Role of atrial natriuretic peptide in the development of arterial hypertension in patients with pubertal hypothalamic syndrome

The role of a depressor factor, atrial natriuretic peptide, in the development of arterial hypertension in adolescents with pubertal hypothalamic syndrome was studied in 52 patients and 13 healthy males aged 13–24 years. The duration of disease was 2–11 years. Radioimmunological methods were used to measure plasma atrial natriuretic peptide, plasma renin activity, and serum aldosterone. Patients with borderline arterial hypertension were found to have a significant reduction in their atrial natriuretic peptide levels, and this correlated directly with the renin-aldosterone system, demonstrating insufficiency of the depressor system in patients with pubertal hypothalamic syndrome and the involvement of atrial natriuretic peptide in the development of arterial hypertension, along with disturbances in the functional relationship between atrial natriuretic peptide and the renin-aldosterone system. This article was presented at the III All-Russian Congress of Endocrinologists. Samara Medical University. Translated from Problemy éndokrinologii, Vol. 43, No. 4, pp. 21–22, July–August, 1997.     

Conditioned reflex responses of the sympathetico-adrenal system to an aversive taste stimulus

Studies were carried out on male and female rats in which the effects of isolated presentation of a conditioned stimulus (a saccharine solution) to which the animals had previously developed conditioned reflex taste aversion (RTA) on the level of urinary catecholamine secretion were determined. The studies showed that presentation of an aversive taste stimulus without reinforcement by a negative stimulus increased the levels of urinary adrenaline, noradrenaline, and dopamine secretion; this repeated, albeit more weakly, the effects of the negative reinforcement (angular acceleration) used for development of RTA. After presentation of the isolated aversive taste stimulus, the greatest increase in catecholamine excretion affected adrenaline, which indicates an anxiety state (fear). There was also a significant increase in noradrenaline excretion in these conditions. The accompanying increase in dopamine excretion in experimental and control animals showed this change to be largely nonspecific in nature, and to result from the experimental procedures. Isolated presentation of the conditioned taste stimulus elicited significantly greater increases in urinary catecholamine excretion in males than in females. It is suggested that the time for which the RTA is retained could be increased by activation of the sympathetico-adrenal system resulting from presentation of the nonreinforced taste stimulus which had acquired aversive properties. Laboratory for the Ontogenesis of Higher Nervous Activity, I. P. Pavlov Institute of Physiology, Russian Academy of Sciences, 199034 St. Petersburg. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 82, No. 3, pp. 57–65, March, 1996.     

Electrical stimulation of the C1 region of the rostral ventrolateral medulla of the rat increases mean arterial pressure and adrenaline release in the posterior hypothalamus

By using intracerebral dialysis in combination with high performance liquid chromatography and electrochemical detection, extracellular posterior hypothalamic adrenaline, noradrenaline, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid were measured in the anaesthetized rat and changes in their levels monitored following administration of tranylcypromine and electrical stimulation of the rostral ventrolateral medulla. Tranylcypromine (10 mg/kg i.p.) administration decreased basal extracellular 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid levels with a simultaneous increase in adrenaline and noradrenaline levels. Electrical stimulation of the C1 area of the rostral ventrolateral medulla increased (+56.6%) extracellular adrenaline levels in the posterior hypothalamus with a simultaneous increase in mean arterial pressure (+48 mm Hg) compared to prestimulation control values. No change was seen in posterior hypothalamic extracellular levels of noradrenaline, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid during the stimulation period. Electrical stimulation of areas close to but outside the C1 region had no effect on either mean arterial pressure or posterior hypothalamic extracellular levels of the amines or the metabolites. The increase in adrenaline levels in the hypothalamus during stimulation of the C1 region supports the evidence for an adrenergic pathway from the rostral ventrolateral medulla to the hypothalamus and suggests that the increase in mean arterial pressure during electrical stimulation to the C1 region may relate to a specific increase in adrenaline levels.     

