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Paolo Scarpazza1, Cristoforo Incorvaia2, Paolo Amboni3, Giuseppe di Franco1, Stefania Raschi1, Pierfranco Usai1, Monica Bernareggi1, Cristiano Bonacina1, Chiara Melacini1, Roberta Cattaneo1, Serena Bencini1, Chiara Pravettoni2, Gian Galeazzo Riario-Sforza2, Gianni Passalacqua4, Walter Casali11Divisione di Broncopneumotisiologia, Ospedale Civile, Vimercate, Italy; 2Pulmonary Rehabilitation, Istituti Clinici di Perfezionamento, Milan, Italy; 3Clinical Chemistry Laboratory, Ospedali Riuniti, Bergamo, Italy; 4Allergy and Respiratory Diseases, University Of Genoa, Genoa, ItalyBackground: Noninvasive mechanical ventilation (NIMV) is an effective tool in treating patients with acute respiratory failure (ARF), since it reduces both the need for endotracheal intubation and the mortality in comparison with nonventilated patients. A particular issue is represented by the outcome of NIMV in patients referred to the emergency department for ARF and with a do-not-intubate (DNI) status because of advanced age or excessively critical conditions. This study evaluated long-term survival in a group of elderly patients with acute hypercapnic ARF who had a DNI order and who were successfully treated by NIMV.Methods: The population consisted of 54 patients with a favorable outcome after NIMV for ARF. They were followed up for 3 years by regular control visits, with at least one visit every 4 months, or as needed according to the patient’s condition. Of these, 31 continued NIMV at home and 23 were on long-term oxygen therapy (LTOT) alone.Results: A total of 16 of the 52 patients had not survived at the 1-year follow-up, and another eight patients died during the 3-year observation, with an overall mortality rate of 30.8% after 1 year and 46.2% after 3 years. Comparing patients who continued NIMV at home with those who were on LTOT alone, 9 of the 29 patients on home NIMV died (6 after 1 year and 3 after 3 years) and 15 of the 23 patients on LTOT alone died (10 after 1 year and 5 after 3 years).Conclusion: These results show that elderly patients with ARF successfully treated by NIMV following a DNI order have a satisfactory long-term survival.Keywords: COPD, acute respiratory failure, mortality rate, respiratory failure

COVID-19 Acute Respiratory Distress Syndrome (CARDS) is the most serious complication of COVID-19. The SARS-CoV-2 outbreaks rapidly saturated intensive care unit (ICU), forcing the application of non-invasive respiratory support (NIRS) in respiratory intermediate care unit (RICU). The primary aim of this study is to compare the patients' clinical characteristics and outcomes (Helmet-Continuous Positive Airway Pressure (H-CPAP) success/failure and survival/death). The secondary aim is to evaluate and detect the main predictors of H-CPAP success and survival/death. A total of 515 patients were enrolled in our observational prospective study based on CARDS developed in RICU during the three Italian pandemic waves. All selected patients were treated with H-CPAP. The worst ratio of arterial partial pressure of oxygen (PaO 2 ) and fraction of inspired oxygen (FiO 2 ) PaO 2 /FiO 2 during H-CPAP stratified the subjects into mild, moderate and severe CARDS. H-CPAP success has increased during the three waves (62%, 69% and 77%, respectively) and the mortality rate has decreased (28%, 21% and 13%). H-CPAP success/failure and survival/death were related to the PaO 2 /FiO 2 (worst score) ratio in H-CPAP and to steroids' administration. D-dimer at admission, FiO 2 and positive end expiratory pressure (PEEP) were also associated with H-CPAP success. Our study suggests good outcomes with H-CPAP in CARDS in RICU. A widespread use of steroids could play a role.

