v.) administration of clonidine elicited a dose-independent hyperthermia (circa 1 degree C.); this effect was unaltered by prior administration of yohimbine or idazoxan. 4. Naloxone (5 mg kg-1, s.c.) elicited a small fall in temperature (< 1 degree C.) in both control and STZ-treated rats; naloxone pretreatment did not alter the temperature response to clonidine in either group. 5. Nicotinic acid (10 mg kg-1, s.c.) caused a similar small elevation in temperature in both groups. 6. Administration of replacement insulin to STZ-treated rats maintained weight gain and low blood glucose while the thermoregulatory response to clonidine slowly reverted to normal. 7. These results show that altered central temperature control is an element of the generalised abnormality of alpha 2-receptor function induced by STZ.     

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on food and water intake in the rat.

1. Idazoxan (1, 3, 10 mg kg-1, i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2. The more selective and specific alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg kg-1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3. The peripherally acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect RX811059 and RX821002 on food intake contrasts with the large dose-related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.     

Role of adrenoceptors in vitro and in vivo in the effects of lithium on blood glucose levels and insulin secretion in the rat.

1. Pretreatment of rats with the non-selective alpha-adrenoceptor antagonist dihydroergotamine counteracts the inhibition of glucose-induced insulin secretion caused by lithium both in vitro and in vivo. The present study was therefore carried out to specify further which type of adrenoceptor is involved in lithium-induced hyperglycaemia and inhibition of insulin secretion. 2. The lithium-induced effects were reversibly blocked by pretreatment of rats with the alpha 2-adrenoceptor antagonist yohimbine or a combination of yohimbine and the non-selective beta-receptor antagonist propranolol, whereas the alpha 1-receptor antagonist prazosin and propranolol alone were ineffective in blocking these effects. 3. These findings suggest that the effects of lithium on plasma glucose and insulin levels are mediated mainly by the stimulation of alpha 2-adrenoceptors.     

Effect of pertussis pretreatment on plasma glucose and insulin responses to lithium in rats.

1. Administration of lithium to rats causes a rise in plasma glucose and suppresses glucose-stimulated insulin secretion. These effects are blocked by the alpha 2-adrenoceptor antagonist, yohimbine. 2. Pretreatment of rats with Bordetella pertussis toxin resulted in a reversal of the usual plasma glucose and insulin responses to intravenously administered lithium (4 mEq kg-1). There was a slow fall in plasma glucose, while plasma insulin rose to 267 +/- 42% (+/- s.e.mean) of control values at 30 min. The effect of lithium on glucose-stimulated insulin secretion was also reversed; there was a marked increase in the insulin response which contrasted with the suppression seen in normal controls. 3. In perifused islets of Langerhans isolated from pertussis pretreated rats, the previously described inhibition by lithium of the second phase of glucose-stimulated insulin secretion from normal islets was almost completely abolished. 4. The results are consistent with the hypothesis that these effects of lithium are mediated by the influence of catecholamines on the islets. When the inhibitory effect of alpha 2-adrenoceptors is abolished by pertussis treatment, which blocks the action of the inhibitory guanine nucleotide-binding protein Gi, effects of beta-adrenoceptor stimulation predominate, leading to an increased secretion of insulin.     

Altered glucose homeostasis in alpha2A-adrenoceptor knockout mice

To elucidate the functions of alpha2-adrenoceptor subtypes in metabolic regulation, we determined plasma glucose and insulin levels and tissue uptake of the glucose analogue 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) in C57Bl/6J wild-type (WT) and alpha2A-adrenoceptor knockout (alpha2A-KO) mice at baseline and following alpha2-adrenoceptor agonist ((+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole (dexmedetomidine)) and antagonist (4-[2-ethyl-2,3-dihydro-1H-inden-2-yl]-1H-imidazole (atipamezole)) administration. Basal glucose levels were 30% lower in alpha2A-KO mice than in WT mice. In WT mice, dexmedetomidine lowered insulin and elevated glucose levels, and atipamezole reduced glucose levels. In alpha2A-KO mice, neither drug affected the glucose or insulin levels. [18F]FDG uptake was investigated in plasma, heart, liver, kidney, pancreas, lung, fat, and skeletal muscle. Cardiac [18F]FDG uptake was a sensitive indicator of sympathetic function. Liver [18F]FDG uptake conformed to the plasma glucose levels. In alpha2A-KO mice, drug effects on [18F]FDG tissue uptake were absent. Thus, the alpha2A-adrenoceptor is the alpha2-adrenoceptor subtype primarily involved in the regulation of blood glucose homeostasis in vivo.     

