Giovanna Pelà

Mechanism of action of human calcitonin gene-related peptide in rabbit heart and in human mammary arteries

We investigated the effects of human calcitonin gene-related peptide (CGRP) on isolated rabbit hearts to evaluate the mechanisms responsible for the vasodilatory action of the peptide on the coronary district, monitoring contemporaneously the effects on left ventricular pressure (LVP) and heart rate (HR). We also evaluated the reactivity of the human internal mammary artery (IMA) to excitatory drugs acting with different mechanisms and the inhibitory response to CGRP in comparison with the commonly used vasodilatory agents. The peptide induced a slight inhibitory effect on the basal coronary perfusion pressure (CPP), whereas it was ineffective on the inotropism and chronotropism. A more detectable coronary vasodilation was evident when CPP was increased by spasmogenic agents [vasopressin, methoxamine, Bay K 8644, and prostaglandin F2 alpha (PGF2 alpha)]. This inhibitory effect was dose dependent (10(-11)-10(-8) M) and apparently not specific, occurring to the same extent on different stimuli. Forskolin (10(-8) M), an adenylate-cyclase activator, and indomethacin (1.4 x 10(-5) M), a cyclooxygenase inhibitor, did not modify the spasmolytic activity of CGRP on precontracted coronary smooth muscle. The experiments performed on the segments of IMA, used for myocardial revascularization of patients affected by coronary diseases, have shown an evident spasmolytic action of CGRP on increased vascular tone induced by KCl (90 mM), noradrenaline (10(-5) M), serotonin (10(-6) M), and angiotensin II (10(-6) M). These inhibitory responses of CGRP on the spasmogenic compounds disappeared when the endothelial function of IMA, validated by the acetylcholine test, was abolished by mechanical ablation. A series of IMA segments was incubated (30 min) with N(G)-monomethil-L-arginine (L-NMMA), which inhibits nitric oxide (NO) synthase. In these experiments, the peptide failed to induce the vasodilation, suggesting that its action may be related to synthesis of NO. All these results show that CGRP is able to induce a potent vasodilatory action on different vessels of humans (internal mammary artery) and animals (rabbit coronary arteries). In particular the data obtained from IMA demonstrated that the vasorelaxant effect was related to synthesis of NO, one of the most studied endothelium-derived relaxing factors (EDRFs).

Circadian blood pressure and heart rate changes in patients in a persistent vegetative state after traumatic brain injury.

Alteration of autonomic nervous system regulation is known to be present in the persistent vegetative state after traumatic brain injury, termed the dysautonomic syndrome. This study assessed the circadian blood pressure and heart rate pattern and variability in the persistent vegetative state through noninvasive 24‐hour ambulatory blood pressure monitoring. The study was performed in 20 subjects: 10 patients (six men and four women; mean age, 29.5±9.9 years; range, 19–39 years) in a vegetative state (mean, 27.3±5.6 days after trauma) and 10 healthy subjects as controls (six men and four women; mean age, 28±5.7 years; range, 29–37 years). The patients showed a blood pressure nondipper pattern; 24‐hour, daytime, and nighttime values of blood pressure and heart rate were significantly higher in patients than in controls. The day‐night difference in heart rate and blood pressure was also significantly lower in patients. Finally, SD and variation coefficients were significantly lower in patients. The results show changes in the variability and circadian blood pressure and heart rate patterns in persistent vegetative state patients with dysautonomic syndrome, as an expression of the sympathetic‐parasympathetic activity imbalance in the control of vasomotor tone.

