[Aldosterone as an endogenous cardiovascular toxin and the options for its therapeutic management]. / Aldosteron jako endogenní kardiovaskulární toxin a moznosti jeho terapeutického ovlivnení.

In physiological, as well as pathological situations, aldosterone significantly influences volume, pressure and electrolyte balance. Primary hyperaldosteronism is caused by autonomous over-production, most frequently due to adrenal adenoma. Patients with primary hyperaldosteronism (Conn's syndrome) have more pronounced left ventricular hypertrophy and higher frequency of cardiovascular events than patients with essential hypertension (EH) with comparable blood pressure values. Consequently, there is an increased interest in the role ofaldosterone tissue function in cardiovascular disease. The aim of the present paper is to emphasise the pleiotropic actions of aldosterone on cardiovascular system and the options for their therapeutic management. Apart from the effects of circulating aldosterone on BP and its renal actions on water and electrolyte excretion, extra-renal effects are also been explored; paracrine affects through tissue mineralocorticoid receptors (MR) may impact on endothelial dysfunction, vascular elasticity, inflammatory changes in the myocardium, vessels and kidneys. Initial oxidative stress due to increased aldosterone concentrations may initiate subclinical endothelial changes and subsequent myocardial fibrosis. The effects on all three layers of vascular wall, together with increased blood coagulation and vascular thrombogenicity increases likelihood of microthrombosis and tissue microinfarctions. Slight increase in aldosterone concentrations in cardiac tissue adversely affects myofibrils as well as coronary artery function. Similar to peripheral vessels, it increases collagen content and changes vascular rigidity and the velocity of pulse wave and facilitates development of perivascular fibrosis. Higher salt intake may potentiate these pathophysiological effects of aldosterone, while higher intake of potassium may restrict them. Aldosterone vasculopathy together with perivascular fibrosis occurring at aldosterone concentrations seen with heart failure contributes to manifestation of heart failure. Consequently, aldosterone may rightly be called "cardiovascular toxin". The adverse effects of aldosterone in patients on long-term ACEI therapy are further facilitated by the aldosterone's ability to evade inhibitory effects of ACEI and parallel activation of renin-angiotensin system. To manage these situations, receptors of mineralcorticoids or direct renin inhibitor aliskiren are used. The positive effect of MR blockade is based on an increased release of nitric oxide (NO) with further improvement in endothelial functions. Detailed review of pleotropic effects of aldosterone helps to clarify a number of pathophysiological situations in essential hypertension, supports the view ofaldosterone as a potential cardiovascular toxin and indicates the use of mineralocorticoid receptor blockers in resistant hypertension and patients with cardiovascular or renal organ damage.

[Recommendations for the treatment of tobacco dependence]. / Doporucení pro lécbu závislosti na tabáku.

This first Czech version of guidelines formulated by the working group of mentioned medical associations is based on current literature and international guidelines. They are aimed mainly on clinical medicine and on incorporation of this treatment into the health care system according to WHO recommendations. They should serve to the treatment of tobacco dependence at any level: during any contact with the smoking patient (short intervention), in specialised centres or for the health care providers or health system itself.

[Cell adhesion molecules and their role in pathophysiologic processes]. / Bunecné adhezivní molekuly a jejich úloha v patofyziologických dejích.

Cell adhesion molecules are substances with a protein character expressed on the cell surface of all tissues. They participate in the control of basic vital processes, in processes of embryogenesis, cellular growth and differentiation, they ensure the interaction of cells with the environment. At present four main classes of cytoadhesion molecules are known: integrins, the immunoglobulin group of adhesion molecules, cadherins and selectins. Cytoadhesion molecules play an important role in the pathophysiology of cardiovascular, neoplastic, infectious and skin diseases. Some cardiovascular diseases are associated with pathological impairment of the structure and function of endothelial cells-with endothelial dysfunction. In case of damage or inflammatory processes of the blood vessels due to the action of released cytokines increased expression of adhesion molecules of the integrin, selectin and immunoglobulin groups occurs and subsequently increased adhesion and migration of inflammatory cells across the vascular wall. Impaired function of the vascular endothelium is also the first step in the genesis and development of chronic vascular disease--atherosclerosis. In the initial stage of development of atherosclerosis--during rolling, adhesion and migration of leucocytes across the endothelium the cytoadhesion molecules play a crucial role.

[Endothelial dysfunction and arterial hypertension]. / Endoteliální dysfunkce a arteriální hypertenze.

