Biomedical subjects
Publications and source records attributed to M Condorelli.
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The antihypertensive efficacy of a new agent, indenolol, was compared with that of the well-established antihypertensive drug, metoprolol, and its hemodynamic effects were investigated using echocardiography. Eighteen hypertensives completed a double-blind, crossover, randomized study using indenolol and metoprolol. Two four-week courses with indenolol or metoprolol were preceded and followed by a two-week placebo period; the total duration of the study was 14 weeks. Indenolol proved to be significantly more effective than metoprolol in decreasing blood pressure values at rest (P less than .05). Furthermore, three patients that failed with metoprolol were successfully treated with indenolol. Both drugs induced a significant decrease in cardiac output that was mediated mainly through a reduction in heart rate, because stroke volume, left ventricle circumferential fiber shortening velocity, and ejection fraction were not significantly reduced by either drug. However, after indenolol, a significant direct relationship was found between the basal values of both cardiac output (r = .809) and total peripheral resistance (r = .800), and the reduction of these parameters. On the contrary, after metoprolol only, the correlation between the basal value of cardiac output and its reduction was significant (r = .790).
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Male Sprague-Dawley rats (200-220 g) were employed to study the effect of a calcium antagonistic drug on hypoxia-induced myocardial hypertrophy. The hypoxic condition was obtained by exposure of animals to reduced barometric pressure in a hypobaric chamber. The rats, divided in groups, were exposed to acute or chronic intermittent hypoxia (0.42 atmospheres of air for 24 hrs or 0.42 atm for 12 hrs per day for 10 days, respectively). Verapamil (VRP) was given subcutaneously in a total dose of 200 mg/kg/b.w./rat. In hypoxic rats, the drug significantly reduced the values of dry heart weight calculated on the basis of its relationship to total body weight. This phenomenon is probably due to: (1) reduced activation of the contractile system and a thereby resulting decrease in ATP breakdown as a result of blocking of Ca++ inflow into myocardial cells; (2) the effect of Verapamil on hypoxia-induced pulmonary hypertension and/or (3) a direct effect of the drug on the myocardial cell.
We have examined the influence of isoproterenol and hydrocortisone on the cycle AMP content and lysosomal enzyme release from highly purified human polymorphonuclear leukocytes. It was found that isoproterenol, although a potent stimulus for cAMP accumulation in human lymphocytes, had only marginal effects on both cAMP content of PMN and enzyme release. Since corticosteroids have been reported to increase the response to beta-agonists in various tissues, it was considered that some of the anti-inflammatory potential of corticosteroids might be related to enhancing the response of PMN to beta-agonists. The influence of hydrocortisone on the response to isoproterenol was accordingly examined. It was found that hydrocortisone did in fact augment the isoproterenol-induced increase in cAMP content. In contrast to the potentiation of cAMP accumulation caused by hydrocortisone and isoproterenol together, the two agents produced only an additional inhibition of enzyme release. Since the inhibition of lysosomal enzyme release from human PMN did not closely reflect the changes observed in the cAMP content, a possible compartmentalization of intracellular cAMP is suggested.
We investigated the effect of cyclosporin A (CsA) on in vitro release of chemical mediators from mast cells purified from human lung tissues. CsA (3 X 10(-2) to 1 microgram/ml) dose-dependently inhibited IgE-mediated release of histamine and peptide leukotriene C4 (LTC4) from human lung mast cells. The same concentrations of CsA also inhibited the release of histamine from lung mast cells challenged with the Ca2+ ionophore A23187. Therefore, CsA in pharmacological concentrations inhibits the IgE- and non-IgE-mediated release of inflammatory mediators from mast cells purified from human lung tissues.
Prolonged incubation (18h) of human polymorphonuclear leukocytes (PMNs) with betamethasone (BT) (10(-7) M) increased (3H)-DHA binding to human PMN membranes, apparently causing an increase in the number of beta-adrenergic receptors. Inhibition of this effect by cycloheximide (2 micrograms/ml) suggests that it is dependent on protein synthesis. BT had no effect on basal levels of cAMP in PMNs, but synergistically potentiated the increase in cyclic AMP (cAMP) induced by isoproterenol. Propranolol completely abolished the synergistic effect of BT plus isoproterenol, suggesting that the potentiating effect of BT on cAMP metabolism required the activation of beta-adrenergic receptors. Thus, BT increased the number of beta-adrenergic receptors in human PMN membranes and potentiated the cAMP changes induced by beta-agonists.
