Activation of human prorenin by lipidic constituents of the cell membrane.

Activation of semipurified human kidney prorenin was found to occur in vitro in presence of a mixture of lipids that mimics the composition of the inner human cell membrane. The lipid-dependent activation was indeed only partial (38 +/- 4%) when compared to that obtained by trypsin in liquid phase (100 micrograms/mL) used as a control of maximal activation (100%) under our experimental conditions (semipurified human kidney prorenin in presence of semipurified human plasma renin substrate at a concentration of 1400 ng/mL, at pH 7.2). The phenomenon was time-dependent up to 60 min whereas the angiotensin I generated after 120 min was virtually the same as that generated after 60 min thus indicating a possible reversible activation of human prorenin. We speculate that prorenin may be reversibly activated by contact with the lipidic portion of the cell membrane either inside or outside the cells thus allowing a limited angiotensin II-generating cascade at a local site initiated by prorenin independently from the presence of active renin.

The brainstem cardioarrhythmogenic triggers and their possible role in sudden epileptic death.

The cardiovascular effects of simultaneous activation of hypothalamic and mesencephalic cardioarrhythmogenic triggers were studied in hemispherectomized rats. Paroxysmal activity of hypothalamic neurons (HEF), elicited by topical application of penicillin G on the thalamus, triggered short-lasting bradyarrhythmic episodes, up to a maximum of 6 s, and alterations in repolarization. In the hypothalamic neurons, an additional penicillin G epileptic focus at mesencephalic level (MEF) induced the enhancement of paroxysmal activity by a recruitment of new units and potentiation of their background activity. HEF+MEF triggered second-degree 2:1-8:1 atrioventricular (A-V) blocks, impairment of the A-V conduction, alterations in the recovery phase and bundle branch blocks. After HEF, the arterial blood pressure decreased by 4-6%. HEF+MEF induced a further reduction of 17% in systolic pressure only. It is possible that the enhancement of the HEF following MEF could depend on MEF spreading upward. The HEF, in turn, by spreading downward could influence the MEF and so activate, between HEF and MEF, a circuitry with reciprocal co-excitation that could explain the more serious cardiovascular alterations observed during HEF+MEF compared with those observed during HEF only or during MEF only. However, this cardiovascular impairment, which must be neurogenic in origin as it was observed in animals with normal acid-base and blood parameter values, did not induce heart death. Thus, additional concomitances must be considered, such as metabolic derangement which can occur during seizures, to explain sudden death in epileptic patients. Some aspects of metabolic complications in cardiac activity during epilepsy are also discussed.

Analysis of central cardioarrhythmogenic triggers in experimental epilepsy.

The cardioarrhythmogenic potential of epileptic foci induced at mesencephalic and rhombencephalic levels was analyzed in hemispherectomized rats. Topical application of penicillin-G onto the mesencephalic quadrigeminal lamina or onto the fourth ventricle induced paroxysmal activity at the mesencephalic or bulbar neurone level. At the mesencephalic levels, the paroxysmal activity was characterized by a significant increase in the spontaneous frequency of the neurones, with the appearance of multiunit activity and rhythmical outbursts. The simultaneous recording of myocardial electrical activity and blood pressure showed that the paroxysmal activity triggered short-latency sinus bradyarrhythmias with wandering of the sinus pacemaker, the appearance of biphasic or negative P waves, some premature ventricular contractions and non-significant reduction of systolic and diastolic pressures. When the paroxysmal activity stopped, the cardiac rhythm and blood pressure returned to basal values. At the bulbar level, the paroxysmal activity appeared with longer latency and usually the rhythmical outbursts were not observed. Following bulbar paroxysmal activity only short-lasting episodes of sinus bradyarrhythmias appeared. Midcollicular transection eliminated paroxysmal activity at the bulbar level, and blood pressure and cardiac rhythm resumed basal values. After transection, an additional application of convulsant drug (penicillin-G or pentylenetetrazole) onto the fourth ventricle did not induce the reappearance of paroxysmal activity and the consequent cardiovascular alterations. The results showed the existence of a cardioarrhythmogenic trigger localized at the mesencephalic level which spreads paroxysmal activity upwards. A hypothesis to explain the appearance of fetal haemodynamic modifications and life-threatening arrhythmias has been proposed.

Effect of fetal hypoxia on seizure susceptibility in rats.

