High-dose ACEi might be harmful in COVID-19 patients with serious respiratory distress syndrome by leading to excessive bradykinin receptor activation.

PURPOSE: We aimed to critically review the available information on the potential contribution of excessive kallikrein-kinin systems (KKSs) activation to severe respiratory inflammation in SARS-CoV-2 infection, and the likely consequence of ACE inhibition in seriously affected patients. METHODS: The literature related to the above topic was reviewed including papers that analysed the connections, actions, interactions, consequences and occasionally suggestions for rational interventions. RESULTS/CONCLUSION: Severe broncho-alveolar inflammation seems to be caused, at least in part, by upregulation of the KKS that increases plasma and/or local tissue concentrations of bradykinin (BK) in patients with COVID-19 infection. Besides KKS activation, suppression of ACE activity results in decreased bradykinin degradation, and these changes in concert can lead to excessive BK B1 and B2 receptor (BKB1R/BKB2R) activation. Aminopeptidase P (APP), and carboxypeptidase N also degrade bradykinin, but their protein expression and activity are unclear in COVID-19 infection. On the other hand, ACE2 expression is upregulated in patients with COVID-19 infection, so ACE2 activity is unlikely to be decreased despite blockade of part of ACE2 by the virus for entry into the cells. ACE2 cleaves lys-des-arginine9BK and arg-des-arginine9BK, the active metabolites of bradykinin, which stimulate the BKB1R receptor. Stimulation of BKB1R/BKB2R can exacerbate the pulmonary inflammatory response by causing vascular leakage and edema, vasodilation, smooth muscle spasm and stimulation of pain afferent nerves. Despite all uncertainties, it seems rational to treat comorbid COVID patients with serious respiratory distress syndrome with ARBs instead of high-dose ACE inhibitor (ACEi) that will further decrease bradykinin degradation and enhance BKB1R/BKB2R activation, but ACEi may not be contraindicated in patients with mild pulmonary symptoms.

Analysis of the cough sound frequency in adults and children with bronchial asthma.

It is well known that the frequency distribution of cough sound varies in different pathological conditions. Its identification could have diagnostic value. In this study the cough sound frequency in adults (n=20, 51.7 +/- 11 yrs), children (n=21, 11.8 +/- 0.4 yrs) asthmatics and healthy volunteers (n=25, 21 yrs) was explored. All patients were suffering from bronchial asthma. They were on a stable therapeutic regime and in a quiet status. Voluntary cough sound was recorded by a microphone and a tape recorder an ddigitally processed. Overlapping technique and Fast Fourier Transform were used to estimate the sound spectra. The records were smoothed by the method of Pascal triangle. They demonstrate the mean values of cough sound spectra. The registered pseudo three-dimensional plots of cough sound frequency (1 K spectra as function in time) of adults showed that the intensity of frequencies increased from 100 to 900 Hz in 3-4 waves. These frequencies afterwards decreased and between 1 to 2 kHz a smaller elevation was present. The spectra of children resembled to the spectrum of adults but had a smoother course. The spectra of asthmatics had some specificity and differed from the spectrum of healthy volunteers.

[Use of recording methods and sound analysis of cough in the study of sound phenomena associated with respiration]. / Pouzitie metódy registrácie a analýzy zvuku kasl'a pre stúdium zvukových fenoménov spojených s dýchaním.

The objective registration of the human body functions is one of the main tasks of the modern and prospective medicine. The registration of the heart, brain, muscles etc. activity have a long tradition. The registration of sound processes, for instance coughing was not solved completely despite their diagnostic importance. The authors worked out a new non invasive and precise method for cough sound registration and analysis which allows evaluation of the sound pattern, intensity and time duration. Application of this method for registration and analysis of the cry of new-borns gave rise to doubts about its suitability for an assessment of other sounds related to respiratory organs, except that of a cough. We registered and analysed the sound samples from Hirschberg's and Szende's (1982) sound archive for the purpose of the evaluation of the acceptability of the described method. The sound phenomena (109 samples of coughing, crying, barking and breathing) we transcribed from a record on a tape. The recorded signal was converted by A/D converter and analysed by computer by means of our own application programme. The sound and its pattern was transformed into a graphical record. This examination was completed by a sound frequency analysis based on the fast Fourier transformation with help of a computer likewise with our own application programme. It was found out that the used method reflected well the quantitative an qualitative differences of the evaluated sound samples. The graphical records reliably expressed the acoustic sound timbre as it shows the records of dog's and seelion's barking, cough, cry and cackling stridor of new-borns. The histographic curves which expressed the sound pattern showed a principally similar course. The intensity of sound examples was different. The sound samples duration were very often longer as the measurable time extent of software (0-819.2 ms) and therefore its evaluation was omitted. The repeated evaluation of the same sound phenomenon gave equal values. The spectrographic analysis confirmed the differences in sound samples. The values of the evaluated cough and cry sounds do not differ principally from the values registered in the previous author's observations. The results proved that the described method of cough sound registration and analysis was suitable for evaluation of different sound phenomena related to respiratory organs. (Fig. 3, Ref. 14.)

