Biomedical subjects

G Gambassi

Publications and source records attributed to G Gambassi.

At least 91 records · Page 5Linked to original sources

PubMed1993

Enantiomeric dissection of the effects of the inotropic agent, EMD 53998, in single cardiac myocytes.

The effects of the thiadiazinone derivative, 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl]-6-met hyl-3,6- dihydro-2H-1,3,4-thiadiazin-2-on (EMD 53998), and of its (+)EMD 57033 and (-)EMD 57439 enantiomers, were tested on the contractile properties and cytosolic [Ca2+] ([Ca2+]i) transients of single intact guinea pig cardiac myocytes. Cells were loaded with the ester form of the fluorescent probe, indo-1, and bathed in a N-2-hydroxyethyl-piperazine-N'-2-ethanesulfonic acid-buffered solution at 25 degrees C (1 mM of CaCl2, 1 Hz stimulation rate). All three substances exerted a pronounced increase in twitch amplitude: the maximal effect of the racemate (380% of control value) was approximately the sum of the effects of its two enantiomers (186 and 236% of control value for the (+)- and (-)-enantiomer, respectively). The [Ca2+]i transient, measured as the 410-to-490 nm indo-1 fluorescence ratio transient after excitation, was increased by the racemate and its (-)-enantiomer (172 and 152% of control value, respectively), but was not increased by the (+)-enantiomer. The racemate and the (-)-enantiomer, but not the (+)-enantiomer, markedly reduced the contraction duration and [Ca2+]i transient duration. In unstimulated cells resting length was significantly reduced by the (+)-enantiomer, and this was accompanied by a decrease in indo-1 fluorescence; the (-)-enantiomer had no effect on either parameter. In the presence of 2,3 butanedione monoxime (BDM), which markedly reduces twitch amplitude by inhibiting cross-bridge mechanics, addition of the (+)-enantiomer restored the twitch contraction to above the pre-BDM level without augmenting the [Ca2+]i transient. In contrast, the (-)-enantiomer failed to reverse the BDM-induced contractile depression, even though it caused a significant increase of the [Ca2+]i transient. Thus, in intact cells the positive inotropic effect of EMD 53998 is due to specific properties of its enantiomers: the (-)-enantiomer has adenosine 3',5'-cyclic monophosphate-like effects (increase in amplitude and reduction of [Ca2+]i transient and contraction durations), whereas the (+)-enantiomer enhances the myofilament-Ca2+ interaction.

Animals↗

PubMed1993

Altered pyruvate dehydrogenase control and mitochondrial free Ca2+ in hearts of cardiomyopathic hamsters.

The fraction of total pyruvate dehydrogenase in the active, dephosphorylated form is much lower in the glucose-perfused isolated hearts of two myopathic strains of Syrian hamster (BIO 14.6 and TO-2) than in the hearts of healthy control animals (F1B). The myopathic hearts also develop significantly less pressure under these conditions. Experiments with isolated myocytes from the BIO 14.6 heart reveal that intramitochondrial free Ca2+ ([Ca2+]m), a positive effector of pyruvate dehydrogenase interconversion, rises much less in response to a protocol of increased frequency of electrical stimulation and adrenergic stimulation than does [Ca2+]m in cells from the healthy control animals (viz from 248 +/- 15 to 348 +/- 44 nM in BIO 14.6 vs. from 241 +/- 35 to 830 +/- 124 nM in F1B, at 4 Hz). As the concentration of Ca2+ that produces half-maximal activation of pyruvate dehydrogenase within mitochondria is 650 nM, this difference between strains is likely the mechanism of the altered enzyme interconversion. The lesser response of [Ca2+]m to electrical stimulation in the BIO 14.6 cells probably results mainly from smaller systolic transients in cytosolic free Ca2+ in response to excitation of single myocytes from the BIO 14.6 animal. Lowered values of [Ca2+]m within the range described would compromise not only pyruvate dehydrogenase activity, but also flux through the tricarboxylate cycle in the myopathic heart, owing to the sensitivity of 2-oxoglutarate dehydrogenase to Ca2+. This may explain the decreased activity of oxidative phosphorylation and performance of work in the myopathic heart.

Animals↗

PubMed1993

Assay, isolation and characterization of circulating immune complexes from serum of gastrointestinal cancer, stage III and IV melanoma and chronic inflammatory bowel disease patients.