We investigated the clinical course of 57 patients with acute inferior myocardial infarction as regards anterior S-T segment depression. Thirty of them showed S-T segment depression greater than or equal to 0.15 mV in at least 2 precordial leads, and 27 did not exhibit such changes. Twenty-seven patients underwent post-infarction exercise stress test. Furthermore, coronary arteriographic findings and left ventricular performance were evaluated in 8 of these patients with and in 8 without anterior S-T segment depression. Patients with anterior S-T segment depression showed greater inferior S-T segment elevation on admission ECG and deeper Q wave in lead aVF in ECG tracings recorded 1 month later. Higher incidences of in-hospital angina (10/30 vs 2/27, P = 0.01) and of late development of cardiac failure (5/21 vs 0/19, P = 0.03) were found among patients with anterior S-T segment depression. They showed a higher overall coronary score (82.4 +/- 31.0 vs 32.5 +/- 28.9, P = 0.002) and left anterior descending artery score (44.1 +/- 20.7 vs 8.5 +/- 16.1, P = 0.0009) and a reduced ventricular performance, evaluated by ventriculography score (49.5 +/- 2.7 vs 51.8 +/- 2.4, P = 0.05). A higher incidence of mitral regurgitation, secondary to papillary muscle dysfunction, was also found among patients with anterior S-T segment depression (4/8 vs 0/8, P = 0.04). Furthermore, the degree of anterior S-T segment depression in each of these subjects was closely correlated with the corresponding difference from normal ventricular score (r = 0.86, P less than 0.01). Finally, no difference between the two groups of patients was found as to incidence of positive exercise stress tests.
In two patients with orthostatic hypotension, due to autonomic dysfunction, hemodynamic changes induced by the assumption of erect position have been evaluated before and during chronic propranolol treatment. Under control conditions, the change in posture induced in Patient 1 a fall in systolic and diastolic blood pressure by 51.4 and 30.7%, respectively. Cardiac output was reduced by 26.8% and systemic vascular resistance by 23.3%. During propranolol treatment, systolic pressure decreased only by 28% and diastolic pressure by 7.7%. The decline in systemic vascular resistance on standing was abolished, while the reduction in cardiac output remained unmodified. In Patient 2, symptoms of orthostatic hypotension were related to marked decrease in systolic blood pressure, the diastolic pressure remaining unchanged. Moreover, systemic vascular resistance increased and, thus, orthostatic hypotension was exclusively dependent upon the severe fall in cardiac output on standing. As a consequence, propranolol failed to control orthostatic hypotension in this patient. These data suggest that when orthostatic hypotension is secondary to failure in peripheral vasoconstriction, propranolol may act beneficially. When it is secondary to a fall in cardiac output, beta-blockade is ineffective.
We assessed the effect on blood pressure of administration of slow-release nifedipine tablets (20 mg) by continuous intraarterial blood pressure monitoring (Oxford system) in 10 patients with untreated essential hypertension. Blood pressure was recorded under control conditions and during nifedipine therapy. During each monitoring period patients were instructed to perform various types of exercise. The initial dose of nifedipine was 20 mg twice a day (8:00 a.m. and 8:00 p.m.). For patients in whom arterial pressure control was not achieved, the dose of the drug was increased at weekly intervals, first to 40 mg in the morning and 20 mg at night and then to 40 mg twice a day. The average daily dose was 52 mg. Nifedipine twice a day significantly reduced systolic and diastolic blood pressures both during the day and during the night. The rise in blood pressure due to dynamic or isometric exercise or to mental testing was blunted. Heart rate did not change. Orthostatic hypotension was not observed, and there were only minor side effects, which did not require withdrawal of the patient from the trial. Bioavailability of nifedipine from this preparation was satisfactory, as shown by plasma concentrations which remained constantly in the therapeutic range. Thus, slow-release nifedipine given twice a day represents an effective treatment in patients with essential arterial hypertension. The reduced frequency of administration required may improve patient compliance with this treatment.