The endothelium lines all blood vessels in the human body, it is the basic structure which ensures the action of substances circulating in the blood stream on the vascular wall. It is an organ the sound state of which is essential for the physiological function of the vascular system. Its impaired function is a basic factor in the genesis and development of vascular disease. Under physiological conditions the endothelium has antiadhesive and antithrombotic properties, it produces vasoactive substances, prevents the penetration of circulating substances and formed elements across the vascular wall, and via adhesion molecules it participates in the interaction with cells in the circulation. Risk factors of cardiovascular diseases such as hypertension, hyperlipidaemia, hyperglycaemia, smoking damage the function of endothelial cells and cause the development of endothelial dysfunction. In patients with arterial hypertension endothelial dysfunction is characterized by an impaired endothelium dependent relaxation, increased adhesion and permeability of endothelial cells, structural changes of the vascular wall. When the endothelium is damaged by released cytokines an increased expression of adhesion molecules occurs, adhesion and migration of inflammatory cells across the vascular wall. Cytoadhesion molecules are released from the surface of the endothelium into the circulation where the rise of their plasma levels can serve as a marker of endothelial damage. Endothelial dysfunction in hypertonic subjects contributes in a significant way to the development and progression of chronic vascular disease--atherosclerosis. Improvement of the damaged endothelial function is therefore at present a desirable therapeutic objective in the treatment of hypertension.

[Hypertensive crisis and its treatment]. / Hypertenzní krize a moznosti její lécby.

Hypertensive crises threaten, due to the rapid rise of blood pressure the patient's life by cerebral, cardiovascular and renal complications. It may cause left-sided heart failure, dissection of the aorta, cerebral haemorrhage, renal failure. Patients with hypertensive crises are admitted to intensive care units with the possibility of systematic monitoring of the pulse rate, BP, ECG, diuresis and other vital functions. Treatment is started immediately by injections (usually i.v.) of antihypertensive drugs while monitoring the BP, vital functions and the general condition. At first small amounts of antihypertensives are administered and, depending on the BP, the dosage is adjusted. The recommended safe drop of BP which should be achieved within one hour is 100-110 mm Hg of diastolic BP or a 20% drop of the initial pressure. Concurrently with injections oral administration of antihypertensives is started. Correct treatment leads in the majority of patients to regression of hypertension and of acute danger to the patient's life. On the other hand, inadequate treatment threatens the patients with fatal complications.

Unilateral juxtaglomerular hyperplasia, hyperreninism and hypokalaemia relieved by nephrectomy.

Two women with spontaneous hypokalemia (1 normotensive, 1 hypertensive in the absence of renal artery stenosis), underwent unilateral nephrectomy because of angiographic and/or split renin-based suspicion of a reninoma. The normotensive patient clinically resembled Bartter syndrome but had some elements suggestive of a renin-secreting tumour, justifying surgical exploration and resection. The hypertensive patient presented clinically as a typical reninoma except for negative angiography. Surprisingly, the histology of the kidneys in both cases demonstrated juxtaglomerular hyperplasia without evidence of reninoma. The postoperative follow-up (8 and 19 yrs, respectively) has shown in the normotensive patient a considerable improvement in the hyper-reninism and previously uncontrollable hypokalaemia and in the hypertensive patient a complete normalisation of BP, renin and electrolyte status. Although the histological condition of the contralateral kidneys remains unknown in both patients the preoperative lateralisation of hyper-reninism to one kidney, the postoperative complete relief of the hyper-reninism in the hypertensive patient after uninephrectomy and its decrease, exceeding that corresponding to the removal of one kidney in the normotensive patient, suggest that the juxtaglomerular hyperplasia might have been unilateral or asymmetrical and that nephrectomy may, unexpectedly, relieve the hyper-reninism caused by juxtaglomerular hyperplasia. An increased unilateral susceptibility to trophic or renin-releasing factors or an asymmetrical abnormality in the macula densa-initiated mechanism of juxtaglomerular hyperplasia may be implicated in this disorder.

[Is it possible to predict the development of Nelson's syndrome in Cushing's disease after bilateral adrenalectomy?]. / Je mozná predikce vývoje Nelsonova syndromu u Cushingovy choroby po bilaterální adrenalektomii?