Circulating immune complexes (CIC) have been detected in several autoimmune diseases, and studies have also suggested that CIC provide a useful tool as tumor markers. In order to identify differences or similarities in antigenic composition, CIC from 23 patients with gastrointestinal (GI) tumors, from 20 patients with stage III and IV melanoma and from 6 patients with inflammatory bowel disease (IBD) were studied. Serum from all GI, melanoma and IBD patients showed higher levels of CIC than controls. SDS/PAGE electrophoresis under reducing conditions revealed some differences between cancer and IBD patients as far as the CIC protein composition was concerned. In melanoma patients, two fast-migrating bands, in the regions of 71-74 and 30-49 kD, were found, consistent with previously isolated and characterized antigens described in the literature.

Antigen-Antibody Complex↗

PubMed1993

Stereoselective actions of thiadiazinones on canine cardiac myocytes and myofilaments.

Thiadiazinones are cardiotonic agents that have potent, direct, and stereoselective actions on the myofilament response to Ca2+ in intact myocardium. Their mechanism of action is unknown. We studied the effects of racemic thiadiazinone, EMD 53998 (5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6-quinolyl]-6-meth yl-3,6- dihydro-2H-1,3,4-thiadiazin-2-one), and its enantiomers on Ca2+ signaling in myocytes, myofilaments, and myofilament proteins. Intact canine ventricular myocytes responded to the positive enantiomer, EMD 57033, with an increase in the extent of shortening during twitch contractions without increasing the peak amplitude of the Ca2+ transient. The negative enantiomer, EMD 57439, also increased the extent of shortening, but in this case there was a concentration-dependent increase in the peak amplitude of the Ca2+ transient. This is predicted from in vitro data showing that this enantiomer is a relatively potent inhibitor of phosphodiesterase activity. There was no effect of EMD 57439 on the relation between pCa and actomyosin Mg-ATPase activity of canine heart myofibrils. In contrast, EMD 57033 shifted the pCa-Mg-ATPase activity relation to the left. There was no effect of either enantiomer on Ca2+ binding to myofilament troponin C. Moreover EMD 57033, but not EMD 57439, stimulated actomyosin ATPase activity of myofilament preparations in which either troponin or troponin-tropomyosin had been extracted. EMD 57033 had no effect on Mg-ATPase activity of pure ventricular myosin. EMD 57033 also stimulated the velocity of actin filament sliding on myosin heads adhered to nitrocellulose-coated glass coverslips. We propose that the action of EMD 57033 is at the actin-myosin interface on a "receptor" that may be on actin or the crossbridge. Drug binding to this domain appears to reverse the inhibition of actin-myosin interactions by troponin-tropomyosin and also to promote transition of crossbridges from weak to strong force-generating states.

Actin Cytoskeleton↗

PubMed1993

[Stimulation of the alpha-1 adrenergic receptors during simulated reperfusion after myocardial acidosis. The evidence for an arrhythmogenic role of the Na+/H+ exchanger].

Myocardial ischemia is associated with an intracellular acidosis recovering after reperfusion. Alpha 1-adrenergic stimulation (alpha 1) exacerbates ischemic injury and triggers ventricular arrhythmias during the reperfusion phase. We have tested the hypothesis that the arrhythmogenic effect of alpha 1 is due to a cytosolic alkalinization secondary to proteinkinase C (PKC)-dependent activation of the sarcolemmal Na+/H+ exchanger. In addition, the effect of the 2 distinct receptor subtypes, alpha 1A and alpha 1B, has also been evaluated. We used single, enzymatically dissociated, adult rat ventricular myocytes. Cells were loaded with the ester derivative of the Ca2+ probe, indo-1 or with the intracellular pH probe SNARF-1. Fluorescence was monitored simultaneously with contractility and was taken as an index of intracellular [Ca2+] or as pHi value. Cells on a stage of an inverted microscope were superfused with a bicarbonate buffer continuously gassed with 95% O2 and 5% CO2 (pH = 7.37; Ca2+ 1.5 mM) and electrically stimulated at 0.5 Hz, at 25 degrees C. Alpha 1 (phenylephrine 50 microM + nadolol 1 microM) increased twitch amplitude and pHi (delta pHi = 0.05 +/- 0.01; pHi in control = 7.24 +/- 0.06, n = 10; p < 0.05). This effect was abolished by the PKC inhibitor staurosporine (5 nM), by overnight (12-24 hours) exposure to 0.2 microM phorbol esters and by the perfusion with 10 microM ethylisopropylamiloride (EIPA), a Na+/H+ exchange inhibitor. During 15 min of hypercarbic acidosis, achieved by switching to a buffer equilibrated with 85% O2 and 15% CO2 (pH = 7.01), alpha 1 had a more pronounced effect on pHi (delta pHi = 0.11 +/- 0.02; pHi in control = 7.02 +/- 0.04, n = 10; p < 0.05). During the 10 min following the removal of acidosis, alpha 1 induced aftercontractions in 75% (n = 20) versus only 25% (n = 8) of the cells in the absence of phenylephrine (p < 0.05). Superfusion with 10 microM EIPA (n = 6) abolished the occurrence of aftercontractions. Selective alpha 1A-adrenergic receptors stimulation (alpha 1 + 2 microM CEC, which inactivates alpha 1B receptors) further increased them (92%, n = 12) whereas selective alpha 1B-adrenergic receptors stimulation (alpha 1 + 2 microM WB-4101, a alpha 1A receptors antagonist) greatly reduced the occurrence of aftercontractions (11%, n = 18). These results show that the PKC-mediated activation of the Na+/H+ exchanger is the mechanism for the arrhythmias induced by alpha 1 during simulated reperfusion after a period of acidosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Acidosis↗