Background: Noninvasive mechanical ventilation (NIMV) is an effective tool in treating patients with acute respiratory failure (ARF), since it reduces both the need for endotracheal intubation and the mortality in comparison with nonventilated patients. A particular issue is represented by the outcome of NIMV in patients referred to the emergency department for ARF and with a do-not-intubate (DNI) status because of advanced age or excessively critical conditions. This study evaluated long-term survival in a group of elderly patients with acute hypercapnic ARF who had a DNI order and who were successfully treated by NIMV., Methods: The population consisted of 54 patients with a favorable outcome after NIMV for ARF. They were followed up for 3 years by regular control visits, with at least one visit every 4 months, or as needed according to the patient's condition. Of these, 31 continued NIMV at home and 23 were on long-term oxygen therapy (LTOT) alone., Results: A total of 16 of the 52 patients had not survived at the 1-year follow-up, and another eight patients died during the 3-year observation, with an overall mortality rate of 30.8% after 1 year and 46.2% after 3 years. Comparing patients who continued NIMV at home with those who were on LTOT alone, 9 of the 29 patients on home NIMV died (6 after 1 year and 3 after 3 years) and 15 of the 23 patients on LTOT alone died (10 after 1 year and 5 after 3 years)., Conclusion: These results show that elderly patients with ARF successfully treated by NIMV following a DNI order have a satisfactory long-term survival.

Noninvasive mechanical ventilation (NIMV) is effective in the treatment of patients with acute respiratory failure (ARF). It proved to reduce the need of endotracheal intubation (ETI), the incidence of ETI-associated pneumonia, and mortality compared to nonventilated patients. A particular aspect concerns the outcome of NIMV in patients referring to an emergency room (ER) for ARF, and with a do-not-intubate (DNI) status due to advanced age or critical conditions. The aim of our study is to assess the outcome of NIMV in a group of elderly patients with acute hypercapnic ARF who had a DNI status. An overall number of 62 subjects (30 males, 32 females, mean age 81 +/- 4.8 years, range 79-91 years) referred to our semi-intensive respiratory department were enrolled in the study. The underlying diseases were severe chronic obstructive pulmonary disease (COPD) in 50/62 subjects, restrictive thoracic disorders in 7/62 subjects, and multiorgan failure in 5/62 subjects. Fifty-four/62 patients were successfully treated with NIMV while 2/62 did not respond to NIMV and were therefore submitted to ETI (one survived). Among NIMV-treated patients, death occurred in 6 patients after a mean of 9.9 days; the overall rate of NIMV failure was 12.9%. Negative prognostic factors for NIMV response proved to be: an older age, a low Glasgow Coma Score, a high APACHE score at admission, a high PaCO2 after 12 hours and a low pH both after 1 and 12 hours of NIMV. We conclude that elderly patients with acute hypercapnic ARF with a DNI status can be successfully treated by NIMV.

NCX 4016, a nitro-ester of aspirin endowed with antithrombotic activity, appears to have clinical potential in treating cardiac complications related to coronary insufficiency. This compound has been shown to improve postischemic ventricular dysfunction and to reduce myocardial infarct size in the rabbit. The cardioprotection conferred by NCX 4016 (10, 30, and 100 mg/kg) and aspirin (ASA, 54 mg/kg) was evaluated in anesthetized rats subjected to 30 min of myocardial ischemia followed by 120 min of reperfusion (MI/R). Drugs were given orally for 5 consecutive days. NCX 4016 displayed remarkable cardioprotection in rats subjected to MI/R as was evident in the reduction of ventricular premature beats and in the incidence of ventricular tachycardia and fibrillation; they were reduced dose dependently and correlated with survival of all rats treated with the higher dose of NCX 4016. In these animals, infarct size was restricted proportionally to the dose of NCX 4016 associated with diminution of both plasma creatine phosphokinase and cardiac myeloperoxidase activities. ASA showed only a minor degree of protection against MI/R damage. Rats treated with N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) demonstrated aggravated myocardial damage in terms of arrhythmias, mortality, and infarct size. Supplementation of nitric oxide (NO) with NCX 4016 (100 mg/kg) greatly reduced the worsening effect caused by L-NAME. The beneficial effects of NCX 4016 appear to derive in large part from the NO moiety, which modulates a number of cellular events leading to inflammation, obstruction of the coronary microcirculation, arrhythmias, and myocardial necrosis.