Brain catecholamines and the hypothalamo-hypophyseal-adrenocortical system in inherited arterial hypertension

Rats with inherited stress-induced arterial hypertension (NISAG rats) and normotensive Wistar rats were used for studies of age-related changes in arterial pressure (BP), in the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS), and noradrenaline levels in brain structures involved in regulating these functions, with the aim of identifying possible relationships between them. It is suggested that the noradrenaline deficiency seen at the age of four weeks in the hypothalamus and medulla oblongata in NISAG rats is involved in the pathogenesis of hypertension and in disturbing the function of the HHAS. Transient increases in brain catecholamine synthesis in the fourth week of life lead to prolonged reductions in BP and complete recovery of HHAS responses to stress in adult animals. Correction of BP and HHAS function is accompanied by changes towards the normal in noradrenaline levels in the hypothalamus and medulla oblongata and in the numbers of α₁-adrenoceptors in the medulla oblongata. Deceased. Laboratory for the Genetic Bases of Neuroendocrine Regulation. Laboratory of Evolutionary Animal Genetics, Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, 630090 Novosibirsk, Russia. Translated from Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 82, No. 4, pp. 30–38, April, 1996.     

Participation of adrenal hormones in the genesis of arterial hypertension of hypothalamic origin

Continuous electrical stimulation for many hours of hypothalamic negative emotiogenic centers (the ventromedial nuclei) evoked persistent arterial hypertension with a characteristic phasic dynamics of adrenal secretory activity in waking, immobilized rabbits. Bilateral extirpation of the adrenals lowered the original level of the mean arterial pressure and inhibited the development of persistent arterial hypertension. Stimulation of the above-mentioned hypothalamic structures for many hours in adrenalectomized rabbits, in conjunction with administration of hydrocortisone and adrenalin, evoked persistent arterial hypertension again. After administration of hydrocortisone and adrenalin separately to adrenalectomized rabbits, stimulation of the ventromedial hypothalamic nuclei for many hours resulted in only a transient rise of blood pressure. It is concluded that an essential role in the formation of persistent arterial hypertension in rabbits during continuous stimulation of the hypothalamic negative emotiogenic centers for many hours is played by activation of adrenal cortical and medullary hormones.Department of Normal Physiology and Interclinical Hormonal Laboratory, I. M. Sechenov First Moscow Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Fedorov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 4, pp. 399–402, April, 1976.     

Centrally evoked increase in adrenal sympathetic outflow elicits immediate secretion of adrenaline in anaesthetized rats

To examine whether feedforward control by central command activates preganglionic adrenal sympathetic nerve activity (AdSNA) and releases catecholamines from the adrenal medulla, we investigated the effects of electrical stimulation of the hypothalamic locomotor region on preganglionic AdSNA and secretion rate of adrenal catecholamines in anaesthetized rats. Pre- or postganglionic AdSNA was verified by temporary sympathetic ganglionic blockade with trimethaphan. Adrenal venous blood was collected every 30 s to determine adrenal catecholamine output and blood flow. Hypothalamic stimulation for 30 s (50 Hz, 100–200 μA) induced rapid activation of preganglionic AdSNA by 83–181% depending on current intensity, which was followed by an immediate increase of 123–233% in adrenal adrenaline output. Hypothalamic stimulation also increased postganglionic AdSNA by 42–113% and renal sympathetic nerve activity by 94–171%. Hypothalamic stimulation induced preferential secretion of adrenal adrenaline compared with noradrenaline, because the ratio of adrenaline to noradrenaline increased greatly during hypothalamic stimulation. As soon as the hypothalamic stimulation was terminated, preganglionic AdSNA returned to the prestimulation level in a few seconds, and the elevated catecholamine output decayed within 30–60 s. Adrenal blood flow and vascular resistance were not affected or slightly decreased by hypothalamic stimulation. Thus, it is likely that feedforward control of catecholamine secretion from the adrenal medulla plays a role in conducting rapid hormonal control of the cardiovascular system at the beginning of exercise.     