Acid-base balance and cardiac index in SO2-bronchitic, papaine-emphysematous and paraquat-fibrotic rats after isoproterenol treatment.

SO2-bronchitis, papaine-emphysema and paraquat fibrosis were induced in Wistar rats. Blood pressure, cardiac index, total peripheral resistance, arterial blood gas values, parameters of acid-base balance were determined. Effects of 0.1 and 0.3 microgram.-1.min-1 isoproterenol iv. infusion were examined. Morphologic alterations of the lungs were verified by histopathological examinations. All the parameters investigated were found to be normal in the control rats. The treated groups differed from the normal ones: an increased blood pressure was observed in emphysema and fibrosis. A decreased cardiac index was characteristic of chronic bronchitis, high cardiac index of emphysema, high TPR of bronchitis and arterial hypoxaemy of fibrosis. The groups reacted differently to beta adrenergic stimulation: in bronchitic and fibrotic rats the cardiac index was augmented, whereas in emphysematous ones the increase proved to be smaller. The effects of isoproterenol infusion can be related to the altered beta-receptor function in the various experimental pulmonary diseases.

Spectra of the voluntary first cough sounds.

The voluntary cough sounds recorded according to Korpas and Sadlonova-Korpasova were sampled at a frequency of 20.000Hz and spectra of six consecutive windows of 50ms were estimated. To digitize signals an autotrigger mode was used. The subjects were healthy volunteers as well as patients with chronic bronchitis, asthma, bronchial carcinoma (growing intraluminarly in the 1st or in the 2nd or in the 3rd order bronchi), emphysema, laryngeal nerve paralyzis or laryngotomy. The duration of averaged cough sounds of patients was longer than that of healthy volunteers. The mean power of the spectra in the successive windows showed different patterns in the same group. In the third window of healthy volunteers (0.10 s-0.15 s) a high modulus broad bandwidth (between 1-2 kHz) spectrum was found which was considered as a bronchial "flute", and was probably related to the lowest resistance as well as to the velocity of airflow of cough manoeuvre. This pattern appeared with a delay and/or it was changed in the diseased groups compared to the healthy volunteers. Due to this delay, the spectra of the fifth window (0.20 s-0.25 s) showed somewhat higher harmonics (400-800 Hz) in the patients with chronic obstructive pulmonary diseases (COPD), carcinoma and laryngeal nerve paralyzis than in healthy volunteers. In emphysematous patients in the first (0.00-0.05 s), in the third (0.10-0.15 s) and in the fifth (0.20-0.25 s) windows the fundamental frequency was low (156-176 Hz) compared to that of the other groups. The paralyzed vocal cords functioning as an added resistance to the expiratory effort caused a phase-shift in the cough patterns, similarly to that seen in COPD patients. Due to the cannula, the spectra of patients having laryngotomy had a lot of high harmonics. They also had peaks nearly identical to that of bronchitic patients because they suffered from serious chronic bronchitis. It was found that by examination the cough spectra of series of voluntary cough sound signals it was possible to distinguish healthy volunteers from patients. This examination would therefore be useful for screening of bronchial diseases.

Effects of arachidonic acid and prostaglandin F2 alpha in isolated rat lungs.