PubMed1992

Antipyrine metabolism in patients with liver metastases from colorectal cancer.

BACKGROUND: The influence of cancer on antipyrine metabolism is under debate. METHODS: To assess the functional activity of a liver with solid metastases from primary colorectal cancer, antipyrine metabolism was studied after the drug was administered orally (18 mg/kg body weight) to 55 healthy volunteers, 62 patients with well-compensated cirrhosis, and 42 patients with small (Class A) or massive (Class B) metastatic liver involvement. RESULTS: In patients with cancer, antipyrine clearance (0.472 +/- 0.177 ml/min/kg) was similar to that in healthy volunteers (0.456 +/- 0.198 ml/min/kg) and significantly higher than in those with cirrhosis (0.259 +/- 0.17 ml/min/kg, P less than 0.001). There was no difference in antipyrine pharmacokinetics between Class A and B involvement. In the entire population, antipyrine clearance was correlated with serum albumin levels (r = 0.294, P = 0.0002) and prothrombin activity (r = 0.416, P = 0.001). This positive correlation was not present when only the neoplastic group was considered. No correlation was found between antipyrine clearance and alkaline phosphatase levels. In patients with cancer, no relationship was found between antipyrine clearance and carcinoembryonic antigen and lactic dehydrogenase levels. CONCLUSIONS: These results show that patients with livers largely replaced by solid metastases are able to metabolize antipyrine to the same extent as healthy subjects.

Adult↗

PubMed1992

Perindopril versus captopril: efficacy and acceptability in an Italian multicenter trial.

The aim of this 3-month, double-blind, double-dummy, parallel group study was to compare the antihypertensive efficacy and acceptability of perindopril (4-8 mg/day) in 54 patients (30 males, 24 females, 25-68 years of age) and captopril (50-100 mg/day) in 54 patients (39 males, 15 females, 29-66 years of age) in the treatment of essential hypertension. In a subgroup of 38 patients a complete echocardiographic study was performed. The two groups had similar (ANOVA) blood pressure (BP), heart rate (HR), body mass index, and duration of hypertension. Supine and standing BP was significantly reduced by both drugs, without differences between them. Owing to poor control of BP, hydrochlorothiazide (25 mg/day) was added to 27% of patients on perindopril and to 41% of patients on captopril (p less than 0.05). Normalization of supine diastolic BP (less than or equal to 90 mm Hg) was obtained in 67% of patients on perindopril and in 47% of patients on captopril (p less than 0.01). No change in HR was detected. Only mild untoward effects were recorded. Left ventricular mass was significantly reduced by either drug, with no change in systolic function. In conclusion, perindopril and captopril, at these doses, were both well tolerated and on average reduced BP to a similar extent; however, treatment with perindopril showed that fewer patients needed the addition of a thiazide and BP became normal in a larger number of patients.

Adult↗

PubMed1992

The efficacy of chemotherapy with mebendazole in human cystic echinococcosis: long-term follow-up of 52 patients.

