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E H Herman

Publications and source records attributed to E H Herman.

At least 37 records · Page 2Linked to original sources
PubMed1993

Cardiotoxicity of human recombinant interleukin-2 in rats. A morphological study.

BACKGROUND: One of the side effects of interleukin 2 (IL-2) cancer immunotherapy in humans is the vascular leak syndrome, which is frequently associated with depression of myocardial function, myocarditis, and myocardial necrosis. METHODS AND RESULTS: To investigate this cardiotoxicity, IL-2 (three doses of 5 x 10(5) Cetus units/day i.p.) was given to rats for 2, 3, or 5 days. Heart, lung, liver, spleen, and kidney tissues were studied by light and electron microscopy and with immunoperoxidase techniques. Cardiac changes consisted of focal lymphocytic and eosinophilic infiltration, myocyte vacuolization, myofibrillar loss, and necrosis. Ultrastructural alterations included swelling of endothelial cells, with dissociation of intercellular junctions, migration of lymphocytes into the interstitium, and interstitial hemorrhage and edema. Close contact between infiltrating lymphocytes, particularly large granular lymphocytes, and cardiac myocytes was often observed in areas of tissue damage. All lesions were more severe on day 5 than on days 2 and 3. Immunoperoxidase stains demonstrated asialo GM1 ganglioside antibody-positive, granular lymphocytes to be much more frequent in myocardium of IL-2-treated rats than in that of control rats. CONCLUSIONS: Although we cannot exclude the possibility of a direct toxic effect of IL-2 on myocytes, our observations suggest that the myocardial damage produced by this agent is triggered by IL-2-activated lymphocytes that exert cytolytic effects, first on endothelial cells and then on cardiac myocytes, thus producing lesions that involve both the cardiac microcirculation and the muscle cells.

Animals↗
PubMed1993

Dendritic cells in the hearts of spontaneously hypertensive rats treated with doxorubicin with or without ICRF-187.

Histological and immunohistochemical studies using specific monoclonal antibodies were made to evaluate the severity of the chronic cardiomyopathy and the quantitative changes in interstitial dendritic cells (antigen-presenting cells), T helper lymphocytes, T cytotoxic/suppressor lymphocytes, and macrophages in the hearts of spontaneously hypertensive rats (SHRs) treated with doxorubicin at 1 mg/kg per week for 3, 6, 9 or 12 weeks. In addition, an assessment was made of the modifications of the responses of these cell populations by pretreatment of the SHR with ICRF-187, which protects against doxorubicin cardiotoxicity. The number of interstitial dendritic cells/mm2 of section of left ventricle was similar in saline-treated control SHRs (76 +/- 6) and in those treated with ICRF-187 alone (75 +/- 2) but increased markedly (319 +/- 33) in animals receiving a total cumulative dose of 12 mg/kg doxorubicin. Treatment with ICRF-187 prior to each administration of doxorubicin attenuated in a dose-dependent manner the increase in numbers of dendritic cells induced by doxorubicin (231 +/- 47, 174 +/- 11, and 100 +/- 16 cells/mm2) after treatment with 6.25, 12.5, and 25 mg of ICRF-187, respectively. Doxorubicin also induced increases in the numbers of T helper lymphocytes and macrophages but not of T cytotoxic/suppressor lymphocytes. These increases were also attenuated by pretreatment with ICRF-187. These data were interpreted as indicating that doxorubicin cardiotoxicity results in the release of substances that initiate immune reactions involving the antigen-presenting cells of the heart and that such reactions are attenuated by pretreatment with ICRF-187.

Animals↗
PubMed1992

Effect of ICRF-187 on the pulmonary damage induced by hyperoxia in the rat.