Isolated rat lungs were ventilated and perfused by saline-Ficoll perfusate at a constant flow. The baseline perfusion pressure (PAP) correlated with the concentration of 6-keto-PGF1 alpha the stable metabolite of PGI2 (r = 0.83) and with the 6-keto-PGF1 alpha/TXB2 ratio (r = 0.82). A bolus of 10 micrograms exogenous arachidonic acid (AA) injected into the arterial cannula of the isolated lungs caused significant decrease in pulmonary vascular resistance (PVR) which was followed by a progressive increase of PVR and edema formation. Changes in perfusion pressure induced by AA injection also correlated with concentrations of the stable metabolites (6-keto-PGF1 alpha: r = -0.77, TxB2: -0.76), and their ratio: (6-keto-PGF1 alpha/TXB2: r = -0.73). Injection of 10 and 100 micrograms of PGF2 alpha into the pulmonary artery stimulated the dose-dependent production of TXB2 and 6-keto-PGF1 alpha. No significant correlations were found between the perfusion pressure (PAP) which was increased by the PGF2 alpha and the concentrations of the former stable metabolites. The results show that AA has a biphasic effect on the isolated lung vasculature even in low dose. The most potent vasoactive metabolites of cyclooxygenase, prostacyclin and thromboxane A2 influence substantially not only the basal but also the increased tone of the pulmonary vessels.

Effects of ketotifen and clenbuterol on beta-adrenergic receptor functions of lymphocytes and on plasma TXB-2 levels of asthmatic patients.

Clinical observations indicate that beta-adrenergic drugs may increase bronchial reactivity in asthmatics. To find out possible reasons for this phenomenon the beta-adrenergic receptor function of isolated lymphocytes of asthmatic patients treated with clenbuterol alone or with ketotifen and clenbuterol together were studied. The cAMP levels of lymphocytes stimulated by different doses of isoproterenol were measured by radioimmunoassay and have been compared in the groups of healthies, and asthmatic patients after 3-months running of clenbuterol (Spiropent, Sandoz), as well as in the same asthmatics after one-week running of parallel administration of ketotifen and clenbuterol. There was no difference between the beta-adrenergic receptor function in asthmatic patients treated with clenbuterol alone vs. untreated healthies. Applying ketotifen and clenbuterol together the beta-adrenergic receptor function increased compared to the values obtained after application of clenbuterol alone (intraindividual-control) as well as vs. the group of healthies (control). Data presented support the view that therapeutic doses of selective beta 2-agonists do not lead to damage of the beta-adrenoceptor function. The improvement of receptor function after parallel administration of clenbuterol and ketotifen may be a consequence of the participation of ketotifen in the control of beta-adrenergic receptor system. Thus it seems unlikely that down-regulation of beta-adrenergic receptors is responsible for the beta-agonist induced bronchial hyperreactivity. That's why TXB-2 levels in the plasma of the same asthmatic patients and healthy volunteers were determined by RIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of propranolol, nalorphine and haloperidol on the breathing and on the metabolism of PGI2 and TXA2 of normotensive and spontaneously hypertensive rats.

The influence of propranolol, nalorphine and haloperidol on the breathing pattern and on the blood levels of cyclooxygenase products of anaesthetized spontaneously-breathing normotensive Wistar rats (WR) and of spontaneously hypertensive rats (SHR) were investigated. The respiratory rate was higher and the effective lung resistance was smaller in the SHR than in the WR. Breathing frequency decreased after nalorphine in both groups, while only in SHR after haloperidol. Propranolol augmented the dynamic lung resistance in both groups. The blood 6-keto-PGF1 alpha level was higher and the TXB2 level was lower in the SHR than in the WR. The central inspiratory activity as well as the levels of peripherally acting substances involved in the regulation of respiration and in the control of bronchial smooth muscle tone are different in the SHR and WR.

Effect of intracerebrally injected aminophylline, vinpocetinum, vasoactive intestinal peptide and onion extract on breathing pattern of rats.

Aminophylline or VIP (Vasoactive Intestinal Peptide) given ip. or iv. have marked bronchodilatory effects. The onion extracts protect guinea pigs as well as human patients against allergen-induced bronchial spasms (Dorsch et al.). Recently it has been shown that lipophilic components of onions seem to be responsible for the antiasthmatic effects. The purpose of this study was to investigate the effect of intracerebrally injected aminophylline (3 microM), Vinpocetinum (0.1 mg/kg), VIP (5 micrograms) and onion oils (30 microliters of extracts) on the respiratory center and on the resistance of lower airways of rats. The following respiratory parameters were evaluated: respiratory rate (RR), tidal volume (VT), mean inspiratory flow (Vin), respiratory minute volume (VE), and dynamic lung resistance (R). Respiratory rate was increased and values of all the other parameters were decreased after aminophylline treatment. VIP increased the tidal volume, minute ventilation and the respiratory drive. After injection of onion extracts the respiratory rate and the dynamic lung resistance decreased, but the tidal volume increased. The beneficial effects of onion oil are manifested not only peripherally acting on bronchial smooth muscle but via the reflexogenic pathways.