Influence of catecholaminergic and serotonergic receptor antagonists on the hyperglycaemic response to the neuroglucopaenic agent, 2-deoxy-D-glucose.

The intravenous administration of 2-deoxy-D-glucose (2-DG) to conscious catheterised rats dose-dependently increased the levels of glucose in plasma throughout the analysis (60 min); the levels of insulin in plasma remained unchanged, except for an early significant decrease in rats treated with the largest dose (1 g/kg). Pretreatment (10 min beforehand) with the beta 2-adrenoceptor antagonist, ICI 118,551 (3 mg/kg) or the alpha 2-adrenoceptor antagonist, idazoxan (1 mg/kg) decreased the rise in levels of glucose in plasma elicited by 2-DG (250 mg/kg). Conversely, the alpha 1-adrenoceptor antagonist, prazosin (1 mg/kg) or the dopaminergic receptor blocker, haloperidol (0.5 mg/kg) amplified the hyperglycaemic response to 2-DG. Previous administration of either the 5-HT1A/5-HT2 receptor antagonist, spiperone (3 mg/kg), the 5-HT1/5-HT2 receptor antagonist, methysergide (1 mg/kg), the 5-HT1C/5-HT2 receptor antagonist, ritanserin (1 mg/kg) or the 5-HT3 receptor antagonist, ICS 205.930 (0.1 mg/kg) did not affect 2-DG-induced hyperglycaemia. On the other hand, the mixed 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, (-)-propranolol (5 mg/kg) and the 5-HT1/5-HT2 receptor antagonist, methiotepin (1 mg/kg), respectively, diminished and amplified the hyperglycaemia elicited by 2-DG. Lastly, in rats pretreated with prazosin (1 mg/kg, 30 min beforehand), an additional pretreatment (10 min beforehand) with prazosin or methiotepin (both at 1 mg/kg) did not further amplify the hyperglycaemic response to 2-DG. These results indicate that 2-DG-induced hyperglycaemia is mediated by alpha 2- and beta 2-adrenoceptors and amplified by alpha 1-adrenoceptor blockade. Conversely, neither 5-HT1, 5-HT2 nor 5-HT3 receptors played a role in the hyperglycaemic response to 2-DG.     

Pharmacokinetic and pharmacodynamic studies with two alpha-adrenoceptor antagonists, doxazosin and prazosin in the rabbit.

The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]-prazosin from specific binding sites. However, the lower pA2 value for doxazosin at alpha 1-adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. The dose-related pressor effects of intravenous phenylephrine were used to assess vascular alpha 1-adrenoceptor antagonism in vivo. There was a close agreement between alpha 1-adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The alpha 1-adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. Studies using either radioligand binding or pressor responses to B-HT 920 showed that doxazosin did not show any significant affinity for the alpha 2-adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. Doxazosin has a longer terminal elimination half-life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. Following pharmacological 'autonomic blockade' and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through alpha 1-adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained alpha 1-adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has alpha 1-adrenoceptor blocking properties.     

Metabolic and cardiovascular side effects of the beta 2-adrenoceptor agonists salbutamol and rimiterol.

The metabolic and cardiovascular side-effects of intravenous infusions of therapeutic doses of beta 2-adrenoceptor agonists salbutamol and rimiterol have been determined in four healthy male subjects. There were dose-related increases in plasma glucose, renin activity, serum insulin and heart rate, and significant hyperlactataemia and ketonaemia. There were dose-related decreases in plasma potassium, phosphate and corticosteroids and significant hypocalcaemia and hypomagnesaemia. The effects of equivalent molar amounts of salbutamol and rimiterol were similar. Whichever drug is used, special care is required with patients who may have abnormal glucose tolerance, potassium depletion, or be predisposed to lactic acidosis. Rimiterol may be preferable for infusion because of its short plasma half-life.     