Sex-related differences in left ventricular structure in early adolescent non-professional athletes

Background Professional athletes exhibit lower left ventricular wall thicknesses, diameters and mass (in females), with less frequent training-related electrocardiogram (ECG) changes, as compared with controls. Methods We studied the association of sex with left ventricular structure in trained early adolescents. Two hundred and six adolescent Caucasian athletes (mean age 13.8 ± 1.6, range 11.8–16.9 years, 158 males and 48 females), with similar degree of training underwent ECG and echocardiographic measurements of left ventricular diameters, thicknesses and mass, with relative wall thickness as the remodelling index. Results As compared with females, males exhibited greater maximal wall thickness (males = 8.7 ± 1.2 vs. females = 7.9 ± 0.8) and indexed left ventricular mass (100 ± 18 g/m2 vs. 79 ± 12, p < 0.001), without differences in relative wall thickness (males = 0.35 ± 0.04 vs. females = 0.34 ± 0.04) and with higher prevalence of ECG-based left ventricular hypertrophy, sinus bradycardia and ST-elevation. An analysis of covariance, using age, body surface area, systolic blood pressure, heart rate and sex as the covariates, reported that sex is a strong predictor of left ventricular mass, maximal wall thickness, left ventricular diastolic diameter and ECG-based left ventricular hypertrophy. In a binary logistic regression model analysis sex, like left ventricular mass, predicted ST-trait elevation. Conclusions Our results suggest that, in early adolescence, female athletes have lower left ventricular mass and thicknesses compared with males, without geometrical differences. Therefore, sex, independent of age, is a strong determinant of structural parameters also in early adolescent athletes. These data indicate that sex-specific parameters are needed in the pre-participation cardiovascular screening of adolescent athletes.

Assessment of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis: a tissue Doppler echocardiographic analysis.

Aim: Tissue Doppler echocardiography was investigated for its applicability in detecting subtle myocardial involvement in multiple sclerosis patients receiving a low dose of mitoxantrone. Methods and Results: Twenty Caucasian patients with multiple sclerosis (mean age 43.9±9.3 years, 12 males and 8 females) treated with mitoxantrone (mean cumulative dose 35.4±21.6 mg/m2), were compared to 20 healthy subjects (mean age 45.4±15.3 years, 11 males and 9 females) matched for age and gender. All subjects underwent conventional and Tissue Doppler echocardiography. Patients with heart failure, life‐threatening arrhythmias, and other prominent manifestations of heart disease were excluded. No differences were observed in blood pressure, heart rate, and conventional systolic and diastolic echocardiographic parameters. At Tissue Doppler echocardiography, patients with multiple sclerosis showed differences of the systolic mechanic expressed by a significant lower S‐wave peak velocity at the lateral site of mitral annulus (11.4±2.5 cm/sec vs. 15.0±4.1 cm/sec, P < 0.02). Such S‐wave peak velocity significantly correlated with a cumulative dose of mitoxantrone (r =−0.37, P < 0.05). Conclusion: Tissue Doppler echocardiography suggests an early involvement of the systolic myocardial function at the low dose of mitoxantrone. Therefore, Tissue Doppler echocardiography may be used as a noninvasive method for monitoring subclinical cardiotoxicity in multiple sclerosis patients receiving mitoxantrone.

Different effects of captopril and other angiotensin converting enzyme inhibitors on cardiovascular preparations

The effects of captopril and of other angiotensin-converting enzyme inhibitors (zofenopril, fosenopril and enalaprilic acid) were tested on the isolated rabbit heart and aorta. Captopril elicited an erratic negative inotropic effect and a reduction in basal coronary perfusion pressure (10(-5)-10(-4) M). The increase of coronary perfusion pressure induced by vasopressin, methoxamine, angiotensin II and Bay K 8644 was partially antagonized by captopril (10(-7)-10(-4) M) in a non-specific manner. These actions were not modified by saralasin or indomethacin and by ex vivo pretreatment with captopril itself. On the aortic strips, the contraction plateau induced by KCl and angiotensin II was partially inhibited (10(-6)-10(-4) M), while no effect was observed on those induced by noradrenaline, serotonin and PGF2 alpha. The Ca2+ concentration-response curve appeared shifted to the right in a non-competitive manner. The other angiotensin-converting enzyme inhibitors showed no effect up to 10(-4) M on isolated heart or aorta. Results obtained with captopril were consistent with vasorelaxant activity independent of the tissue renin-angiotensin system. Modulatory activity on the intracellular calcium movement may be involved.