Breathing pattern of spontaneously hypertensive rats.

The trachea of rats anaesthetized with sodium pentobarbitone was cannulated and the air flow velocity and the pressure of the oesophagus were measured. In the spontaneously hypertensive rats the breathing frequency was higher, the tidal volume and the effective lung resistance were smaller than that of the normotensive Wistar rats. It seems that the neurohumoral control of respiration in SHR animals differs from that of normotensive rats.

A case of Churg-Strauss syndrome.

A 54-year-old woman died after being battered, but the forensic autopsy revealed that her injuries were not serious or lethal. A detailed histological examination revealed that the basic disease had been Churg-Strauss syndrome. The differentiation of this syndrome of pulmonary infiltration and eosinophilia (PIE syndrome) from other allergic and noninfectious granulomatoses needs cautions consideration.

Effects of drugs on aminophylline elimination in rats.

Effects of phenobarbital, phenytoin, carbamazepine, cimetidine, erythromycin, combination of sulfamethoxazole + trimethoprim (5:1), and rifampicin (rifampin) on the elimination of aminophylline were examined in female rats. Aminophylline was administered i.p. in a dose of 13.33 mg/kg. Blood samples were collected 0.5, 2, 4 and 7 h after the administration of the injection; one measurement was performed from one blood sample. Plasma aminophylline levels were measured by a modified HPLC method. The elimination half-life of the untreated control group (n = 27) was 4.62 h. The pretreatments with drugs examined were carried out by a gastric tube. The half-life of aminophylline after phenobarbital (10 mg/kg, 7 days, n = 29) was 2.09 h; after phenytoin (10 mg/kg, 7 days, n = 29), 2.47 h; after carbamazepine (400 mg/d, 7 days, n = 25), 2.19 h; after cimetidine (in cimetidine-treated group the blood samples were collected 0.5, 4 and 7 h after the aminophylline injection) (40 mg/kg, 7 days, n = 13), 1.77 h; after erythromycin (800 mg/d, 7 days, n = 28), 2.51 h; after the combination of sulfamethoxazole + trimethoprim in ratio of 5:1 (50 mg/kg, 7 days, n = 23), 2.85 h; and after rifampicin (300 mg/kg, 21 days, n = 23), 2.74 h. Sulfamethoxazole presumably interfered with the HPLC examination of aminophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

A model for experimental asthma: provocation in guinea-pigs immunized with Bordetella pertussis.

Guinea-pigs were sensitized with killed Bordetella pertussis (3.85 X 10(11) cells . kg-1). The presence of the immediate type of immune response was verified by passive cutaneous anaphylaxis (PCA). In anaesthetized spontaneously-breathing guinea-pigs respiration rate, tidal volume, minute ventilation, dynamic lung resistance and dynamic lung elastance were estimated on the basis of airflow velocity and pressure in the oesophagus. After provocation by a single intravenous injection of the killed cells, respiratory frequency, elastance and resistance increased but tidal volume decreased. The preventive effects of aminophylline and clemastine (50 microns . kg-1, i.v.) were observed. B. pertussis not only alters adrenergic function but provocation in B. pertussis-sensitized guinea-pigs seems to be a good model for bronchial asthma.

The beta-adrenoceptors of lymphocytes in asthmatic patients treated with beta-agonists.

Numbers of beta-adrenoceptors in intact human lymphocytes of asthmatics treated continuously with the usual doses of beta-agonists have been estimated. Lymphocytes were isolated by density gradient centrifugation as described by BOYUM [4]. The binding experiment was performed with (-)3H-dihydroalprenolol which is a high affinity beta-adrenoceptor antagonist. There was no difference between the mean values of the binding sites of asthmatic patients and those of the normal volunteers. In asthmatic patients, a significant correlation was found between the density of receptors and the percentage increase of FEV1 after salbutamol inhalation. Symptoms of drug tolerance were not observed in patients treated with therapeutic doses of beta-agonists.