The lipolytic effect of beta 1- and beta 2-adrenoceptor activation in healthy human volunteers.

1. We investigated the effect of activation beta 1- and beta 2-adrenoceptors on the process of lipolysis in human volunteers. Ten male subjects underwent a single-blind randomized cross-over trial using infusions of terbutaline (a specific beta 2-adrenoceptor agonist), xamoterol (a partial beta 1-agonist with beta 2-adrenoceptor blocking activity) and saline (placebo control). The effect of these infusions on plasma potassium, glucose, free fatty acids (FFA) (total and individual) and insulin levels was studied. 2. Terbutaline infusion induced a significant rise in plasma glucose and a fall in plasma potassium in keeping with its beta 2-adrenoceptor stimulant properties. Xamoterol infusion had no significant effect on these values. Terbutaline infusion caused a greater rise in total and individual FFA than xamoterol, but both effects were significantly different from placebo. 3. The possible reasons for these results and their implications on the beta-adrenergic control of lipolysis are discussed.     

Vascular and aldosterone responses to angiotensin II in normal humans: effects of nicardipine

The effects of the dihydropyridine calcium antagonist nicardipine on pressor responsiveness and hormone release were investigated in healthy normotensive men following both acute intravenous administration and 1 week of oral treatment. There were no significant changes in baseline supine blood pressures but the pressor responsiveness to the intravenous infusion of angiotensin II was significantly attenuated by both intravenous and oral nicardipine. This reduction tended to be greater following intravenous nicardipine, which achieved the highest mean plasma nicardipine concentrations. Neither intravenous nor oral nicardipine caused any significant differences in the aldosterone response to the angiotensin II infusion and there were no significant differences attributable to nicardipine in the levels of plasma renin activity. However, the progressive increase in the aldosterone/renin ratio observed during placebo was significantly attenuated by both nicardipine treatments. There were no significant effects on plasma cortisol, adrenocorticotropic hormone, or noradrenaline. This study has shown that nicardipine acutely and chronically reduces vascular responsiveness to the pressor effect of angiotensin II. There was no significant effect on the aldosterone response to angiotensin and no evidence of clinically significant interference with the release of other hormones to suggest that this mechanism contributes to the antihypertensive effect of nicardipine.     

Effects of physiological and pharmacological variation of sympathetic nervous system activity on plasma non-esterified fatty acid concentrations in man.

1. The consequence of the sympatholytic effect of clonidine (alpha 2-adrenoceptor agonist) was compared with the effect of a physiological inhibition of sympathetic nervous system activity (change from upright to supine position) on plasma catecholamine and non-esterified fatty acid (NEFA) concentrations in overnight fasting healthy men. 2. Clonidine (150 micrograms orally) administered in upright position induced a significant reduction of plasma noradrenaline and NEFA concentrations. A change from upright to supine position which provoked a more marked decrease in plasma noradrenaline concentrations induced a weak increase in plasma NEFA concentrations. 3. The modification of plasma NEFA and catecholamine concentrations brought about by standing up was studied after placebo or yohimbine (alpha 2-adrenoceptor antagonist) administration. With placebo, standing up promotes a 100% increase in plasma noradrenaline concentrations (measured 5 and 15 min after rising) and a weak transient decrease in plasma NEFA concentrations (5 min after rising). In the supine position, yohimbine increased plasma noradrenaline and NEFA concentrations by about 100% and 55% respectively. Standing after yohimbine administration promoted large increases in plasma noradrenaline and NEFA concentrations. 4. These results indicate that a reduction of sympathetic nervous activity is not associated with a decrease of plasma NEFA concentrations and argue for a role of alpha 2-adrenoceptors in the NEFA mobilization from adipose tissue after sympathetic nervous system activation in man.