Parameters of high-density lipoproteins in patients with arterial hypertension in combination with other components of metabolic syndrome

Parameters of HDL (concentrations of cholesterol, apoprotein A1, and phospholipids and phospholipid composition) determining their functional properties were studied in patients with arterial hypertension in combination with other components of metabolic syndrome (abdominal obesity, hyperlipidemia, and impaired glucose tolerance). Patients with isolated arterial hypertension did not differ from the control group by the concentration of apoprotein A1 and HDL cholesterol, but had lower content of HDL phospholipids and changed phospholipid composition: lower ratio of phosphatidylcholine and higher relative contents of lysophosphatidylcholine, sphingomyelin, and phosphatidylethanolamine. Parameters of HDL in patients with arterial hypertension associated with other components of metabolic syndrome did not differ from those in patients with isolated arterial hypertension. The observed changes in HDL in patients with arterial hypertension alone or in combination with other components of metabolic syndrome can impair functional capacity of HDL in reverse cholesterol transport, which increases the risk of atherosclerosis. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 3, pp. 289–292, March, 2007     

Central and peripheral thermoreceptors. Comparative analysis of the effects of prolonged adaptation to cold and noradrenaline

This report presents results obtained from many years of study of the effects of prolonged adaptation to cold and noradrenaline on the spike activity of central hypothalamic and peripheral skin thermoreceptors. The involvement of the sympathetic nervous system in forming adaptive changes in the regulatory characteristics of temperature homeostasis and the significance of the various components of thermoreceptor activity to the formation of effector responses are discussed. The roles of different groups of thermoreceptors in forming temperature sensations are analyzed. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 91, No. 12, pp. 1492–1503, December, 2005.     

Renal extraction of endogenous and radiolabelled catecholamines in the dog

Efferent renal nerve activity can be studied by measurements of the renal venous outflow of noradrenaline and dopamine. Accurate estimates of the intrarenal release to plasma of these catecholamines, however, require determinations of the net contribution of the catecholamines in arterial plasma to their renal venous outflow. We therefore studied the extractions of endogenous noradrenaline, dopamine and adrenaline, as well as 3H-labelled tracer amounts of noradrenaline, and dopamine in innervated and denervated canine kidneys. Approximately two-thirds of noradrenaline and dopamine in arterial plasma were extracted in the kidney, while 80-90% of adrenaline in arterial plasma was extracted. The fractional extractions of the three catecholamines were not substantially altered when the sympathetic nervous system was moderately activated by bilateral carotid occlusion or when the renal nerve activity was abolished by acute denervation. It is concluded that biochemical assessment of renal sympathetic nerve activity by studies of the renal venous noradrenaline and dopamine outflow requires some estimate of the net arterial contribution to the renal venous outflow. Ideally, catecholamine extraction by the kidney should be evaluated by studies of the renal extraction of 3H-labelled noradrenaline and dopamine, but the extraction of endogenous adrenaline may also be useful for this purpose.     

Brain catecholamines in spontaneously hypertensive and DOCA-salt hypertensive rats

The concentrations and alpha-methyl-p-tyrosine (alpha-MPT) induced disappearance of catecholamines, adrenaline, noradrenaline and dopamine, were measured in selected areas of the brainstem and hypothalamus of spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The catecholamine levels were measured by a sensitive radioenzymatic assay method combined with microdissection of the rat brain. The adrenaline concentration was higher in the area A1 of young SHR, but not in adult SHR, than in age-matched control rats. Noradrenaline concentrations and the alpha-MPT induced noradrenaline disappearance were less in the rostral part of the nucleus tractus solitarii (NTS) and the nucleus hypothalamic anterior of young SHR, and in the rostral part of the NTS of adult SHR. On the other hand in DOCA-salt hypertensive rats, the concentrations of adrenaline and noradrenaline were the same as in control rats in the examined areas. The alpha-MPT induced noradrenaline disappearance was less in the rostral part of the NTS of DOCA-salt hypertensive rats. Dopamine concentrations and the alpha-MPT induced dopamine disappearance were the same in the examined areas of SHR and DOCA-salt hypertensive rats. The results suggest that SHR have a change in adrenergic neural activity in the brainstem and a decrease in noradrenergic neural activity in the brainstem and hypothalamus while DOCA-salt hypertensive rats have a decrease in noradrenergic neural activity in the brainstem. Such changes in brain catecholaminergic neurons may have played an important role in the development of hypertension in these rats.     