Development of drug tachyphylaxis in asthmatic patients treated with beta-adrenergic drugs.

The development of drug tolerance in two groups of asthmatics treated with beta-adrenergic bronchodilators was studied by respiratory function methods. During one-year treatment with conventional therapeutic doses of selective beta-2-receptor stimulant aerosols, none of the patients showed subsensitivity to the bronchodilatory effect of terbutaline. Dose-response curves were plotted upon the inhalation of salbutamol in two-week intervals in patients treated with betamimetics. There was no decrease in the airways beta-adrenergic receptor function as compared to the untreated control group. The results show that prolonged treatment with therapeutic doses of inhaled beta-adrenergic bronchodilators does not result in drug tachyphylaxis, which is in accord with the clinical experience that there is no loss of effect of the preparations during their continuous administration.

Respiratory mechanical impedance in the rat.

The forced oscillatory impedance of the total respiratory system (Zrs) was measured in seven anaesthetized, paralysed rats weighing 351 +/- 55 g. Tracheotomy was performed, and the animals were placed in the supine position in a body box. Pseudo-random pressure variations between 0.5 and 10 Hz were applied around the chest. Central airflow was measured with a heated screen pneumotachograph. Total respiratory resistance (Rrs) and elastance (Ers), corrected for the impedance of the tracheal cannula, were markedly frequency-dependent: Rrs fell from 37.3 +/- 19.1 kPa.l-1.s at 0.5 Hz to 17.6 +/- 4.4 at 2 Hz and 10.3 +/- 3.3 at 10 Hz; the corresponding Ers values were 453 +/- 14, 594 +/- 90 and 713 +/- 104 kPa.l-1, respectively. This indicates that in the frequency range encompassing spontaneous breathing rates the classical resistance-intertance-compliance model provides an inadequate description of the respiratory mechanics in the rat.

Serum angiotensin converting enzyme values in chronic obstructive pulmonary disease.

Angiotensin converting enzyme (ACE) is stored in the endothelium. Its activity depends--among others--on the O2-concentration of the blood. Aim of the study was to examine the serum ACE values in chronic obstructive lung diseases (bronchial asthma, chronic bronchitis, lung fibrosis etc.). At the time of blood sampling, blood-gas tensions and respiratory function parameters of the patients were also determined. On the basis of the blood-gas parameters and SACE x + SD and x--SD values, obtained from the normoxic-normocapnic group, the patients could be divided into sub-groups. In contrast to data in the literature increased enzyme levels in response to hypoxia could be found only in patients suffering from a pulmonary disease associated with severe tissue damage.

Spectral analysis of cough sounds recorded with and without a nose clip.

The voluntary cough sounds of healthy volunteers, patients with chronic rhinitis, chronic rhinitis with bronchial asthma and asthma were recorded with and without a nose clip. A gated series of signals of the first cough sound lasting 200 ms was analysed by a system with a 20 ms delay of the first signal. In the case of filtered cough sounds, low-cut digitally, the mean values of averaged spectra of the healthy volunteers showed a first peak around 350 Hz, similar to the expiratory spectra of respiratory sounds. Second and third harmonics were also identified. The mean values of averaged spectra from the patients with airway disease differed significantly in the range of low frequency components. The upper airways work as narrow-band acoustic filters determining the harmonic contents of speech as well as those of cough sounds. To minimize these effects for acoustic analytical purposes, the application of a nose clip is suggested to find the cough harmonics related to those of pulmonary sounds. The voluntary cough sounds contain diagnostic information, but to build up a quantitative, diagnostic, decision-making system, further investigations as well as standardization of recording and analysis are necessary.

Lung function tests in small experimental animals by means of a signal processing system.

For the analysis of the airflow velocity and oesophageal pressure signals of anaesthetized spontaneously breathing small animals (rats and guinea pigs), a signal processing program package was developed for a multiprocessor system (Electronic Measuring Gears Co., Budapest). 4-10 respiratory cycles were analysed in a signal series and the arithmetic mean value was used to increase the accuracy of the method. Since standardization of the respiratory parameters of small animals has not yet been specified, the normalization of volume values per 100 cm2 body surface is proposed.