Impact of Myocardial Geometry on Left Ventricular Performance in Healthy Black and White Young Adults

Racial differences in left ventricular (LV) structure are suggested by clinical and experimental studies. This study evaluates if racial differences in LV performance exist comparing black to white young males, by tissue Doppler echocardiography and myocardial performance index (MPI). We examined 40 healthy males, 20 blacks (mean age 27.6 ± 4.4 years) and 20 whites (mean age 26.5 ± 6.7 years). All subjects underwent conventional echocardiography, tissue Doppler echocardiography, and MPI assessment. No differences were found in LV diameters, volumes, mass, and hemodynamic measurements. Septal and posterior wall thicknesses were significantly increased in black subjects as well as the relative wall thickness. Systolic and diastolic functions estimated by conventional parameters were superimposable in the two groups. In black subjects, a significant increase of septal S‐wave, peak velocity, and time‐velocity integral were found. MPI was significantly higher in black compared to white subjects (0.46 ± 0.05 vs 0.40 ± 0.06, P < 0.002). A significant correlation between MPI and relative wall thickness (r = 0.54) was demonstrated. Besides, MPI correlated with Spv (r = 0.55) and Stvi (r = 0.38) at the septal site. In conclusion our data show a higher MPI in black subjects that seems to be geometry‐dependent. Correlations between MPI and tissue Doppler echocardiography systolic indexes were found. Our findings suggest that racial differences in LV performance exist, especially, in the systolic function, even in the absence of other conventional echocardiographic changes.

Nitric oxide-angiotensin II interactions and renal hemodynamic function in patients with uncomplicated type 1 diabetes

The objective is to elucidate the effect of nitric oxide (NO)-renin-angiotensin system (RAS) interactions on renal hemodynamic function in uncomplicated, type 1 diabetes mellitus (DM). In 14 salt-replete, male healthy volunteers (C) and 9 male DM patients on euglycemia, glomerular filtration rate (GFR), renal blood flow (RBF), filtration fraction (FF), and sodium excretion (UNaV) were measured at baseline and during a 90-min infusion of 3.0 μg·kg⁻¹·min⁻¹ NG-nitro-L-arginine-methyl-ester (L-NAME) after 3 days of pretreatment with either placebo (PL) or 50 mg losartan (LOS). Baseline GFR, RBF, and FF were higher in DM (P < 0.005). In the C group, PL + L-NAME caused declines in GFR (101 ± 3 to 90 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (931 ± 22 to 754 ± 31 ml·min⁻¹·1.73 m⁻²), and UNaV (158 ± 12 to 82 ± 18 μmol/min) and an increase in FF (0.19 ± 0.02 to 0.21 ± 02; P < 0.001), which were not influenced by LOS pretreatment (P > 0.05 for LOS + L-NAME-C vs. PL + l-NAME-C). In DM, PL + L-NAME resulted in exaggerated renal effects, with changes in GFR (128 ± 3 to 104 ± 3 ml·min⁻¹·1.73 m⁻²), RBF (1,019 ± 27 to 699 ± 34 ml·min⁻¹·1.73 m⁻²), UNaV (150 ± 13 to 39 ± 14 μmol/min), and FF (0.22 ± 0.03 to 0.26 ± 0.02) that were significantly greater vs. PL + L-NAME-C (P < 0.005). LOS pretreatment blunted GFR, RBF, FF, and UNaV responses to L-NAME in DM (P < 0.005 vs. PL + L-NAME-DM), resulting in a response profile that was similar to PL + L-NAME and LOS + L-NAME in C (P > 0.05). Renal responses to L-NAME in uncomplicated, type 1 DM are exaggerated vs. C, consistent with an upregulation of NO bioactivity. LOS, without effects in C, prevents the accentuated actions of L-NAME in DM, thus indicating an augmented role for NO-RAS interactions in renal hemodynamic function in DM.