Mepindolol is a newly developed beta-adrenergic blocking agent reported to counteract the chronotropic effect of catecholamines, with only little effect on contractility. This study was designed to assess whether or not mepindolol is effective in reducing infarct size. Accordingly, 16 rats, serving as controls, underwent coronary artery occlusion and did not receive any treatment; an additional 19 were treated with mepindolol (1 mg/kg s.c. t.i.d.) for 48 h. Finally, a third group (n = 18) underwent sham operation. Forty-eight hours later, infarct size was calculated from left ventricular creatine phosphokinase activity and found to average 52.4 +/- 7.8% (mean +/- SEM) of the left ventricle in control rats and 35.6 +/- 5.4% in treated rats (p less than 0.05). Left ventricular phospholipid content averaged 0.79 +/- 0.08 microgram P/mg protein in sham-operated rats and 0.61 +/- 0.04 microgram P/mg protein in control animals. In contrast, in mepindolol-treated rats, phospholipid concentration was 0.70 +/- 0.04 microgram P/mg protein (p less than 0.05), this suggesting a protective effect of the drug on ischemia-induced phospholipid degradation. The long-term effect of mepindolol on left ventricular hydroxyproline concentration was assessed 21 days post-coronary occlusion. Infarct size calculated by this method was 30.2 +/- 4.8% of left ventricle in 21 control animals and 18.2 +/- 4.2% in 28 treated rats (p less than 0.05), indicating that, as for the acute necrosis, the extent of scar development after coronary artery occlusion can be reduced by mepindolol.
1. This study was designed to compare the response of plasma arginine vasopressin (AVP) to head-up tilt in hypertensive patients and in normals. 2. As expected, plasma AVP showed a consistent increase (P less than 0.005) in normal subjects after tilt while plasma volume decreased significantly (P less than 0.02). On the contrary, in hypertensive patients, after tilt both plasma AVP (P less than 0.025) and plasma volume (P less than 0.05) decreased. 3. These findings, thus, indicate that essential hypertension is characterized by an inverted response of arginine vasopressin to postural change.
We investigated the upright bicycle exercise cardiopulmonary response in 20 patients with left ventricular dysfunction (LVD, secondary to previous myocardial infarction, left ventricular ejection fraction range 18-44%). Ten patients (48 +/- 7 years) asymptomatic (I NYHA class) without drug treatment (LVD group). The others (n = 10) (50 +/- 1 years) complained of dyspnea and/or fatigue despite therapy (NYHA II-III). They represented the heart failure (HF) group. Eight sedentary men (40 +/- 10 years) served as controls. Controls and patients performed stress testings under drug treatment, when administered. Anaerobic ventilatory threshold (ATge) was considered as an index of submaximal exercise while peak exercise VO2 (Peak VO2) was considered the maximal volitional exercise capacity. The ratio between minute ventilation (VE) to carbon dioxide release (VCO2) (VE/VCO2) was assessed to evaluate the ventilatory response during exercise. We coupled gas exchange assessment (2001, MGC) with noninvasive monitoring of stroke volume (SV) by impedance cardiography (NCCOM3, BOMED) and total systemic vascular resistances (TSVR; by auscultatory blood pressure measurement). In controls VO2 increase during exercise was related to higher heart rate (HR) and SV both from resting to ATge and from this point to the peak. TSVR declined during both steps. In patients with HF VO2 rose from resting to ATge (by faster HR and unchanged SV). VO2 increased slightly from this point to Peak VO2. This result was related to flat HR increase and unchanged SV as well as TSVR. In patients with LVD VO2 increased similarly to controls from resting to ATge and less above the threshold. In these patients both HR and SV increased during submaximal exercise. From ATge to Peak VO2 only HR increased. TSVR declined significantly similarly to controls. The VE/VCO2 ratio was higher at peak exercise in patients with HF compared to controls. Different determinants were demonstrated in patients with left ventricular dysfunction with mild or symptomatic chronic heart failure (CHF). These findings and the increased ventilatory response in patients with CHF can explain different changes of VO2 in these patients during submaximal and maximal voluntary exercise and contribute to explain exercise-induced exertion in these subjects.
To investigate the impairment of beta-adrenoceptor responsiveness in human hypertension, we evaluated the effect of an oral salt load (400 mEq/day of NaCl for 7 days) on plasma catecholamine concentrations and beta-adrenoceptor-mediated effects in 11 young patients with mild essential hypertension. Responses of heart rate and plasma cAMP to isoproterenol administration were used as indices of beta-adrenoceptor responsiveness. Salt loading induced a significant reduction in the dose of isoproterenol required to raise the heart rate by 25 bpm (CD25) (from 7.6 +/- 1.5 to 5.3 +/- 0.9 micrograms, p less than 0.05) and an increase in the slopes of the regression lines for heart rate changes and isoproterenol doses (delta HR/IS) (from 3.3 +/- 0.6 to 4.7 +/- 0.7, p less than 0.05) and for plasma cyclic AMP (cAMP) level changes and isoproterenol doses (delta cAMP/IS) (from 0.3 +/- 0.06 to 1.4 +/- 0.3, p less than 0.05). After salt loading there was a significant reduction in plasma catecholamine concentrations with a significant relationship between changes in upright plasma epinephrine levels and changes in CD25 (r = 0.904, p less than 0.01) and in the slopes for delta HR/IS (r = 0.983, p less than 0.001) and delta cAMP/IS (r = 0.922, p less than 0.001). These results support the hypothesis that the impairment of beta-adrenoceptor sensitivity observed in human hypertension is associated with a beta-adrenoceptor overstimulation due to chronically elevated adrenergic tone.
