Increase In Plasma Norepinephrine Concentration Research Articles

Co-released adrenaline markedly facilitates noradrenaline overflow through prejunctional β2-adrenoceptors during swimming exercise

The effect of intravenously applied (−)-adrenaline, taken up by and released from sympathetic nerves, on swimming exercise-induced noradrenaline overflow in permanently cannulated adrenal demedullated rats was studied. Adrenaline (100 ng/min) was infused for 2 h, during which a plasma concentration of 500 pg/ml (approximately 2.5 nM) was reached. One hour later plasma adrenaline had returned to undetectable levels. During swimming, adrenaline was released into the plasma in concentrations up to 133 pg/ml and the noradrenaline concentration was markedly enhanced as well. The total catecholamine increase amounted to 178% of control (saline infusion) in the first 3 min of swimming and 165% for the whole 20 min. Cocaine (2.5 mg/kg plus 0.05 mg/kg/min), infused together with adrenaline and continued throughout the experiment, prevented the exercise-induced release of adrenaline and no increase in plasma noradrenaline concentration was observed. Yohimbine (0.25 mg/kg) strongly further enhanced the exercise-induced overflow of both noradrenaline and adrenaline. This further increase was completely blocked by the selective β 2-adrenoceptor antagonist ICI 118,551 ((±)-1-[(2,3-dihydro-7-methyl-1 H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) (1.0 mg/kg). These results demonstrate that adrenaline can be taken up by sympathetic nerve endings through cocaine-sensitive uptake carriers and is released from these nerves during swimming exercise. Neuronally released adrenaline markedly enhances exercise-induced catecholamine overflow through activation of prejunctional β 2-adrenoceptors.

Muscle sympathetic nerve activity during postural change in healthy young and older adults

Recent evidence suggests that during orthostatic stress the reflex increase in muscle sympathetic nerve activity may be diminished in older adults. To test this hypothesis, we measured muscle sympathetic nerve activity, plasma noradrenaline concentrations, heart rate, and arterial blood pressure in twelve young (mean, 25 years; range, 19-29 years) adults and 14 older (mean 64 years; range, 60-74 years) healthy adults, while supine and during upright sitting. Supine control levels of muscle sympathetic nerve activity were higher in the older subjects (35 +/- 1 vs. 25 +/- 1 bursts/min, p < 0.05), but there were no differences in plasma noradrenaline concentrations, heart rate or arterial pressure. Despite higher supine control levels in the older group, the absolute unit increases in muscle sympathetic nerve activity in response to upright sitting (p < 0.05 vs. control) were not different in the two groups (7 +/- 1 vs. 7 +/- 1 bursts/min), nor were the increases in plasma noradrenaline concentrations. Heart rate did not increase above supine control in response to sitting in either group. Arterial pressure increased slightly (p < 0.05, supine vs. control), but there were no age-related differences. These results indicate that, contrary to recent findings, the reflex increases in muscle sympathetic nerve activity and plasma noradrenaline concentrations and regulation of arterial pressure during this natural orthostatic stress are well preserved in older healthy men and women.

Abnormalities in sympathoneuronal regulation are localized to failing myocardium in rabbit heart

Objetives. This study investigated the differences in sympathoneuronal regulation between acute left ventricular failure and chronic biventricular failure to determine whether an increase in pasma norepinephrine concentration plays a primary role in the genesis of the desensitization phenomenon in heart failure.Background. It remains to be determined whether plasma norepinephrine plays a primary role in the pathogenesis of sympathetic desensitization in heart failure in vivo.Methods. Acute left ventricular failure was induced by aortic regurgitation in seven rabbits. Chronic heart failure was induced by adriamycin treatment in another seven rabbits.Results. Cardiac output was lower in rabbits with aortic regurgitation than in seven sham-operated rabbits. Left ventricular end-diastolic pressure was higher in rabbits with aortic regurgitation, but no significant difference in right ventricular end-diastolic pressure was observed. Beta-adrenoceptor density and norepinephrine concentration in the left ventricular myocardium were lower in rabbits with aortic regurgitation; no such differences were observed for the right ventricular myocardium. Cardiac output was lower in adriamycin-treated rabbits than in seven control rabbits. Both left and right ventricular end-diastolic pressures were higher in experimental rabbits than in control rabbits. Myocardial beta-adrenoceptor density and norepinephrine content were reduced in both ventricles.Conclusions. In chronic heart failure induced by adriamycin, sympathoneuronal activity was altered in both ventricles, whereas in acute left ventricular failure induced by aortic regurgitation, sympathoneuronal activity was affected only in the left ventricle despite a similar increase in plasma norepinephrine concentration in both animal models. Local abnormalities in sympathoneuronal regulation in failing myocardium therefore appear to be responsible for these phenomena.