High fructose diet increases anterior hypothalamic alpha 2-adrenoceptors responsiveness

Activation of α₂-adrenoceptors in the anterior hypothalamic area (AHA) decreases sympathetic nervous system activity and blood pressure. The aim of the present study was to evaluate activity of pre- and postsynaptic α₂-adrenoceptors in the AHA of fructose hypertensive rats (F), an animal model of insulin resistance and hypertension. The AHA of Control (C) and F anaesthetized rats was perfused with Ringer solution in the absence or presence of clonidine (100 or 300 μg ml⁻¹) using reverse microdialysis. Clonidine effects on mean arterial pressure (MAP) and heart rate (HR), and on hypothalamic noradrenaline levels were measured along perfusion time. Noradrenaline extracellular levels in the AHA were significantly diminished in F hypertensive rats compared to C animals. The depressor effect of intrahypothalamic perfusion of clonidine on MAP was enhanced in F rats compared with C animals. Intrahypothalamic perfusion of clonidine reduced HR only in F rats. The effect of clonidine on noradrenaline hypothalamic extracellular levels was enhanced in F rats. These results suggest, in our experimental conditions, the existence of an increased responsiveness of pre- and postsynaptic α₂-adrenoceptors in the AHA of F hypertensive rats. This fact could be a consequence of a compensatory supersensitivity of α-adrenoceptors due to a decrease in noradrenaline release from nerve terminals located in the AHA.     

An L-dopaergic relay from the posterior hypothalamic nucleus to the rostral ventrolateral medulla and its cardiovascular function in anesthetized rats.

We have proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter in the central nervous system [Misu Y. et al. (1996) Prog. Neurobiol. 49, 415-454]. Herein, we attempt to clarify whether lesions in the posterior hypothalamic nucleus decrease the tissue content of L-DOPA in the rostral ventrolateral medulla. We also attempt to clarify whether or not endogenous L-DOPA is evoked by electrical stimulation of the posterior hypothalamic nucleus. It is possible that evoked L-DOPA functions as a transmitter candidate to activate pressor sites of the rostral ventrolateral medulla in anesthetized rats. Electrolytic lesions were made in the bilateral posterior hypothalamic nucleus by a monopolar direct current of 2 mA for 10 s, 10 days before measurements. The effect of the lesions was to selectively decrease the tissue content of L-DOPA by one-half in the right rostral ventrolateral medulla. Decreases in the amounts of dopamine, noradrenaline or adrenaline were not observed. Decreases were also not evident in the right caudal ventrolateral medulla. During microdialysis of the right rostral ventrolateral medulla, extracellular basal levels of L-DOPA and three types of catecholamine were consistently detectable by high-performance liquid chromatography with electrochemical detection. Tetrodotoxin (1 microM) perfused into the right rostral ventrolateral medulla gradually decreased basal levels of L-DOPA by 25%; it decreased basal levels of noradrenaline and adrenaline by 25-30% and dopamine levels by 40%. Intensive electrical stimulation of the ipsilateral posterior hypothalamic nucleus (50 Hz, 0.3 mA, 0.1 ms duration, twice for 5 min at an interval of 5 min) selectively caused the release of L-DOPA in a repetitive and constant manner. The stimulation was accompanied by hypertension and tachycardia. However, catecholamines were not released. Tetrodotoxin suppressed the release of L-DOPA, but partially inhibited hypertension with only a slight inhibition of tachycardia evoked by stimulation of the posterior hypothalamic nucleus. L-DOPA methyl ester, a competitive L-DOPA antagonist, was bilaterally microinjected into pressor sites of the rostral ventrolateral medulla at 1.5 microg x 2 and 3 microg x 2. The antagonist dose-dependently and consistently antagonized pressor and tachycardiac responses to mild transient stimulation of the unilateral posterior hypothalamic nucleus (33 Hz, 0.2 mA, 0.1 ms duration, for 10 s). In addition, the antagonist alone (3 microg x 2) elicited hypotension and bradycardia. These results show that an L-DOPAergic relay may project from the posterior hypothalamic nucleus directly to pressor sites of the rostral ventrolateral medulla and/or indirectly to certain neurons near pressor sites in microcircuits of the same region. When released, L-DOPA appears to function tonically to activate pressor sites; it also appears to be involved in the maintenance and regulation of blood pressure and heart rate.     