Histological and ultrastructural studies were made of the lungs of rats that were exposed to 100% oxygen for 60 h and were treated with either normal saline or with ICRF-187, a bis-diketopiperazine derivative of EDTA that has the capacity to chelate iron. This metal is thought to be needed to catalyze the formation of toxic oxygen free radicals. ICRF-187 (20 mg/kg) was given intraperitoneally at approximately 12 h intervals (5 doses) during the 60 h exposure. Seven of the ten saline-treated rats exposed to oxygen died prior to the end of the study whereas only one of the 10 rats in the ICRF-187-treated group died. This difference in mortality is found to be statistically significant (P less than 0.05). All saline-treated rats showed light and electron microscopic evidence of pulmonary damage. ICRF-187 attenuated the morphologic alterations observed by light microscopy (intra-alveolar edema, inflammatory exudates and bronchiolar epithelial cell swelling and hyperplasia; P less than 0.05). In addition, electron microscopic evaluation revealed that capillary thrombi, endothelial cell alterations and alveolar epithelial cell damage also were less severe in ICRF-187-treated rats. It is concluded that ICRF-187 may provide a new and useful approach for the prevention of hyperoxia-induced pulmonary damage.

Animals↗
PubMed1989

Effects of ICRF-187 on the cardiac and renal toxicity of epirubicin in spontaneously hypertensive rats.

A study was made of the protective effect of ICRF-187 against the cardiotoxicity and nephrotoxicity produced by epirubicin in spontaneously hypertensive rats (SHR). A total of 20 SHR were divided into 4 groups of 5 animals; the first group received i.v. injections of 1.5 mg/kg epirubicin; the second was treated with i.p. injections of 50 mg/kg ICRF-187 30 min before receiving 1.5 mg/kg epirubicin; the two remaining groups received ICRF-187 and saline, respectively, and served as controls. The experiment was terminated after 12 weekly injections (total cumulative dose of epirubicin, 18 mg/kg). Morphologic studies showed that severe cardiomyopathy manifested by myofibrillar loss and dilatation of the sarcoplasmic reticulum and nephropathy characterized by tubular dilatation and atrophy, protein casts in the lumina of renal tubules, and glomerular vacuolization occurred in SHR given epirubicin alone. Animals receiving the combination of ICRF-187 and epirubicin showed a marked reduction in the severity of cardiomyopathy and a moderate reduction in nephropathy. These changes, and their modification by ICRF-187, were similar to those we have previously observed in SHR treated with total cumulative doses of 12 mg/kg doxorubicin. Such pathologic changes were absent in animals receiving ICRF-187 or saline alone. The findings of this study suggest that ICRF-187 can be used clinically to prevent the cardiotoxicity of epirubicin, particularly in situations in which this drug may have to be given either in large doses or to patients at high risk of developing anthracycline cardiotoxicity.

Animals↗
PubMed1989

A comparative study of minoxidil-induced myocardial lesions in beagle dogs and miniature swine.

Minoxidil, a long-acting vasodilating antihypertensive agent, reduces arterial blood pressure by a direct action on arteriolar smooth muscle. The present studies examined the gross anatomic, histologic and ultrastructural myocardial alterations produced by 2 daily doses of minoxidil in beagle dogs (0.5, 1, or 3 mg/kg) and miniature swine (1, 3, or 10 mg/kg). Both myocardial necroses and hemorrhages were observed in dogs and pigs 24 hr after the last dose of minoxidil. In both species, the necroses were most frequent in the left ventricular papillary muscles, particularly the posterior one, but were less severe in swine. An ischemic origin of the necroses was suggested by the location of the lesions and by the pharmacologic effects of minoxidil. Gross epicardial or endocardial hemorrhages involving the atria and, to a lesser extent, the ventricles were observed in both species but were more severe in dogs. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasated erythrocytes and infiltration of mononuclear cells. Hemorrhages, occurring on the epicardial surfaces, were often associated with lesions that involved small arteries having 3-6 layers of medial smooth muscle cells and were characterized by endothelial injury, intramural accumulations of erythrocytes and platelets, periadventitial hemorrhage, fibrin deposits and an inflammatory cell reaction. These lesions preferentially involved the right atrium in dogs and the left atrium in pigs. Pretreatment of beagle dogs with pyribenzamine (3 doses of 6 mg/kg every 8 hr), cimetidine (3 doses of 15 mg/kg every 8 hr), or both, had no effect on the incidence or severity of minoxidil-induced hemorrhagic lesions. The hemorrhagic lesions may be caused by overstretching of the vascular walls due to excessive, prolonged vasodilatation.