Renal sodium handling and neurohumoral systems in patients with cirrhosis in sitting posture: effects of spironolactone and water immersion

Renal sodium handling, neurohumoral systems, and systemic hemodynamics were investigated under baseline conditions in sitting posture in 10 healthy subjects, 11 patients with cirrhosis without, and 10 patients with cirrhosis with ascites. Furthermore, the effects of head-out water immersion, 1-week spironolactone administration, or their combination was assessed in the two groups of patients. Patients without ascites exhibited a significant increase in plasma norepinephrine concentration and a tendency toward an increase in plasma aldosterone concentration. Patients with ascites had a significantly lower mean arterial blood pressure despite significant reduction of urinary sodium excretion and fractional sodium excretion as well as an increase of plasma renin activity, plasma aldosterone, and norepinephrine concentration. In patients with ascites, the increase in renal sodium excretion and fractional sodium excretion following water immersion or spironolactone was clearly augmented by the combination of the two maneuvers. The same pattern was observed in patients without ascites. Our findings (a) underscore the importance of studying hemodynamics, renal function, and neurohumoral systems also in upright posture, (b) suggest a role of sympatico-adrenergic activation and proximal sodium retention in preascitic patients, and (c) are compatible with the vasodilation hypothesis of ascites formation.

Myocardial beta adrenoceptor and voltage sensitive calcium channel changes in a canine model of chronic heart failure

Effects of chronic heart failure upon receptor binding and cardiac function were studied in mongrel dogs. Heart failure was induced by three to seven, graded, sequential, intracoronary microembolizations performed 1 to 3 weeks apart. Depressed systolic and diastolic left ventricular function, reduced cardiac output, increased systemic vascular resistance, increased plasma norepinephrine concentration, left ventricular hypertrophy, and dilation were associated with the development of heart failure in this model. Three months after the last embolization, the density and affinity of myocardial beta adrenoceptors and voltage sensitive calcium channels were quantified by analyzing saturation isotherms of specific radioligand binding. [ 3H]Dihydroalprenolol and [ 3H]nitrendipine bound specifically and with high affinity to cardiac beta adrenoceptors and calcium channels, respectively. Scatchard transformation of the specific binding of these radioligands in membranes prepared following intracoronary embolization demonstrated a 47% decrease in the density of [ 3H]dihydroalprenolol binding sites (605 ± 20 fmol/mg, normal, vs. 323 ± 18 fmol/mg, failed; P<0.05) and a 20% decrease in [ 3H]nitredipine binding sites (371 ± 11 fmol/mg, normal, vs. 298 ± 17 fmol/mg, failed; P<0.05). The binding equilibrium dissociation constants for [ 3H]dihydroalprenolol and [ 3H]nitrendipine were not significantly different between normal and failed myocardium. There was no difference in the sialic acid content in the sarcolemmal membranes prepared from normal and failed dog hearts (31.07 ± 0.76 nmol/mg, normal, vs. 30.58 ± 5.25 nmol/mg, failed). This is inconsistent with the selective purification of membranes utilized in these radioligand binding studies. These data indicate that with left ventricular failure resulting from graded, sequential, intracoronary microembolization in dogs, there is an associated down-regulation of cardiac beta adrenoceptors and voltage sensitive calcium channels. Changes in beta adrenoceptors in this canine model of left ventricular failure parallel those reported in patients suffering from end-stage heart failure.

Effects of acute hypoxia on renal and endocrine function at rest and during graded exercise in hydrated subjects.