A detailed analysis of clinical and laboratory findings in a group of 66 patients with Cushing's disease treated with bilateral adrenalectomy, out of whom 15 developed Nelson's syndrome, gave evidence that Nelson's syndrome mostly affects children and young patients compared to older persons. Bilateral adrenalectomy performed in patients aged over 40 years was never accompanied by Nelson's syndrome. Basal plasma ACTH values prior to adrenalectomy (30.9 +/- 4.53 pmol/l in the absence of Nelson's syndrome and 31.3 +/- 5.41 pmol/l in patients with Nelson's syndrome) as well as the degree of their suppressibility with 8 mg dexamethane (to 18.8 +/- 3.43 pmol/l in Nelson's syndrome and 19.0 +/- 3.44 pmol/l in patients without it) did not provide sufficient evidence for the prediction of later development of Nelson's syndrome. The same is true of the plasma cortisol concentrations. A tendency to a significant plasma ACTH increase after adrenalectomy within a 6-month period, and especially its lesser suppressibility raises a strong suspicion of an incipient development of Nelson's syndrome. These findings will have to be taken into account when deciding on the surgical treatment of Cushing's disease.

[The effect of clonidine on humoral factors in patients with arterial hypertension]. / Vliv clonidinu na nekteré humorální faktory u nemocných s arteriální hypertenzí.

Clonidine, an agonist of central alpha-2-adrenergic receptors, reduced the peripheral sympathetic activity. With regard to the mutual pathophysiological relationship of blood pressure regulating mechanisms, the authors wanted to find out whether after clonidine administration, in addition to the known suppression of catecholamine levels (CA), also changes in the concentration of other pressor and depressor humoral substances will occur. They investigated therefore in 15 patients with essential hypertension (EH) and in three patients with pheochromocytoma the urinary excretion of free noradrenaline (NA), adrenaline (A) and dopamine (DA), the plasma renin activity (PRA), the aldosterone concentration (PAC) and atrial natriuretic factor (ANF) in plasma, using radioimmunoanalysis, always before and 24 hours after clonidine administration (Haemiton retardR) by the oral route. Its administration led in patients with EH to a decline of NA and DA. On the other hand, in pheochromocytoma their urinary excretion did not change in an unequivocal way, and when it declined, never normal NA and DA levels were reached. A excretion remained unaltered in both groups of patients. The drop of PRA after clonidine as a result of the drop of peripheral adrenergic activity was not associated with an expected parallel drop of PAC but by its rise. This effect can be explained by a reduction of the tonic inhibition of PAC output when the DA level declines. The rise of ANF after clonidine administration will be the subject of subsequent investigations. It cannot be ruled out that this effect is due to the direct action of clonidine on alpha receptors in the heart.(ABSTRACT TRUNCATED AT 250 WORDS)

[Levels of ACTH and endogenous-digitalis-like substances in human blood]. / Koncentrace ACTH a endogenní digitalisu podobné látky v plazme u cloveka.

Simultaneous determination of immunoreactive ACTH and immunoreactive digitalis like substances (DLS) in 71 plasma specimens of 44 persons proved that in spite of a great range of ACTH concentrations in the followed individuals (1.7-271 nmol/l) there is not a major correlation between DLS and ACTH or a significant difference in plasma DLS concentrations in the groups of persons with suppressed, normal or increased ACTH concentrations. Acute increase of ACTH plasma concentrations after synthetic ACTH application or a suppression of plasma ACTH by dexamethasone were not accompanied by corresponding changes of immunoreactive DLS. Thus it follows from this investigation that in spite of its biological digitalis like activity and interference of synthetic ACTH 1-24 high concentrations with digoxin enzymoimmunoassay in vitro, ACTH in concentrations found in human plasma is not responsible for endogenous immunoreactive DLS levels in plasma.

[New aspects and possibilities in the diagnosis of pheochromocytoma]. / Nové názory a moznosti v diagnostice feochromocytomu.

Pheochromocytoma is still a dangerous disease which is often difficult to diagnose. Evidence of the wide spectrum of its clinical picture was found in a group of 13 patients who were examined in the last 5 years. Drawing on their experience, the authors evolved a scheme of diagnostic examination. The primary biochemical examination involves the determination of urinary excretion of free catecholamines adrenaline, noradrenaline and dopamine simultaneously with their methylated metabolites metanephrine and normetanephrine, which help to make a more exact diagnosis in cases where the results of free catecholamines are not clear. Patients with pheochromocytoma lack diurnal rhythm of catecholamine excretion and thus the collection is made twice - by day and night. The determination of plasma catecholamines provides additional information. Only half the patients were found to have the level of vanillylmandelic acid increased. A significantly increased dopamine excretion points to the malignant form of the disease. The localization is established with the aid of computed tomography and, if needed, also by the determination of plasma catecholamines through selective cavae sampling. The final step serving to verify the diagnosis involves analysis of catecholamines in tumour tissue.