The effects of hexarelin, a growth hormone (GH) secretagogue, and human GH on the mechanical and metabolic changes measured in isolated rat hearts submitted to 5 min of Ca2+ deprivation followed by reperfusion with Ca2+-containing medium, the so-called calcium paradox phenomenon, were studied. Hexarelin (80 microg/kg bid, subcutaneously) administered for 7 d to male rats effectively antagonized the sudden increase in resting tension measured in vitro on Ca2+ repletion. Moreover, during Ca2+ repletion the release of creatine kinase activity (an index of cell damage) in the perfusate of these hearts was reduced up to 40% compared with controls. By contrast, administration of hexarelin for 3 d or GH (400 microg/kg bid, subcutaneously) for 7 d did not affect the mechanical and metabolic alterations induced by the calcium paradox. To assess its direct and acute cardiac effects, hexarelin (8 microg/mL) was perfused in vitro in recirculating conditions for 60 min through the hearts of normal rats. In this case, hexarelin did not stimulate heart contractility and failed to prevent ventricular contracture upon Ca2+ readmission, whereas diltiazem, a Ca2+channel blocker, effectively antagonized the calcium paradox phenomenon. We conclude that short-term in vivo exposure to hexarelin, but not GH, enables cardiac myocyites to prevent cytoplasmatic electrolytic unbalance and to control intracellular Ca2+ gain, two functions largely impaired during the calcium paradox phenomenon. Moreover, because the effect of hexarelin is not acute but dependent on the length of in vivo treatment, we suggest that it requires modifications of myocardiocyte physiology.

Background: A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency., Methods: In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species., Results: The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity., Conclusions: In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 microg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 microg/kg sc) produced similar results, whereas administration of EP 51389 (80 microg/kg sc), another GH-releasing peptide that does not bind to the heart, was ineffective. In conclusion, we demonstrate that hexarelin prevents cardiac damage after ischemia-reperfusion, and that its action is not mediated by GH but likely occurs through activation of specific cardiac receptors.

The endothelial vasodilation mechanism(s) has been investigated in aortic rings of hypophysectomized male rats as well as hypophysectomized rats treated for 7 days with growth hormone (GH, 400 microg/kg, s.c.) or hexarelin (80 microg/kg, s.c.). Tissue preparations from intact animals were taken as controls. The results obtained indicate that the release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings of hypophysectomized rats was markedly reduced (51%; p<0.01) as compared with that of control preparations; the peak response to cumulative concentration of endothelin-1 (ET-1, from 10(-11) to 10(-5) M) was increased 2.4-fold (p<0.01) versus controls; the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) in norepinephrine-precontracted aortic rings was reduced by 39.5+/-4.4%. Pretreatment of hypophysectomized rats with GH or hexarelin markedly antagonized the hyperresponsiveness of the aortic tissue to ET-1 and allowed a consistent recovery of both the relaxant activity of ACh and the generation of 6-keto-PGF1alpha. Collectively these findings support the concept that dysfunction of vascular endothelial cells may be induced by a defective GH function. Because a replacement regimen of GH restored the somatotropic function and increased plasma insulin-like growth factor-I (IGF-I) concentrations in the hypophysectomized rats, it is suggested that IGF-I may have protected the vascular endothelium acting as a biologic mediator of GH action. In contrast to GH, hexarelin replacement neither increased body weight nor affected the plasma concentrations of IGF-I, indicating that its beneficial action on vascular endothelium was divorced from that on somatotropic function and was likely due to activation of specific endothelial receptors.