Renal effects of altitude hypoxia are unclear. Renal and hormonal function was investigated in eight males at rest and during graded exercise at sea level (SL) and 48 h after rapid ascent to 4,350 m (HA). HA did not change resting values of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), sodium clearance (CNa), urine flow, or lithium clearance (CLi), which was used as an index of proximal tubular outflow. At rest, HA increased plasma norepinephrine concentration and decreased plasma concentrations of renin and aldosterone. Exercise decreased ERPF similarly in both environments. Normoxic exercise progressively reduced GFR, but at HA GFR only decreased during heavy exercise. This resulted in a higher filtration fraction during light and moderate hypoxic exercise. However, calculated absolute proximal reabsorption rate (GFR-CLi) at HA was higher during low-intensity exercise, and there were no significant differences between exercise-induced decreases in CLi, CNa, and urine flow at HA compared with SL. Exercise gradually increased plasma norepinephrine, but values were higher at HA during light and moderate exercise. The small changes in the renal response to low-intensity hypoxic exercise may be secondary to increased adrenosympathetic activity. However, antidiuretic and antinatriuretic effects of exercise were maintained in hypoxia and in both environments seemed to be the consequence of decreased proximal tubular outflow. The results demonstrate that renal glomerular and tubular function is well preserved in acute hypoxia despite marked hormonal changes.

Cardiovascular effects of intrathecal administration of substance P in the rat: interactions with serotonergic mechanisms.

Intrathecal (i.th.) administration of substance P (SP, 6.5 nmol) at the Th 8-10 level in conscious rats increased blood pressure (carotid artery), heart rate and plasma catecholamine concentrations. The responses were antagonized by the intravenous (i.v.) but not i.th. pretreatment with the 5-HT2-receptor antagonists ketanserin and ritanserin and intrathecally administered serotonin (5-HT, 10 micrograms). The pressor response and the increase in plasma noradrenaline concentrations were also antagonized by i.v. or i.th. pretreatment with the 5-HT1A-agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). In contrast the pressor response to SP was facilitated by the 5-HT1A-antagonist 1-pindolol (i.v. or i.th). Pretreatment with SP (i.th) reduced the hypotensive response to i.v. 8-OH-DPAT. These results demonstrate functional interactions between SP and serotonergic mechanisms in the central system, but the precise location and nature were not elucidated.

Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus

The purpose of the present study was to determine the overall cardiovascular and sympathetic nervous system responses to stimulation of neuronal cell bodies in the paraventricular neucleus (PVN) of the hypothalamus. Bilateral microinjections (50 nl) of monosodium glutamate or sodium acetate were made into the PVN of conscious unrestrained rats. Blood pressure, heart rate and plasma concentrations of norepinephrine and epinephrine were measured. The injection of sodium acetate as an osmotic control was without effect on any of the recorded variables. In contrast, the injections of glutamate were associated with a rapid increase in both blood pressure and heart rate. At doses of 15, 25, and 50 nmol blood pressure increased by13 ± 2, 14 ± 3and16 ± 1mmHg while heart rate increased by64 ± 15, 73 ± 8 and50 ± 8 bpm. These responses were associated with increases in plasma norepinephrine concentrations of51 ± 8, 100 ± 16and62 ± 13pg/ml while epinephrine concentrations rose by42 ± 17, 58 ± 18and38 ± 17pg/ml. The responses of glutamate (25 nmol) were not affected by blockade of vascular vasopressin receptors with d(CH 2) 5Tyr(Me)AVP (10 μg/kg) (blood pressure: pre5 ± 3vs post13 ± 3mmHg, heart rate pre77 ± 9bpm vs post91 ± 7bpm, plasma norepinephrine: pre106 ± 22vs post121 ± 28pg/ml and plasma epinephrine: pre61 ± 25vs post34 ± 30pg/ml. These findings indicate that stimulation of neuronal cell bodies in the PVN of conscious rats causes an increase in sympathoadrenal outflow resulting in an increase in blood pressure and heart rate. Vasopressin release into the systemic circulation does not appear to play a major role in the cardiovascular responses associated with PVN stimulation.

Plasma and organ catecholamine levels following stimulation of the rat insular cortex

The posterior insular cortex of the rat contains an area of cardiac chronotropic representation within which tachycardia sites occur rostrally to those producing bradycardia. In the current study using ketamine-anesthetized rats, the insular cortex was stimulated for 1 h using a phasic technique synchronized with the cardiac cycle. Tachycardia was associated with an increase in plasma norepinephrine concentration; epinephrine remained unchanged. This indicates a neural origin of the norepinephrine increment. The tachycardia response was completely blocked by atenolol. Plasma catecholamine levels remained unchanged during stimulation of insular bradycardia sites. Atenolol was without effect during stimulation-induced bradycardia which was completely blocked by atropine. Total cardiac norepinephrine concentration inversely correlated with change in heart rate during stimulation of tachycardia sites. No correlation between intracardiac catecholamines and heart rate variables was found for the bradycardia or control sites. These results indicate that in the ketamine-anesthetized rat, whereas insular stimulation-induced tachycardia is dependent on the sympathetic nervous system, bradycardia elicited by insular cortex stimulation is mediated by parasympathetic mechanisms. No correlation was identified between renal or skeletal muscle norepinephrine levels and any heart rate parameter. This implies that the sympathetic effects of phasic insular microstimulation may be exerted mainly on cardiac nerves, and less so in other visceral beds.