In the present study, susceptibility to Pentylentetrazol (PTZ)-induced seizures was tested in 45 four-wk old rats born to mothers exposed to moderate asphyxia in the last week of pregnancy by breathing N2 99.9% for 6 min in two separate sessions, (Group I--experimental rats) and in 44 rats of the same age, born after a normal pregnancy (Group II--controls). The results showed that the experimental rats, following episodes of asphyxia in intrauterine life, had a higher susceptibility to PTZ-induced seizures than the controls, manifested by earlier onset of convulsions and a higher incidence of fetal epileptic status. This occurred despite normal development and the absence of neurological deficits in the experimental rats in the first 4 wk of extrauterine life.

Autonomic nervous system activity and life threatening arrhythmias in experimental epilepsy.

In the present study the possible derangement of the autonomic system and its influence in life threatening arrhythmias were analysed during paroxysmal activity. In hemispherectomized rats a paroxysmal activation of the hypothalamic and mesencephalic cardioarrhythmogenic triggers was performed by topical application of penicillin-G. Blood gas parameters and electrical activity of the thalamus, hypothalamus, vagal nerve fibre, ECG and arterial blood pressure were simultaneously monitored in basal conditions and repeated after the appearance of paroxysmal activity. Temporal correlation analysis was carried out. Results showed that during activation of these triggers, the spontaneous vagal nerve fibre activity significantly increased and triggered the appearance of cardiac arrhythmias which could become life threatening and induce animal death when blood gas and electrolytic parameters were simultaneously impaired. These experiments suggest that fatal evolution of the heart impairment is related not only to an autonomic cardiac trigger, but also to a concomitant metabolic derangement, which most likely shares the same autonomic origin.

[The Study Group of Quinapril in Arterial Hypertension. The Steering Committee]. / Gruppo di studio del quinapril nell'ipertensione arteriosa. Steering Committee.

The efficacy and safety of the treatment of arterial hypertension with the ACE-inhibitor quinapril, were evaluated in a multicentre study conducted in Italy. The study, lasting 14 weeks, after a preliminary wash-out period, allowed response-based titration of quinapril dose from 10 mg to 40 mg once a day, with provision to combine additional hydrochlorothiazide (12.5 to 25 mg), in case of persistently high diastolic pressure levels. The efficacy sample included 1267 patients: at therapy week 14, 78.6% of patients were treated with quinapril alone. Global response rate (intent-to-treat) was 83.3%, with a mean reduction of diastolic pressure of 15.8 mmHg (95% confidence interval from 15.5 to 16.2 mmHg). 91 patients reported 126 associated adverse events (7.0%); the most frequently reported event was cough (2.7%). First-dose hypotension was rarely reported (1.3%), even in elderly and diabetic patients.

Systolic time intervals in hyperthyroidism.

PEPI (pre-ejection period index), QS2I (total electromechanical systolic index), LVETI (left ventricular ejection time index), and PEP/LVET ratio were measured in 35 thyrotoxic patients. None of the patients had clinical evidence of heart disease nor received drugs which might have affected the systolic time intervals. the hyperthyroid subjects showed significant shortening of PEPI and significant reduction of PEP/LVET, which returned within normal limits when the patients became euthyroid during treatment. No correlation could be found between T3, T4, FTI and PEPI or PEP/LVET. However, serial measurements indicated that the fall toward the normal range of PEPI parallelled that of T3; the latter is considered the most important index of thyroid function. Our study suggests that PEPI and PEP/LVET ratio may be of great usefulness in detecting hemodynamic alterations in subjects with uncomplicated hyperthyroidism. Moreover, these methods may facilitate the diagnosis in unusual types of hyperthyroidism occurring in the absence of clinical signs of toxicosis. In addition, PEPI and PEP/LVET appear to be useful in detecting T3 toxicosis. Finally, serial controls of PEPI could represent a useful index to monitor the response to therapy.

[Determination of the range of physiologic variation of the electrical axes using P, QRS, and T waves in pregnancy]. / Determinazione del limite di variabilità fisiologica degli assi elettrici medi delle onde P, QRS e T in gravidanza.