1 The anti-spasmogenic potential of SK&F 94120 (PDE3-selective), rolipram (PDE4-selective), zaprinast (PDE5-selective), zardaverine (dual PDE3/4 inhibitor) and theophylline (non-selective) was evaluated in guinea-pig trachealis. 2 SK&F 94120 or rolipram (10 and 100 microM) antagonized histamine-induced tension generation in a concentration-dependent and non-competitive manner whereas ACh-induced contractions were unaffected. Similarly, SK&F 94120 and rolipram in combination were anti-spasmogenic with respect to both contractile agonists to an extent that was greater than the effect of either drug alone. Identical results were obtained with zardaverine (1, 10 and 100 microM) and theophylline (100 microM and 1 mM). 3 Zaprinast protected guinea-pig trachealis against histamine-, but not ACh-induced contractile responses in a manner that was indistinguishable from the results obtained with SK&F 94120. However, in contrast to the interaction between SK&F 94120 and rolipram, no further antagonism was seen when zaprinast and rolipram were used in combination. 4 Pre-treatment of tissues with SNP (10 and 100 microM) antagonized histamine-induced tension generation in a concentration-dependent and non-competitive manner. However, no further antagonism was produced when SNP and rolipram were used concurrently. Likewise, the protection afforded by a combination SNP and SK&F 94120 was no greater than that produced by SNP alone. 5 These results demonstrate that an inhibitor of PDE3 enhances the anti-spasmogenic activity of rolipram but not drugs that elevate cyclic GMP mass. Moreover, the ability of SNP and zaprinast to protect guinea-pig trachealis against histamine-induced contractions apparently is not due to the inhibition of PDE3.

The ability of hexarelin, a recently synthesized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against postischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats. Heart preparations from control (saline-treated) senescent rats, subjected to moderate ischemia, showed at reperfusion: (a) a low recovery of postischemic left ventricular developed pressure (LVDP; 37% of the preischemic values; from 90 +/- 5.7 to 33.5 +/- 3.8 mm Hg; p < 0.01; n = 10) coupled to a substantial increase in coronary perfusion pressure (CPP; 71% over baseline; from 68.3 +/- 5.2 to 116.8 +/- 4.6 mm Hg; p < 0.01; n = 10); (b) a marked increase of creatine kinase (CK) released in the perfusates (6.6-fold increase over preischemic values; from 45 +/- 4 to 298 +/- 25 mU/min/g wet tissue; p < 0.001; n = 10). In vivo administration of hexarelin (80 microg/kg, b.i.d., s.c.) for 21 days resulted in a striking heart protection against reperfusion stunning. In fact, the recovery of LVDP at reperfusion was almost complete (90% of the preischemic values; from 93 +/- 5.8 to 83.7 +/- 5.9 mm Hg; p > 0.05; n = 9), and the increase in coronary resistance was minimal (from 67 +/- 5.8 to 79.7 +/- 6.9 mm Hg; p > 0.05; n = 9). Furthermore, the concentration of CK in the perfusates was increased only twofold (from 45.8 +/- 5.5 to 90 +/- 7.2 mU/min/g wet tissue; p < 0.05; n = 9), with a gradual return toward basal values at the end of reperfusion. The protectant activity of hexarelin was divorced from any detectable alteration of the somatotropic function, as assessed by pituitary GH messenger RNA (mRNA) and plasma insulin-like growth factor I levels. In vivo administration of GH (400 microg/kg b.i.d., s.c.) for the same time lapse resulted in only a partial protectant activity: 55% of LVDP recovery (from 91.5 +/- 6.2 to 50 +/- 3.5 mm Hg; p < 0.01; n = 6); 65% increase of coronary resistance (from 68 +/- 4.3 to 112.2 +/- 5.2 mm Hg; p < 0.01; n = 6); 5.3-fold increase of CK concentrations in heart perfusates on reperfusion (from 43.8 +/- 3.8 to 232 +/- 16 mU/min/g wet tissue; p < 0.001; n = 6). Evaluation of the rate of release of 6-keto-prostaglandin F1alpha (PGF1alpha), the stable metabolite of prostacyclin, in heart perfusates, and assessment of the vasopressor activity of angiotensin II on the coronary vasculature, did not show any change in these parameters among the three experimental groups. Collectively these data indicate that hexarelin displays a strong heart-protectant activity against myocardial stunning in senescent rats. The protection afforded by the peptide is likely due to a direct cardiotropic action and is far greater than that of GH. Neither compound appears able to interfere with the endothelium-dependent relaxant mechanism.