Norepinephrine disrupts cytoskeletal framework of microtubules in rat hearts.

Sympathetic activations may deteriorate myocardial failure due to progression of myocardial cell injury. In the present study, to test whether microtubules, calcium ion (Ca2+) sensitive cytoskeletons, are disrupted by norepinephrine (NE) and whether beta-adrenoceptor antagonist could attenuate the disruption of microtubules, structures of microtubules are studied in rat hearts with continuous subcutaneous infusions of norepinephrine. In the sham operated rats the microtubules stained by immunohistochemical technique showed normal network structures. A low dose of NE infusion (2 micrograms/kg/h) for 6 h resulted in a minimal change in microtubule structures. However, infusion for 24 h of NE (2 micrograms/kg/h) and a large dose of NE infusion (20 micrograms/kg/h) for 6h caused disruptions of microtubules in small patchy lesions (8 +/- 3%, 12 +/- 4% of area, respectively). A large dose of NE infusion for 24 h increased systolic blood pressure from 116 +/- 6 to 152 +/- 4 mmHg and increased plasma NE concentration from 430 +/- 40 to 17100 +/- 3700 pg/ml and further disrupted the network of microtubules in 40 +/- 6% of the total area. Propranolol (500 micrograms/kg/h) markedly attenuated NE-induced disruptions of microtubules. Disruptions of microtubules may be one of the underlying mechanism of deterioration of myocardial failure in chronic heart failure in which sympathetic activity is markedly activated.

Prostaglandin E1 and Tracheal Intubation: Relationship between the Cardiovascular Responses and Plasma Catecholamine Concentrations

A study was carried out on 30 normotensive patients (American Society of Anesthesiologists physical status 1) to investigate whether or not a suppressive effect of 0.3 or 0.6 microgram/kg prostaglandin E1 on the hypertensive response to tracheal intubation was due to inhibition of the increase in plasma catecholamine concentrations following the stressful stimulation. A total of 30 patients in three groups underwent elective surgery. Anaesthesia was induced with 5 mg/kg sodium thiopentone given intravenously and tracheal intubation was facilitated by 0.2 mg/kg vecuronium. Either saline (group A) or 0.3 (group B) or 0.6 micrograms/kg (group C) prostaglandin E1 was administered intravenously 15 s before direct laryngoscopy (lasting 30 s) which was attempted 2 min after administering thiopentone and vecuronium. All groups exhibited significant (P less than 0.05) increases in mean arterial pressure, heart rate, rate-pressure product and plasma noradrenaline concentrations following tracheal intubation, but the increases in mean arterial blood pressure and rate - pressure product were significantly (P less than 0.05) less in groups B and C than in group A. Prostaglandin E1, however, enhanced the increase in plasma noradrenaline concentrations following intubation. Data suggest that attenuation of the pressor response to intubation by prostaglandin E1 may not be due to inhibition of the noradrenaline release stimulated by intubation but to inhibition of noradrenaline-induced vasoconstriction.

Abnormal sympathetic and renal response to sodium restriction in compensated cirrhosis