Sixty patients with Echinococcus granulosus infection of the liver, lungs, bone and/or soft tissues were treated for several months with oral mebendazole (50-60 mg kg-1 day-1), in divided doses after fat-rich meals, either without surgery (WS), post-surgery (PS) or pre- and post-surgery (PPS). Long-term follow-up, possible for 52 of the patients, showed that WS, PS and PPS patients have so far remained disease-free following treatment for (means +/- standard deviations) 65.5 +/- 37.7, 82.5 +/- 37.0 and 84.1 +/- 28.3 months, respectively. Ultrasound and computed tomography scans were similar in WS and PPS patients post-treatment. Blood eosinophil levels, which were sometimes elevated initially, returned to normal in all patients and this decrease indicated cyst degeneration before this was evident on the scans. Treatment of patients with cystic echinococcosis may no longer require surgery.

Adolescent↗

PubMed1992

Different effects of alpha- and beta-adrenergic stimulation on cytosolic pH and myofilament responsiveness to Ca2+ in cardiac myocytes.

alpha-Adrenergic stimulation (alpha-AS) and beta-adrenergic stimulation (beta-AS) of the myocardium are associated respectively with an increase and a decrease in myofilament responsiveness to Ca2+. We hypothesized that changes in cytosolic pH (pH(i)) may modulate these opposite actions of alpha-AS and beta-AS. The effects of alpha-AS (50 microM phenylephrine and 1 microM nadolol) and beta-AS (0.05 microM isoproterenol) on contraction and either cytosolic Ca2+ (Cai) or pH(i) were assessed in adult rat ventricular myocytes bathed in bicarbonate buffer (pH 7.36 +/- 0.05). In cells loaded with the ester derivative (AM form) of indo-1, the 410/490-nm ratio of emitted fluorescence indexed Cai. Myofilament responsiveness to Ca2+ was assessed by the relaxation phase of the length-indo-1 fluorescence relation during a twitch. alpha-AS and beta-AS shifted this relation in opposite directions, indicating that alpha-AS increased and beta-AS decreased myofilament responsiveness to Ca2+. In addition, the positive inotropic action of alpha-AS was associated with an increased Cai transient amplitude in 50% of the myocytes (n = 12), whereas beta-AS always increased Cai (n = 5). In cells loaded with the fluorescent pH(i) probe SNARF-1 AM, the emitted 590/640-nm fluorescence is a measure of pH(i). The effect of alpha-AS on the extent of cell shortening during the twitch (ES) was expressed as the percentage of resting cell length. Both ES and pH(i) were assessed in myocytes bathed in 1.5 mM [Ca2+] and stimulated at 0.5 Hz (control ES, 7.4 +/- 1.5%; control pH(i), 7.11 +/- 0.05; n = 10). alpha-AS enhanced both ES (delta ES, 1.8 +/- 0.6%; p less than 0.05) and pH(i) (delta pH(i), 0.06 +/- 0.01; p less than 0.005), and there was a significant correlation between delta ES and delta pH(i) (r = 0.76, p less than 0.05). A similar effect of alpha-AS on pH(i) was observed in the absence of electrical stimulation (n = 8). The alpha-AS-induced enhancement of ES and pH(i) was abolished by 10 microM ethylisopropylamiloride, a Na(+)-H+ exchange inhibitor (n = 7). In additional experiments, myocytes were preincubated either with 0.2 microM 4 beta-phorbol 12-myristate 13-acetate (n = 8) or with 5 nM staurosporine (n = 8), which have been shown to downregulate and inhibit Ca(2+)-activated phospholipid-dependent protein kinase C, respectively. In either group, alpha-AS had no effect on pH(i) and decreased ES to approximately 60% of control.(ABSTRACT TRUNCATED AT 400 WORDS)

Actin Cytoskeleton↗

PubMed1992

Nicotinamide treatment in subjects at high risk of developing IDDM improves insulin secretion.

Nicotinamide (NCT) has been shown to be effective in preventing the onset of type 1 diabetes mellitus (IDDM) in mice with non-obese diabetic (NOD) and beta cell damage, mediated by the diabetogenic agents including streptozotocin. NCT therapy in man has been shown to have a beneficial effect on the remission phase of IDDM, and its use is safe. In this open pilot trial we therefore studied the effect of oral NCT administration on insulin secretion rate and islet-cell antibody (ICA) titres in IDDM high risk subjects. NCT (25 mg/10 kg bw) was administered in 6/13 high risk patients identified by a family screening programme. Those subjects tested after eight months without treatment showed a decreasing secretion in comparison to onset baseline (56,1 +/- 37.8 versus 35,5 +/- 12.2), whereas the treated subjects showed an increasing insulin secretion after treatment (26 +/- 10 versus 50.2 +/- 26.6), in spite of ICA persistence. Statistical analysis shows an increased insulin secretion in the treated group versus the untreated group (chi 2 = 3.899, P = 0.048). No side-effects were observed. We conclude that NCT may repair beta-cell function in high risk subjects too if damage is not too severe; furthermore, the effect seems not to be mediated by an immune mechanism.