The compound 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha), a F2-isoprostane formed mainly via a non-cyclooxygenase pathway, has been shown to constrict both human and guinea pig airway smooth muscle in vitro. We investigated whether this compound has any activity on bronchial resistance and plasma exudation in tracheal tissue of anaesthetised guinea pigs. 8-Epi-PGF2 alpha (12.5, 25 and 50 micrograms kg-1 i.v.) elicited a dose-dependent increase in intratracheal pressure. Diphenhydramine (2 mg kg-1 i.v.), indomethacin (1 mg kg-1 i.v.) and NG-nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1 i.v.) did not affect the 8-epi-PGF2 alpha (25 micrograms kg-1 i.v.)-induced bronchoconstriction. On the contrary, while atropine (0.5 mg kg-1 i.v.) injected 10 min prior to 8-epi-PGF2 alpha (25 micrograms kg-1 i.v.) significantly reduced to 55% (P < 0.05) the increase in intratracheal pressure induced by the isoprostane, the selective thromboxane A2 receptor antagonist, ICI-192,605 (0.5 mg kg-1 i.v.) abolished it (95%, P < 0.001). Furthermore, 8-epi-PGF2 alpha (50, 100 and 200 micrograms kg-1 i.v.) increased plasma leakage, measured according to the Evans Blue dye technique, in tracheal tissue. This effect was particularly evident when 8-epi-PGF2 alpha was injected at the dose of 200 micrograms kg-1 i.v. (105% increase; P < 0.01) and it was markedly reduced by ICI-192,605 (0.5 mg kg-1 i.v.) (36%; P < 0.01) but not by diphenhydramine (2 mg kg-1 i.v.). In isolated perfused lungs, 8-epi-PGF2 alpha (2.5 micrograms ml-1 min-1 perfused for 2 min) increased the thromboxane A2 formation which was significantly reduced by ICI-192,605 (16 micrograms ml-1 min-1 perfused for 5 min) and abolished by indomethacin (1 microgram ml-1 min-1 perfused for 15 min). These data indicate that 8-epi-PGF2 alpha induces bronchoconstriction in guinea pig in vivo and that this effect, which seems to be related to activation of thromboxane A2 receptor, is associated to an augment of vascular permeability with plasma leakage in airway smooth muscle.

The ability of hexarelin, a recently synthesized hexapeptide with a remarkable growth hormone (GH)-releasing activity, to reverse signs of cardiovascular dysfunction in GH-deficient animals was studied in young male rats made GH deficient by the administration of an anti-GH-releasing hormone serum (GHRH-Ab) for 20 days. Heart preparations from GHRH-Ab treated rats, subjected to low-flow ischemia and reperfusion, showed: a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion as compared to control hearts; a decreased rate of formation of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, in perfusates of both preischemic and reperfusion period; an increased vasopressor activity of angiotensin II on the coronary vasculature. The endothelium-dependent relaxing function in GH-deficient rats was also evaluated in aortic ring preparations, which showed: a decreased rate of formation of 6-keto-PGF1 alpha, an hyperreactivity to endothelin-1, a markedly reduced vasopressor response to NG-monomethyl-L-arginine (the nitric oxide synthase inhibitor) and a decreased vasodilator response to acetylcholine of precontracted aortic tissue. Hexarelin (80 micrograms/kg, s.c. twice daily), administered for 15 days to GHRH-Ab-treated rats, fully restored the somatotropic function and reversed all the signs of cardiac and endothelial dysfunction. In fact, in heart preparations from rats treated with hexarelin the trend of the ischemic damage was similar to that observed in control rats and both the rate of formation of 6-keto-PGF1 alpha and the vasopressor activity of angiotensin II were reverted to control levels. Furthermore, all the parameters of endothelial function were in the normal range. These results indicate that GH deficiency in rats is responsible for an impairment of cardiac function that is associated with a damage of the endothelium-dependent relaxing function not limited to coronary vessels but widespread in the circulation. These alterations are fully reverted by an in vivo treatment with hexarelin.