It has been proposed that in liver cirrhosis portal hypertension causes splanchnic vasodilation and this induces blood volume expansion to maintain blood pressure. The current study was designed to explore the homeostatic response to sodium restriction, a maneuver aiming to contract blood volume, in compensated cirrhosis. Mean blood pressure, sympathetic nervous activity, and proximal sodium reabsorption were evaluated in 16 healthy control and 21 nonazotemic cirrhotic patients (11 without ascites and 10 with ascites) under two experimental conditions: after 4 days on a free sodium diet (basal condition) and after 4 days on a restricted sodium diet (40 mmol/day). No differences were observed in basal conditions in the above parameters between control and cirrhotic patients without ascites. However, cirrhotic patients with ascites showed lower basal values of mean blood pressure and higher basal levels of both plasma norepinephrine and fractional proximal sodium reabsorption than controls. Neither control nor cirrhotic patients with ascites showed significant changes in the measured parameters after sodium restriction. In contrast, in nonascitic patients, this maneuver induced an elevation in plasma norepinephrine concentration (164.4 ± 24.6 vs. 270.1 ± 24.9 pg/mL; mean ± SEM; P < 0.005) and in fractional proximal sodium reabsorption (86.4 ± 2.1 vs. 91.8% ± 0.5%; P < 0.01). In addition, the nonascitic cirrhotic patients became hypotensive compared with controls (80.9 ± 1.6 vs. 88.5 ± 4.8 mm Hg; P < 0.05) when subjected to the low-sodium diet. In patients without ascites, under conditions of sodium restriction, the decrease in mean arterial pressure correlated inversely with the increase in plasma norepinephrine concentration (r = −0.713; P < 0.05), whereas the levels of plasma norepinephrine correlated directly with fractional proximal sodium reabsorption (r = 0.893; P < 0.01). These findings suggest that ineffective circulatory volume is detected in nonascitic cirrhotic patients only under conditions of sodium restriction, but it is always present in cirrhotic patients with ascites, irrespectively of the amount of sodium in the diet. These results are compatible with the existence of fixed arterial vasodilation in cirrhosis.

EFFECTS OF LABETALOL ON PERIOPERATIVE STRESS MARKERS AND ISOFLURANE REQUIREMENTS

We have studied the effect of labetalol on anaesthetic requirements, cardiac and humoral responses in 16 healthy women during elective abdominal surgery. The experimental group (n = 8) received increments of i.v. labetalol 0.15-0.3 mg kg-1 to reduce mean arterial pressure (MAP) by 15% from values obtained before anaesthesia. All patients received thiopentone 6 mg kg-1 and anaesthesia was maintained with isoflurane and nitrous oxide. In the placebo group, tracheal intubation provoked a 33% increase in heart rate (HR) and a 52% increase in MAP (P less than 0.001 vs baseline for both). In contrast, pretreatment with labetalol resulted in a 7.3% increase in HR and a 21.3% increase in MAP (P less than 0.05 vs baseline for MAP). Two patients treated with labetalol had a reduction in MAP to 50-60 mm Hg during surgery. After tracheal extubation, the labetalol group had a significantly slower HR than the placebo group (P less than 0.05). The cardiovascular response to tracheal intubation was associated with an increase in plasma noradrenaline concentration in both groups. Labetalol did not affect isoflurane requirements, plasma concentrations of adrenaline, cortisol and aldosterone or arterial PO2, but prevented the decrease in plasma concentration of potassium which occurred in placebo treated patients (P less than 0.05) in early recovery. We conclude that preanaesthetic administration of labetalol attenuated the perioperative hypertensive and tachycardic responses, but was accompanied by intraoperative hypotension when given in doses greater than 0.5 mg kg-1, despite an increase in plasma noradrenaline concentrations.

Plasma norepinephrine concentrations during resuscitation in the dog

The objective of this study was to evaluate whether the adrenal glands contribute to the increase in plasma norepinephrine concentrations during cardiopulmonary resuscitation, by releasing norepinephrine and/or by secreting epinephrine that facilitates the release of norepinephrine from sympathetic nerve endings via stimulation of presynaptic β receptors. The experiments were performed in adrenalectomized and in shamoperated dogs. In adrenalectomized dogs the increase in plasma norepinephrine concentrations during cardiopulmonary arrest and basic life support (BLS) was markedly smaller than in sham-operated dogs. Intravenous infusion of physiologic doses of epinephrine during BLS in adrenalectomized animals did not influence the plasma norepinephrine concentrations. These data indicate that, as suggested by others, the marked increase in plasma norephinephrine concentrations during BLS in dogs is mainly of adrenomedullary origin. They also suggest that presynaptic facilitation of norepinephrine release by epinephrine is not important, but further experiments using higher doses of epinephrine are necessary.

Is the sympathoexcitatory effect of yohimbine determined by brain yohimbine concentration?