Adolescent↗

PubMed1992

[The effect of alpha 1-adrenergic stimulation of the myocardium depends on the opposite actions of 2 receptor subtypes].

Two different myocardial alpha 1-adrenergic receptor subtypes have been recently described. Since their functional role is still unknown we examined the effect of alpha 1A and alpha 1B on contractile properties, cell Ca2+ homeostasis and myofilament sensitivity to Ca2+ in indo-1 loaded ventricular myocytes. Non selective alpha 1-adrenergic stimulation increases twitch amplitude, systolic Ca2+ and myofilament sensitivity. Same effects but amplified are associated with alpha 1A-receptors stimulation. In contrast, alpha 1B-receptors stimulation decreases twitch amplitude and systolic Ca2+ below control value. Myocardial alpha 1-adrenergic stimulation results from the opposite actions of the 2 subtypes.

Animals↗

PubMed1992

[The arrhythmogenicity of alpha 1-adrenergic stimulation following myocardial acidosis].

Ischemia is associated with myocardial acidosis which recovers upon reperfusion. In such conditions, alpha 1-adrenergic stimulation is arrhythmogenic. We used single cardiac myocytes loaded with the pH fluorescent dye, SNARF-1, to determine if a modulation of pH could explain the effect of alpha 1-adrenergic stimulation. Cells were exposed to acidosis (CO2 15%) for 15 min and then normocapnia restored. During acidosis, alpha 1-adrenergic stimulation caused an increase in pH which was abolished by blocking Na+/H+ exchange with ethylisopropylamiloride (EIPA). After removal of acidosis aftercontractions were manifest in 8 out of 10 and 1 out of 5 cells in the presence of an alpha 1-adrenergic agonist and in control, respectively (p < 0.001). EIPA abolished the occurrence of after contractions. Thus, the arrhythmogenicity of alpha 1-adrenergic stimulation depends on activation of Na+/H+ exchanger.

Acidosis↗

PubMed1992

[Acidosis is associated with an intracellular accumulation of Ca2+. Its role in the modulation of myocardial contractility].

Myocardial acidosis, as during ischemia, profoundly modifies excitation-contraction mechanisms. The decreased myofilament sensitivity to Ca2+ reduces contractility regardless of an intracellular accumulation of Ca2+. To determine the source for this increase in Ca2+ we evaluated the effect of acidosis on diastolic [Ca2+] and mitochondrial [Ca2+]. We used single cardiac cells loaded with the fluorescent probes, indo-1 for Ca2+ and SNARF-1 for pH. Acidosis increases [Ca2+] both in cytosol and mitochondria. The cytosolic accumulation depends, most likely, on an active release from mitochondria. A competition among Ca2+ and H+ ions may, instead, explains the increase in mitochondrial [Ca2+].

Acidosis↗

PubMed1992

[Myocardial protection in hypothermia depends on the modulation of intracellular Ca2+ homeostasis].

The effect of a mild hypothermia (30 degrees C) on sarcoplasmic reticulum (SR) Ca2+ content and release has been evaluated in single cardiac cells loaded with the fluorescent indicator, indo-1. SR Ca2+ content, assessed by rapid caffeine application, is more pronounced at 30 than at 37 degrees C. However, hypothermia reduces the occurrence of spontaneous SR Ca2+ oscillations. In fact, following electrical stimulation, the time to onset of first SR Ca2+ oscillation was increased and their frequency reduced. Since spontaneous SR Ca2+ releases are implicated on the genesis of certain forms of ventricular arrhythmias, the protection provided by a mild hypothermia may be dependent on the modulation of intracellular Ca2+ homeostasis.

Animals↗

PubMed1992

[Familial Mediterranean fever and electroencephalographic changes. A clinical case].