The ability of hexarelin, an effective growth hormone (GH)-releasing hexapeptide, to reverse the worsening of cardiac dysfunction in GH-deficient animals was studied in young male rats passively immunized by administration of an anti-GH-releasing hormone (GHRH) serum. Heart preparations from anti-GHRH serum-treated rats, undergoing low-flow ischemia and reperfusion, showed: (1) a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion with a consistent decrease of the left ventricular-developed pressure; (2) a decreased rate of formation of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), a stable metabolite of prostacyclin, in perfusates from preischemic and reperfusion periods; (3) an increased vasopressor activity of angiotensin II. Hexarelin (80 microg/kg, bid, s.c.), administered for 15 days to anti-GHRH serum-treated rats, restored to normal the impaired somatotropic function and counteracted the ischemic damage, improving postischemic left ventricular developed pressure to values higher than those of controls. Furthermore, both the generation of 6-keto-PGF1alpha and the vasopressor activity of angiotensin II reverted to those of control preparations. Administration of hexarelin to control rats induced a considerable improvement of postischemic ventricular function of the perfused hearts which was similar to that present in preparations from anti-GHRH serum-treated rats given hexarelin. This protective activity was divorced from any further stimulation of somatotropic function. Collectively, these data indicate that, in GH-deficient rats, hexarelin is capable of restoring somatotropic function and has a beneficial effect in myocardial ischemia and reperfusion damage. In addition, the increased responsiveness of the coronary vasculature to angiotensin II and the decreased generation of prostacyclin in hearts from GH-deficient rats would indicate that for prevention of injury and dysfunction of the vascular endothelium a normal somatotropic function is mandatory.

Rats were exposed to hyperbaric oxygen (HBO = 100% oxygen; 2.5 atmospheres absolute pressure) for 6 h. Isovolumic left heart preparations from these animals were subjected to global low flow-ischemia (perfusion rate from 12 ml/min to 2 ml/min for 40 min) and reperfusion. Hearts from rats not exposed to HBO underwent the same ischemic-reperfusion procedure (controls). As compared to control, HBO treatment caused in ex vivo hearts a significant aggravation of cardiac ischemic picture as indicated by a marked increase in left ventricular end diastolic pressure (LVEDP) and reduced post ischemic left ventricular developed pressure (LVDP). At the end of the ischemic and reperfusion periods LVEDP values were 6.8 (p < 0.001) and 8 (p < 0.001) times higher than the corresponding control values. Moreover, LVDP and coronary perfusion pressure (CPP) values were decreased (2.8 times; p < 0.001) and increased (56%; p < 0.001), respectively, as compared to control preparations. These events were also associated with a considerable impairment of the cardiac tissue to generate 6-keto-PGF1 alpha. Treatments of rats with different doses of acetylcysteine (N-acetylcysteine, CAS 616-91-1, NAC; 0.25-0.5-1 g/kg p.o.) before HBO displayed a clear-cut and dose-related protective activity in hearts subjected to ischemia-reperfusion. Also the generating capacity of 6-keto-PGF1 alpha from these hearts were restored according to the dose of NAC employed. When aortic rings from rats exposed to HBO were considered, they showed a reduced capacity to release 6-keto-PGF1 alpha and an increased sensitivity to endothelin-1. At the same time, the relaxant activity of acetylcholine in these tissues was almost lost. Again, NAC treatment of the animals before HBO restored in a dose-dependent way the capacity of the aortic rings to generate 6-keto-PGF1 alpha. This event was paralleled by normalized responses of the preparations to endothelin-1 and acetylcholine. Taken together these results clearly indicate that acute HBO treatment of the rats markedly aggravates the ischemic-reperfusion damage in ex vivo hearts. This event is coupled with a compromised integrity of cardiac and extracardiac endothelial cell functions. The protective activity of NAC observed in this study once more emphasises its therapeutic role in increasing antioxidant defence mechanisms.

Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.