Plasma noradrenaline and adrenaline concentrations, plasma renin concentration (PRC), and serum and brain yohimbine concentrations were measured in conscious Sprague-Dawley rats after the s.c. and i.v. injection of yohimbine. The s.c. and i.v. administration of 1 and 3 mg/kg of yohimbine (30 min post-injection) elicited equivalent and dose-related increases in plasma noradrenaline concentration. At 30 min post-injection, the 1 mg/kg dose given s.c. or i.v. did not increase plasma adrenaline concentration or PRC, whereas the 3 mg/kg dose caused comparable increases in plasma adrenaline concentration and PRC when given s.c. or i.v. Brain yohimbine concentration increased in a dose-related manner whereas serum yohimbine concentration was not significantly different 30 min after treatment with the 1 1 and 3 mg/kg doses regardless of the route of injection. Despite the fact that serum yohimbine concentration was 5-fold greater after i.v. injection as compared to s.c. administration (1 and 3 mg/kg doses), brain yohimbine concentrations were comparable after s.c. and i.v. injection and thus not dependent on either the route of administration or serum yohimbine concentration. The fact that the s.c. and i.v. injection of yohimbine lead to comparable dose-related increases in both brain yohimbine concentrations and neuroendocrine responses suggests that increased sympathetic outflow resulted primarily from an action of yohimbine at central, rather than peripheral, alpha 2-adrenoceptors. However, the data also are consistent with a purely peripheral prejunctional action of the 1 mg/kg dose and a combined central and peripheral action of the 3 mg/kg dose.

Beta-adrenergic function in aging. Basic mechanisms and clinical implications.

Catecholamines have an important endocrine and neuroendocrine role in mediating a variety of autonomic functions. One consequence of normal aging, in particular in the cardiovascular system, is a decline in beta-adrenergic function associated with an alteration in responsiveness to beta-adrenergic therapy. The intrinsic ability for muscle contractility or relaxation is maintained with age and there appears to be an alteration in the process linking the receptor with the contractile or relaxation mechanisms. In rats, beta-adrenergic receptor density decreases with age in adipose tissues and most brain areas, is unchanged in lymphocytes, heart and lung, and increases in the liver. In humans, there are no receptor changes with age in either lymphocytes or brain. In contrast, the number of high-affinity receptors (or coupled receptors) decreases with age in most tissues. In addition, there is a decrease in membrane adenylate cyclase activity or cellular production of cyclic adenosine monophosphate (adenosine 3',5'-cyclic phosphate; cAMP). Plasma noradrenaline (norepinephrine) concentration increases with age. The reduced receptor number in some tissues (down-regulation), the reduced high-affinity receptors and the reduced hormone-stimulated adenylate cyclase activity with age suggests receptor desensitisation to increased plasma noradrenaline concentration. The inability of older animals to desensitise to beta-adrenergic agonists further supports this hypothesis. However, there is an additional post-receptor reduction in catalytic unit activity with age independent of desensitisation. Medications directed at the beta-adrenergic system are commonly used in the elderly. Many of the data on the impact of age on clinical responses are conflicting or unavailable. Concomitant disease, functional status, nutritional state and polypharmacy may play an even greater role than age. However, the available data can be used to guide the selection of therapy, anticipate side effects, and predict potential interactions with other medications and diseases.

Reduced plasma noradrenaline concentrations in simple-obese and diabetic obese patients

1. Obesity may be associated with a decreased activity of the sympathetic nervous system and also with a deficiency of the response to stimuli activating the sympathetic nervous system. As insulin activates the sympathetic nervous system, the present study was undertaken to measure the plasma noradrenaline concentration in the fasting state and after 75 g of oral glucose in simple-obese patients (n = 13), in non-insulin-dependent (type 2) diabetic patients (n = 37) and in normal control subjects (n = 12). 2. The fasting plasma noradrenaline concentration was similarly reduced in the simple-obese group and in the diabetic obese group compared with the control group (P = 0.005). The glucose-induced increase in plasma noradrenaline concentration was normal in the simple-obese group, but was abolished in the obese diabetic patients (P = 0.008). 3. Step-wise regression analysis indicated that independent effects on the fasting plasma noradrenaline concentration were exerted by age (r = +0.32, P = 0.002), glucose concentration (r = -0.32, P = 0.02) and the degree of obesity (r = -0.37, P = 0.007), but not by plasma insulin concentration. 4. These results show that obese patients have a reduced fasting plasma noradrenaline concentration independently of accompanying diabetes, but that the response of noradrenaline to oral glucose is only abolished in the obese diabetic patients.