The extrinsic coagulation pathway is activated when circulating factor VII (FVII) gains access to tissue factor (TF) exposed as a consequence of vascular injury. Increasing evidence indicates that this TF-dependent activation of the coagulation plays an important role in the pathophysiology of intravascular thrombus formation. In the present study, we tested the effects of recombinant human, active site-blocked activated FVII (FVIIai) in a rabbit model of carotid artery thrombosis. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were obtained in stenotic rabbit carotid arteries with endothelial injury. Carotid blood flow velocity was measured by a Doppler flow probe. After 30 minutes of CFVs, the animals received FVIIai (100 microg x kg(-1) x min(-1) intracarotid infusion for 10 minutes, n=9). If CFVs were abolished, animals were followed for 30 additional minutes, after which recombinant human activated FVII (FVIIa) was infused into the carotid artery (100 microg x kg(-1) x min(-1) for 10 minutes) to determine whether FVIIai could be displaced from TF by FVIIa, thus restoring CFVs. To establish the duration of action of FVIIai, an additional group of animals received FVIIai at the same dose as above, and after CFVs were inhibited, they were followed until CFVs were restored or for up to 6 hours. To determine whether CFVs could be restored by epinephrine after their abolition with FVIIai, increasing doses of epinephrine were administered to a third group of 6 animals. FVIIai abolished CFVs in 8 of 9 rabbits (P<.01). This effect was reversible, as FVIIa administration restored CFVs in all animals. Prothrombin times and activated partial thromboplastin times did not change significantly throughout the study. One single 10-minute infusion exerted complete antithrombotic effects for at least 6 hours, despite the fact that at this time point, plasma FVIIai levels were well below threshold concentrations. Epinephrine restored CFVs in 3 of 6 animals in which CFVs were inhibited by FVIIai. FVIIai exerts potent antithrombotic effects in this model; these effects were prolonged even after FVIIai was almost completely cleared from the circulation, probably as a result of the tight binding of FVIIai to TF. Thus, FVIIai might represent an antithrombotic substance of potential interest.
The Authors studied the behaviour of some prothrombotic (fibrinogen, factor VII, antithrombin III and tissue plasminogen activator) and prethrombotic (beta thromboglobulin, D-dimer) markers in a group of obese subjects in relation to various physiopathological parameters. The series consist of 93 obese subjects (29 m, 64 f, mean age 55 +/- 6 yrs, BMI 33 +/- 1), of whom 62 suffering from type 2 diabetes in good metabolic control obtained by oral hypoglycemic (42 cases) or insulin (20 cases) treatment. For each subject the Authors determined the plasmatic levels of glucose, total cholesterol, triglycerides (enzymatic method, Boehringer kits), fibrinogen (coagulometric method, Organon kit), factor VII (chromogenic method, IL kit), antithrombin III (chromogenic method, IL kit), tissue plasminogen, beta thromboglobulin and D-dimer (ELISA method, Boehringer kits). The results were examined in relation to sex, age, overweight degree, waist/thigh ratio, total cholesterol, triglycerides and, for diabetics, to the therapeutical treatment. The fibrinogen plasma levels proved statistically (0.05) increased proportionally to the overweight degree (BMI over 35), cholesterol levels (over 250 mg%) and age (51-65 yrs); factor VII showed a significant increase (0.05) related to the cholesterol levels, the overweight degree and, surprisingly, to female sex; as regards antithrombin III, its sharp reduction was related with ageing and with the "gynoid type" waist/thigh ratio; tissue plasminogen activator showed a statistically significant reduction (0.05) in the group with older age (over 65 yrs); the beta thromboglobulin levels were obviously increased (0.05) in the hypercholesterolemic and hypertriglyceridemic subjects (over 250 mg%), the D-dimer values increased proportionally with age (0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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