Inhibitory actions of amiodarone on the isolated rabbit heart and aorta

1. The inhibitory actions of amiodarone on the isolated rabbit heart and aorta have been studied. 2. Amiodarone inhibited vasopressin- and ergonovine-induced coronary spasm, starting from a concentration of 10(-7) M which did not affect myocardial contractility to 10(-4) M, which decreased myocardial contractility. 3. Sinus node activity was largely unaffected even when the highest dose of 10(-4) M was used. 4. Amiodarone did not modify the smooth muscle contraction in rabbit aorta strips precontracted with noradrenaline or potassium. 5. Comparison with other inhibitors of the cardiovascular system (alpha- and beta-blockers, nitrates, calcium entry blockers) points out a peculiar pharmacological profile of amiodarone and indicates some doubts about its presumed anti-adrenergic properties.

Left ventricular structure and remodeling in patients with COPD.

Background Data on cardiac alterations such as left ventricular (LV) hypertrophy, diastolic dysfunction, and lower stroke volume in patients with COPD are discordant. In this study, we investigated whether early structural and functional cardiac changes occur in patients with COPD devoid of manifest cardiovascular disease, and we assessed their associations with clinical and functional features. Methods Forty-nine patients with COPD belonging to all Global Initiative for Chronic Obstructive Lung Disease (GOLD) classes were enrolled and compared with 36 controls. All subjects underwent clinical history assessment, lung function testing, blood pressure measurement, electrocardiography, and conventional and Doppler tissue echocardiography. Patients were also subjected to computed tomography to quantify emphysema score. Results Patients with COPD had lower LV cavity associated with a marked increase in relative wall thickness (RWT), suggesting concentric remodeling without significant changes in LV mass. RWT was significantly associated with ratio of the forced expiratory volume in 1 second to the forced vital capacity and emphysema score and was the only cardiac parameter that – after multivariate analysis – significantly correlated with COPD conditions in all individuals. Receiver operating characteristic curve analysis showed that RWT (with a cutoff point of 0.42) predicted the severity of COPD with 83% specificity and 56% sensitivity (area under the curve =0.69, 95% confidence interval =0.59–0.81). Patients with COPD showed right ventricular to be functional but no structural changes. Conclusion Patients with COPD without evident cardiovascular disease exhibit significant changes in LV geometry, resulting in concentric remodeling. In all individuals, RWT was significantly and independently related to COPD. However, its prognostic role should be determined in future studies.

Ethnicity-related variations of left ventricular remodeling in adolescent amateur football players

Adult and adolescent elite black athletes display – as compared with their white counterparts – excessively increased left ventricle (LV) wall thickness (LVWT), mass (LVM), and relative wall thickness (RWT). To investigate such ethnicity‐related differences in non‐professional adolescent athletes, 138 male, amateur football players [age 14.0 ± 1.7 years, 42 West‐African blacks (BA) and 96 Italian whites (WA)] underwent an echocardiographic study of LV diameters, LVWT, maximal wall thickness (MWT), LVM, and RWT as remodeling index. BA vs WA exhibited greater thickness of septum and posterior wall, higher MWT (10.3 ± 1.7 vs 8.8 ± 1.1 mm), and higher LVM (117 ± 27 vs 101 ± 20 g/m2) and RWT (0.44 ± 0.07 vs 0.35 ± 0.04). Age, systolic blood pressure, body mass index, and ethnicity predicted MWT and LVM, whereas ethnicity was the sole strong predictor of RWT. The greater MWT, LVWT, and LVM of 14‐year‐old, amateur‐level BA vs WA indicates that ethnicity substantially affects LV structure in adolescent, non‐professional athletes. In contrast with MWT and LVM, elevated RWT was predicted by black ethnicity only. We suggest that concentric‐type LV remodeling is a peculiar LV phenotype in adolescent African athletes.