Relationship between the baroreceptor reflex and the variability of arterial pressure and of the heart beat period in rats with arterial hypertension

The relationship between depression of the cardiochronotropic component of the baroreceptor reflex and arterial pressure and heart beat variabilities was investigated in normotensive rats and rats with renal hypertension (one kidney — one clamp). In the hypertensive rats, the arterial pressure and heart rate were both increased and more variable, while the cardiochronotropic component of the baroreceptor reflex was depressed. No cause-effect relationship between baroreceptor reflex attenuation and increased variability of hemodynamic parameters was found in this rat model of arterial hypertension. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 119, No. 5, pp. 474–476, May, 1995 Presented by B. I. Tkachenko, Member of the Russian Academy of Medical Sciences     

Specific response to adrenaline in arterial hypertension induced by exogenous calcium deficiency

Injection of a synthetic analog of parathyroid hypertensive factor to WKY rats considerably increases and prolongs pressor response to adrenaline. Synthetic analog injected after adrenaline induces a short-term (3–4 min) and potent (to 250%) rise of arterial pressure. Each subsequent injection of the synthetic analog induces a less pronounced in the amplitude and duration pressor response. The α-adrenoblocker phentolamine completely abolishes the effects of the parathyroid hypertensive factor analog. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 8, pp. 148–150, August, 1997     

Decreased sensitivity of adenylate cyclase to sodium ions in lymphocytes of patients with arterial hypertension

Patients with arterial hypertension showed decreased sensitivity of isoproterenol-stimulated adenylate cyclase of mononuclear lymphocytes toward sodium ions compared with normotensive donors. Ouabain, an inhibitor of Na,K-ATPase, increased the half-maximal inhibition of adenylate cyclase activity by sodium ions in the cells of healthy subjects and did not change enzyme sensitivity to sodium in the lymphocytes of hypertensive patients. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 120, N ^o 8, pp. 206–207, August, 1995 Presented by V. N. Smirnov, Member of the Russian Academy of Medical Sciences     

Renin inhibitors,clinical experience

The inhibition of the renin–angiotensin system is one of the most commonly utilized ways to lower blood pressure in patients with arterial hypertension. Up till now, angiotensin-converting enzyme inhibitors as well as angiotensin receptor blockers are the established inhibitors of this system, and both classes are used in clinical routine. There is a wealth of information about those classes, which are known not only to lower blood pressure, but also to prevent end-organ damage and, ultimately, reduce mortality in patients. Direct renin inhibition was already targeted 30 years ago to inhibit the renin–angiotensin system, but low bioavailability and short duration of action of the first generations of renin inhibitors withheld their clinical success. With the new generation of non-peptide orally available renin inhibitors, a third substance to inhibit the renin–angiotensin system is on the market, and the prototype of this class, aliskiren, has now been tested in various clinical trials in arterial hypertension. We review the studies of aliskiren and discuss its current role in the contemporary treatment of arterial hypertension as well as the possible new fields of action for aliskiren in treating heart failure and diabetic nephropathy.     