Neurohumoral activation in congestive heart failure

This article reviews the evidence that congestive heart failure is accompanied by an increased plasma norepinephrine concentration and that this is due not only to a reduced tissue clearance of the substance but also to a marked increase in sympathetic nerve activity. It also reports data that indicate that the sympathetic activation is associated with an activation of the renin-angiotensin system and an increased plasma level of vasopressin. At which degree of congestive heart failure these phenomena become manifest is not clear, but some studies suggest that the sympathetic and renin-angiotensin systems may be normal in asymptomatic congestive heart failure but already somewhat activated when this condition reaches New York Heart Association class II. There is also evidence that this activation, though initially compensatory, is eventually responsible for a number of adverse cardiovascular effects that account for the negative relationship between this event and survival. Finally, the article discusses the inability of the increased plasma level of atrial natriuretic peptide that characterizes congestive heart failure to offset the adverse effects of the neurohumoral activation and the variable influence of drug treatment on this phenomenon. This is not impossible to achieve, however, because heart transplantation appears to rapidly normalize a major factor in the increased sympathetic activity observed before surgical intervention, that is, impairment of the arterial baroreflex.

Adrenalectomy abolishes antagonism of α‐adrenoceptor‐mediated hypotension by a β‐blocker in conscious rats

1. The effects of a single bolus injection of propranolol, atenolol or ICI 118,551, non-selective beta-, selective beta 1- and selective beta 2-adrenoceptor antagonists, respectively, on mean arterial pressure (MAP) and plasma catecholamine concentrations were examined in seven groups of conscious and unrestrained adrenalectomized rats receiving a continuous infusion of the alpha-adrenoceptor antagonist phentolamine. In all rats adrenaline was undetectable in the plasma four days after adrenalectomy. 2. In the first three groups, phentolamine significantly decreased MAP and increased the plasma concentrations of noradrenaline. The injection of propranolol, atenolol or ICI 118,551 in Groups I, II and III, respectively, caused a small increase in MAP and a small, but not significant, decrease in plasma noradrenaline concentrations. 3. Groups IV, V and VI were given a continuous infusion of adrenaline for 1 h prior to the infusion of phentolamine, followed by a bolus injection of propranolol, atenolol or ICI 118,551, respectively. Group VII was treated similarly to IV, but was also given daily cortisone replacement after adrenalectomy. Adrenaline slightly, but not significantly, decreased MAP while phentolamine significantly decreased MAP and increased plasma noradrenaline concentrations in all groups. A subsequent injection of a beta-blocker caused a significant increase in MAP in each group and a slight decrease in the plasma level of noradrenaline which reached statistical significance in group VII. The pressor effect of propranolol was significantly greater in the cortisone-treated rats (Group VII) than in Group IV. 5. The results suggest that adrenaline and adrenocortical steroids are both involved in the antagonism of alpha-adrenoceptor-induced hypotension by a beta-blocker.

Pindolol Increases Plasma Norepinephrine Concentration by Stimulation of β2-Adrenoceptors in Conscious Spontaneously Hypertensive Rats

The beta-adrenoceptor antagonist pindolol [10-1,000 micrograms/kg subcutaneously (s.c.)] caused dose-related decreases in mean arterial pressure (MAP) and increased heart rate (HR) in conscious spontaneously hypertensive rats (SHR). The lowest dose of pindolol (10 micrograms/kg) decreased MAP by 25 mm Hg (-16%) without affecting plasma norepinephrine (NE) or plasma renin concentration (PRC). However, higher doses of pindolol elicited dose-related increases in plasma NE concentration and PRC. Plasma epinephrine concentration was not altered by pindolol. The selective beta 2-adrenoceptor antagonist ICI 118,551 (3 mg/kg, s.c.) prevented the tachycardia but not the increase in PRC caused by 100 micrograms/kg pindolol. Treatment with ICI 118,551 completely eliminated the 45% increase in plasma NE elicited by 100 micrograms/kg of pindolol even though the decrease in MAP caused by this dose of pindolol was the same in the presence (-33 mm Hg) and absence (-34 mm Hg) of beta 2-adrenoceptor blockade. These results indicate that the vasodepressor action of pindolol in SHR does not result from an agonistic effect at postjunctional beta 2-adrenoceptors in the vasculature. In addition, the increases in plasma NE concentration produced by pindolol result from stimulation of beta 2-adrenoceptors. These beta 2-adrenoceptors may be located prejunctionally on sympathetic neurons.