Acute myocardial infarction was induced in New Zealand male albino rabbits. 3 days after surgery, the mortality rate and plasma CPK activity were reduced by 64% and 66% respectively by intravenous infusion of Oligotide (32 mg/kg/h for 6h), a single-stranded oligodeoxyribonucleotide of mammalian origin. Perfused hearts, obtained from Oligotide-treated rabbits 3 days after surgery, showed a strength of contraction in the range of that of hearts of sham-operated animals and an ameliorated postsynaptic beta-adrenergic and cholinergic receptor function. In addition, in these hearts, "ex vivo" treatment with Oligotide resulted in almost complete preservation of both adrenergic and cholinergic responses to their specific agonists. These data suggest that Oligotide by protecting the hearts from the ischemic damage and possibly by restricting left ventricular tissue necrosis may have normalized the biological responses of this organ to isoproterenol and preserved the integrity of coronary endothelial-dependent relaxant function.

The anti-ischemic action of ITF 296 was evaluated in isovolumic, electrically driven rabbit heart preparations subjected to temporary ischemia and reperfusion. Reduction of perfusion rate from 20 to 0.2 ml/min produced a sharp decrease of peak systolic pressure, left ventricular (LV)-developed pressure, and LV dP/dt, which culminated in complete ventricular arrest within 3-4 min. Thereafter, LV end-diastolic pressure (LVEDP) progressively increased, suggesting a severe ischemic episode. Reperfusion with 20 ml Krebs solution/min after 40 min of low-flow perfusion produced only minimal recovery from the rhythm disturbances associated with cardiac mechanical activity. During reperfusion, loss of myocardial elasticity was associated with a significant increase in coronary vascular resistance, as indicated by the augmentation of coronary perfusion pressure. Injection of ITF 296 (0.3-10 microM) into the perfusion system dose-dependently inhibited the increase in LVEDP that took place during ischemia and progressively improved the recovery of a regular rhythm in the isolated heart. Isosorbide dinitrate (ISDN) at a concentration of 10 microM exerted a protective action on the myocardium similar to that obtained with ITF 296 (3 microM). Treatment with ITF 296 (1 and 10 microM) resulted in a dose-dependent increase in the rate of 6-keto-PGF1 alpha biosynthesis during both the ischemia and the reperfusion period (+157% over basal values). Similar results were obtained when hearts were pretreated with ISDN (10 microM). Infusion of a buffer containing NG-monomethyl-L-arginine (L-NMMA; NO synthase inhibitor at 10 microM) just before reduction of flow, markedly exacerbated the effects of ischemia and reperfusion on the myocardium and increased coronary perfusion pressure. The effects of L-NMMA were clearly antagonized by ITF 296 (10 microM) or L-arginine (100 microM). Mechanical activity and sinus rhythm during reperfusion were rapidly and completely restored, and coronary resistance values were close to the preischemic values. As with ISDN, ITF 296 significantly increased the rate of synthesis of 6-keto-PGF1 alpha both under basal conditions and during reperfusion.

In anaesthetized ventilated guinea-pig, acetaldehyde (CAS 75-07-0) (40-80 mg/kg i.v.) elicits a dose-dependent increase in intratracheal pressure accompanied by an increase in circulating histamine. When acetaldehyde is injected repeatedly at 15 min intervals in capsaicin-desensitized animals, it already loses its activity at the second administration (50% reduction; p < 0.01); this does not happen in control animals. This phenomenon is even more marked when acetaldehyde is given at the dose of 80 mg/kg i.v., since at the third injection both the bronchoconstriction and the increase in blood histamine are almost completely reduced to baseline values. The increase in intratracheal pressure caused by acetaldehyde (20, 40, 80 mg/kg i.v.) is associated with a dose related increase in microvascular permeability and leakage of protein-bound Evans blue in lower tracheal tissue. This event and the bronchoconstrictor response caused by acetaldehyde (40 mg/kg i.v.) are 87% and 35% inhibited, respectively, (p < 0.01) in tachykinin-depleated animals. On the contrary, thiorphan (2 mg/kg i.v.) remarkably potentiates both the rise in intratracheal pressure (110%; p < 0.01) and Evans blue extravasation (215%; p < 0.01) induced by acetaldehyde (20 mg/kg i.v.) in normal guinea-pigs. Furthermore, treatment with CP-96,345, a selective tachykinin NK1-receptor antagonist, only prevents plasma extravasation in lower tracheal tissue (82% inhibition; p < 0.01) without affecting the bronchoconstriction caused by acetaldehyde (40 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)