Captopril in Cushing's syndrome

Summary To analyse the role of the renin angiotensin system in the pathogenesis of hypertension in Cushing's syndrome ten patients with hypercorticism (five with pituitary hypothalamic dysfunction, three with adrenal adenomas and two with adrenal carcinomas) received a single oral dose of 25 mg captopril. Mean arterial pressure was then determined at short intervals over periods of up to 240 min. Plasma renin activity (PRA) was measured immediately before the administration of captopril. Eleven patients with severe essential hypertension, who showed a comparable distribution of basal PRA values, served as a control. Patients with elevated basal PRA values (>3 ng/ml·3 h) showed, both in the subgroup of cases with essential hypertension and in that with Cushing's syndrome, a statistically significant fall (P<0.05–P<0.001) in mean arterial pressure, the decrease being slightly more pronounced in essential hypertensives. On the other hand patients with normal PRA values (3 ng/ml·3 h) exhibited only a minor fall in mean arterial pressure reaching statistical significance (P<0.05) only after 60 min (essential hypertension) and 180 min (Cushing's syndrome), respectively. Our results document that in patients with Cushing's syndrome the effect of captopril seems to be determined by the activity of the renin angiotensin system. Thus, in a substantial number of patients with hypercorticism, the renin angiotensin system may be an important factor in the pathogenesis of hypertension, whereas in patients with low PRA values other factors like oversecretion of mineralocorticoids may be responsible for the observed blood pressure increases.     

Adaptive regulation of the nonlinear dynamics of electrical activity of the brain

A programmable system was used to provide contingent reinforcement of EEG cycles corresponding to a selected criterion in a dynamic regime. Use of automated reinforcing stimulation of emotionally positive zones of the hypothalamus led to a significant increase in the number of cycles with the characteristics specified by the dynamic regime within the dominant EEG frequency bands. This effect lasted for some time after withdrawal of reinforcing stimulation, and then died down gradually. These changes in the EEG activity structure did not occur in conditions of nonassociated hypothalamic stimulation. Pseudoreinforced background EEG cycles showed complex nonlinear dynamics with competitive interactions between processes in which the large dimensionality of the attractor was difficult to interpret because of indeterminacy in the trends of the dominant process. In contingent hypothalamic stimulation, the form of the correlation integral changed towards a predominance of a single nonlinear process determining all the activity recorded. In fact, a single dominant nonlinear process was formed, which became responsible for the entire dynamics of the system with concordance of its internal structure. B. I. Verkin Low-Temperature Physical-Technical Institute, Ukraine. Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 47, No. 1, pp. 147–158, January–February, 1997.     

Effect of bombesin (6–14) on arterial pressure in health and in hypovolemic shock

Injection of active fragment of the neuropeptide bombesin (6–14) into cerebral ventricles of intact rabbits induces marked arterial hypertension accompanied by bradycardia and partial redistribution of blood to specialized heat-emitting organs (auricular conchae), which reduces body temperature. After a considerable blood loss, the peptide normalizes arterial pressure without affecting cardiac activity and body temperature. It is suggested that bombesins may be used for compensation of arterial hypotension during the early period of hypovolemic shock. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 122, No. 10, pp. 372–374, October, 1996     

Vasoactive pressure hormones during and after cardiopulmonary bypass

The differences in the pattern of the vasoactive hormone release in response to the stress of surgery and cardiopulmonary bypass (CPB) (pulsatile n = 15 and non pulsatile n = 23) were studied in the adult patients with mitral valve disease (MVD), aortic valve disease (AVD), and the coronary artery disease (CAD). A differential stimulation of the osmoreceptors, baroceptors, renin-angiotensin and the sympathetico-adrenal systems in these patients, resulted in the variations in the pattern of hormone release. Patients with MVD showed a greater stimulation of osmoreceptors, baroceptors and release of Arginine vasopressin (AVP). Renin-angiotensin system was more easily triggered in patients with AVD or CAD; and sympathetico-adrenal system in patients with CAD. The renin-angiotensin-aldosterone axis was better preserved in patients with CAD (r = 0.49, p less than 0.001) than in the patients with MVD (r = 0.38, p less than 0.02). Plasma renin release showed a significant correlation with noradrenaline release in the patients with MVD (r = 0.47, p less than 0.01); but this relationship was lost in the patients with the CAD, due to an excessive noradrenaline release. Pulsatile bypass reduced but did not abolish this response. Under unfavourable conditions, the stress response may persist in the early post-operative period.