Atrial natriuretic peptide concentration and natriuretic hormone activity in plasma of patients with chronic renal failure.

To elucidate further the possible role of atrial natriuretic peptide (ANP) and hypothetical natriuretic hormone (NH) in volume and BP regulation in chronic renal failure (CRF) we measured plasma ANP, digitalis-like substances (DLS) and Na+-K+-ATPase activity (using 86Rb influx into RBC) in 9 patients with CRF before and after hemodialysis. Volume expansion between consecutive dialyses led in all patients to the elevation of plasma ANP (83.4 +/- 14.2 pmol/l) reaching in some overhydrated subjects and/or patients with concomitant cardiac insufficiency concentration greater than 150 pmol/l. Reduced 86Rb influx into RBC before hemodialysis (37.7 +/- 4.9% of controls) was accompanied by higher DLS concentrations (201 +/- 32 pmol/l). Ultrafiltration during hemodialysis with ECFV reduction lowered both ANP and DLS concentrations to 28.1 +/- 9.4 pmol/l and to 151 +/- 23 pmol/l, respectively, and abolished partly the inhibition of Na+-K+-ATPase activity (64.9 +/- 7.6% of controls). These changes corresponded to the degree of ECFV alteration. Our results suggest that both natriuretic principles are activated during ECFV expansion in CRF, probably as a corrective mechanism, with a tendency to normalize when ECFV is reduced during hemodialysis.

Long-term results of surgical and conservative treatment of patients with primary aldosteronism.

The long-term results of surgical and specific drug therapy were compared in a group of 57 patients with primary aldosteronism (PA) (46 with aldosterone-producing adenoma (APA), 11 with idiopathic hyperaldosteronism (IHA) and bilateral adrenal hyperplasia). Unilateral adrenalectomy completely normalized blood pressure (BP) in 77.1% of surgically treated APA, evidently improving hypertension in remaining 22.9%. No recurrence of the adenoma in the remaining adrenal was seen in any of the surgical APA cases. In 19 of the non-surgical patients (11 with APA, 8 with IHA) monotherapy with spironolactone reduced blood pressure in 73%, though total BP normalization was an exception. The treatment normalized hypokalemia, low total exchangeable potassium, tendency to hypernatremia, and high total exchangeable sodium. Surgical as well as conservative therapy increased to normal or above-normal levels plasma renin activity suppressed prior to treatment. Pre-operatively high urine and plasma aldosterone levels normalized in all adrenalectomized patients, but remained above the normal range during spironolactone therapy in spite of a small decline in its absolute values. The disturbances of maximum renal concentrating capacity due to impaired nephron responsiveness to sufficiently high endogenous vasopressin concentrations were completely eliminated after kaliopenic nephropathy had been repaired. The other renal functions remained within normal values. Echocardiographically diagnosed left ventricular hypertrophy was seen less often than in the other types of arterial hypertension, tending to regress after APA management. Our longitudinal study (2-16 years) showed primary aldosteronism as a well curable, albeit rare, cause of hypertension. As regards BP and laboratory tests normalization, better results were achieved in surgical APA cases than in patients treated with spironolactone. Older age, longer history of hypertension and more frequent incidence of obesity, nephrosclerosis and pyelonephritis may be responsible for hypertension persisting after surgical treatment.

Urinary excretion of catecholamines in patients with primary aldosteronism before and after unilateral adrenalectomy.

The authors compared urinary excretion of noradrenalin (NA), adrenalin (A) and dopamine (DA) in 12 patients with primary aldosteronism (PA), 54 healthy controls and 17 patients with fixed benign essential hypertension (BEH), and in PA investigated the changes occurring in the catecholamine spectrum after removal of aldosterone-producing adrenal adenoma. The patients with PA before adrenalectomy differed from the controls and patients with BEH by low NA excretion and high DA excretion. After unilateral adrenalectomy, patients with PA presented simultaneously with BP, aldosterone and renin normalization a rise in NA excretion and a drop in urinary DA to similar or lower values than those found in the controls and BEH. The results show that changes in urinary catecholamines excretion in A may be a secondary consequence of hypermineralocorticism. High DA may be the consequence of a mobilization of contra-regulatory natriuretic mechanisms in the course of aldosterone-induced sodium retention. Low NA and A may participate in lowering the plasma renin activity which in PA in suppressed, sometimes disproportionately to the actual body sodium content.