Since functional overload in pregnancy frequently induces the appearance of symptoms that could arouse suspicion of myocardiopathy, it is important to analyse and characterize all electrocardiographic modifications during a healthy subject's pregnancy. Variations of the mean electrical axis (A) of P, QRS and T waves were evaluated in 52 healthy volunteers, 17-37 years, during pregnancy. The A values were measured, in the frontal plane, at the end of both I and III quarter of pregnancy, using a method of scalar determination. The As in I and III quarters was compared with those observed in the post-partum (at 5th day) and statistical evaluations were performed (Student t-test for paired observations). In the I quarter the mean A was 40 +/- 3 degrees for P, 40 +/- 16 degrees for QRS and 32.5 +/- 9 degrees for T wave, whereas in the III quarter the mean A changed to 37 +/- 2 degrees for P, 34 +/- 18 degrees for QRS and 31 +/- 9 degrees for T. During pregnancy, all mean As significantly diverted to the left side, AP about 3 degrees, AQRS about 6 degrees and AT about 1.5 degrees. These results were also confirmed by analysis of A frequency distribution histograms. In the post-partum (5th day) the A resumed basal values (I quarter's values). These results show: i) the physiological range of AP, AQRS and AT, during pregnancy; ii) left deviation of all three As at the end of III quarter. It is possible to conclude that variation over this range, particularly for QRS, could give evidence of the onset of cardiopathy.

[Hypertrophic cardiomyopathy during adrenocorticotrophic hormone administration in infants: a case report]. / Cardiomiopatia ipertrofica in corso di terapia con ormone adrenocorticotropo: descrizione di un caso in età neonatale.

We report a 2-month-old child with infantile myoclonic seizures, who developed congestive heart failure secondary to hypertrophic cardiomyopathy while receiving adrenocorticotropic hormone (ACTH) therapy. Treatment with propranolol and withdrawal of ACTH led to the resolution of cardiac hypertrophy as determined by two-dimensional echocardiography. Possible links between ACTH therapy and the development of hypertrophic cardiomyopathy are examined. Our report confirms that a careful monitoring is required to detect cardiac abnormalities during ACTH administration.

Neurogenic myocardial arrhythmias in experimental focal epilepsy.

The potential for cardiac arrhythmia was studied in an experimental focal epilepsy induced in hemispherectomized rats by topical application of buffered penicillin G onto the thalamus. The epileptic burst triggered cardiac and hemodynamic responses, as simultaneously monitored by arterial pressure, and hypothalamic and heart activity. During interictal epileptic activity, the single burst triggered a short-latency cardiac arrhythmia, characterized by sinus bradyarrhythmia and junctional rhythm, and lengthening of intervals between sphygmic waves with significant reduction of diastolic pressure. When the epileptic burst stopped, the cardiac activity resumed normal rhythm, and diastolic pressure returned to basal value. During ictal epileptic activity, the sinus and junctional bradyarrhythmic episodes lasted longer, and supraventricular extrasystoles, sinus arrest, and bigeminal ventricular extrasystoles were observed. Both systolic and diastolic pressures decreased from 120/85 to 100/65 mm Hg. The end of the ictal episode always marked resumption of normal cardiac rhythm and systemic pressure. Considering the absence of metabolic complications (blood-gas analytic parameters and acid-base balance being controlled) and the short latency of the cardiac and hemodynamic responses, it is suggested that during paroxysmal hypothalamic activity the observed cardiac arrhythmias and the hemodynamic modifications were neurogenic in origin. A role for cardiovascular alterations in sudden unexplained epileptic death is postulated.

[Circadian rhythm of spontaneous ventricular arrhythmias in elderly patients with myocardial ischemia at low risk for sudden death]. / Il ritmo circadiano delle aritmie ventricolari spontanee in pazienti anziani con ischemia miocardica a basso rischio di morte improvvisa.

In 26 patients (65-80 yr) with low risk of sudden death, the circadian rhythm of spontaneous ventricular arrhythmias was analyzed, throughout 72 h, by the Holter monitoring method. The prolonged ECG monitoring is indispensable to evaluate the real necessity of an antiarrhythmic therapy and to establish the therapeutic approach. Premature ventricular complexes (PVC): isolated, couplets and runs of ventricular tachycardia have been considered. The isolated PVC showed uniform distribution throughout 24h, with higher frequency/hour ratio (f/h) in females. Couplets and runs showed circadian diurnal distribution with higher f/h ratio in smokers and males. After analysis of the results, the patients were additionally subdivided into smokers and non-smokers. Since smokers showed a diurnal distribution of all kinds of arrhythmias, antiarrhythmic drugs whose pharmacological peak corresponds to the distribution peaks of arrhythmias were proposed. Non-smokers could be divided into two groups: a) patients with isolated extrasystoles which did not show a circadian rhythm of arrhythmias and who must be treated with retard-drugs, which give protection throughout 24h; b) patients with runs or couplets of PVC showing a circadian rhythm of arrhythmias and who must be treated with drugs whose pharmacological peak corresponds to the distribution peaks of arrhythmias.