The Authors describe the case of a non-Hebrew Italian girl suffering from short-lasting fever episodes, associated with abdominal colic, since the age of 3. The occurrence of acute arthrosynovitis during the last episode, at 12 years of age, clinically confirms the diagnosis of familial mediterranean fever, as previously supposed. The increase in urinary coproporphyrins, with normal values of delta-aminolevulinic acid and porphobilinogen poses the problem of the differential diagnosis between hereditary coproporphyria and secondary coproporphinuria. The importance of this case lies in the presence of electroencephalographic alteration since the first years of life, suggesting a temporal epilepsy for which the patient was at length submitted to anti-epileptic treatment. Electroencephalographic alterations, of different type and uneasy interpretation, are described in the literature with a frequency which does not seem accidental. Renal biopsy does not show amyloid, nor the RMN reveals cerebral abnormalities. The anti-epileptic therapy being withdrawn, the patient was treated with daily administrations of colchicine (1 mg/die); 18 months after, she is disease free.

Biochemical Phenomena↗

PubMed1991

[Evaluation of latent changes in blood coagulation by the determination of plasma thrombin-antithrombin complex in gastrointestinal neoplasms].

The relationship between cancer and coagulation disorders is widely accepted. Such disorders can contribute to the metastatic spreading of the primary tumor. Aim of our study was to evaluate the alterations of thrombin-antithrombin III complex (TAT) measured by an ELISA plasma assay in a population of 78 patients suffering from various gastrointestinal tumors. We found high levels of TAT in 68.6% of the patients. Our data show that assay of TAT plasma levels may be a useful test in detecting early coagulation disorders in cancer patients.

Antithrombin III↗

PubMed1991

Lack of correlation between the antiarrhythmic effect of L-propionylcarnitine on reoxygenation-induced arrhythmias and its electrophysiological properties.

1. The antiarrhythmic effect of L-propionylcarnitine (L-PC) was evaluated in the guinea-pig isolated heart; arrhythmias were induced with hypoxia followed by reoxygenation and by digitalis intoxication. 2. L-PC 1 microM, was found to be the minimal but effective antiarrhythmic concentration against reoxygenation-induced ventricular fibrillation. No antiarrhythmic effect was observed against digitalis-induced arrhythmias. D-Propionylcarnitine, L-carnitine and propionic acid did not exert antiarrhythmic effects. 3. During hypoxia and reoxygenation L-PC consistently prevented the rise of the diastolic left ventricular pressure, and significantly reduced the release of the cardiac enzymes creatine kinase (CK) and lactic dehydrogenase (LDH). 4. The electrophysiological effects of L-PC were then studied on either normal sheep cardiac Purkinje fibres or those manifesting oscillatory after potentials induced by barium or strophanthidin. 5. L-PC (1 and 10 microM) did not significantly modify action potential characteristics and contractility of normal Purkinje fibres, or the amplitude of OAP induced by strophanthidin or barium. 6. It is concluded that the antiarrhythmic action of L-PC on reoxygenation-induced arrhythmias is not correlated with its direct electrophysiological effects studied on normoxic preparations.

Animals↗

PubMed1991

Enalapril prevents cardiac fibrosis and arrhythmias in hypertensive rats.

To evaluate the effects of hypertension on cardiac hypertrophy, on myocardial structure, and on ventricular arrhythmias, 27 3-month-old spontaneously hypertensive rats were treated with enalapril (10 mg/kg) daily for 11 months and compared with 26 untreated control rats. Systolic arterial pressure was significantly decreased in treated rats, and at the end of the experiment, it was 199 +/- 3 mm Hg (treated) versus 237 +/- 3 mm Hg (controls) (p less than 0.001). At this time, spontaneous arrhythmias and induced arrhythmias either by programmed electrical stimulation (train of stimuli +1 or 2 extrastimuli) or by trains of eight stimuli at decreasing coupling intervals were observed in isolated heart preparations. Comparing enalapril-treated and control rats, spontaneous arrhythmias (9 of 27 versus 20 of 26, respectively; p less than 0.01), programmed stimulation-induced arrhythmias (3 of 26 versus 12 of 23, respectively; p less than 0.01), and trains of stimuli-induced arrhythmias (4 of 26 versus 14 of 19, respectively, p less than 0.001) were less frequent in the enalapril group. Left ventricular weight was decreased in treated rats by 18% (p less than 0.001). Enalapril administration diminished the fraction of myocardium occupied by foci of replacement fibrosis normally occurring in control rats by 59% (p less than 0.001). Finally, a significant correlation was found between left ventricular weight, the extent of myocardial fibrosis, and the occurrence of ventricular fibrillation. It was concluded that chronic treatment with enalapril, which resulted in attenuation of systemic arterial pressure by limiting cardiac hypertrophy and myocardial fibrosis, decreases the propensity of the heart of hypertensive rats to arrhythmogenesis.

Analysis of Variance↗