Animals↗
PubMed1988

Effect of pretreatment with ICRF-187 on the total cumulative dose of doxorubicin tolerated by beagle dogs.

Studies were made of the influence of ICRF-187 on the functional and morphological effects of very large cumulative doses of doxorubicin given over a prolonged period of time. Adult beagles of either sex (6.2-11.6 kg) were given doxorubicin (1.75 mg/kg i.v.) either alone or 15 min after ICRF-187 (25 mg/kg, i.v.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg, i.v.) or 0.9% saline without doxorubicin. Of eight animals receiving doxorubicin alone, five died; two after a total dose of 12.25 mg/kg and three after 14 mg/kg; three others were in poor condition at the time of euthanasia after 14 mg/kg. Of eight animals receiving both ICRF-187 and doxorubicin, four died; two after 35 mg/kg, one after 43.75 mg/kg, and one after 52.5 mg/kg; two other dogs were euthanized after 43.75 mg/kg because of difficulties encountered in giving i.v. injections, and two dogs survived a total dose of 52.5 mg/kg. All control dogs survived. None of the treatment or control groups developed consistent echocardiographic changes or alterations in mean arterial pressure. By 300 days after onset of treatment, dogs given ICRF-187 and doxorubicin developed significant prolongation of the PQ interval; by 550 days, surviving dogs in this group developed ventricular premature contractions. Each animal receiving doxorubicin alone had severe myocardial lesions (lesion score 3+). Of the animals given ICRF-187 and doxorubicin, one that received 35 mg/kg doxorubicin had no lesions; of four given 43.75 mg/kg, three had no lesions and one had minimal lesions (lesion score 1+); of three given 52.5 mg/kg, one had minimal (lesion score 1+), and two had moderate (lesion score 2+) lesions. Control animals had no myocardial lesions. Thus, ICRF-187 provided significant protection when administered with doxorubicin over a period of 90 weeks, and made it possible to give doses of doxorubicin which otherwise would have been lethal.

Animals↗
PubMed1988

Influence of minoxidil on myocardial hemodynamics, regional blood flow, and morphology in beagle dogs.

Studies were made of the effects of two doses of minoxidil (3 mg/kg), given 24 hours apart, on cardiovascular hemodynamics, regional myocardial blood flow, and cardiac morphology in beagle dogs. Minoxidil caused increases in mean right atrial and left ventricular end-diastolic pressure. Systemic and pulmonary vascular resistance were reduced; cardiac output was increased. Left ventricular stroke work and the systolic pressure time index were unchanged by monoxidil administration. The diastolic pressure time index and ratio of diastolic/systolic pressure time index were decreased by minoxidil. Regional myocardial blood flow, measured with radioactive microspheres, increased in all regions of the heart except to the left ventricular papillary muscles. Minoxidil increased blood flow to left ventricular subendocardial tissue; however, this increase was significantly less than that observed in corresponding areas of subepicardial tissue, thus reducing the subendocardial/subepicardial tissue blood flow ratio. These results suggest that minoxidil is an effective peripheral vasodilator but may result in inadequate subendocardial perfusion. Morphologic studies disclosed two types of minoxidil-induced cardiac lesions: left ventricular papillary muscle necroses, and hemorrhagic lesions which were most prominent in right atrium and were associated with inflammation, intramural hemorrhage, and fibrinoid necrosis of small arteries. The papillary muscle necrosis were attributed to hypoxia. The atrial lesions were not of ischemic or hypoxic origin, because minoxidil did not decrease blood flow to atrial tissue. It is suggested that the atrial lesions are related to excessive vasodilation.

Animals↗
PubMed1988

Protective effect of ICRF-187 on doxorubicin-induced cardiac and renal toxicity in spontaneously hypertensive (SHR) and normotensive (WKY) rats.

Loss of body weight, cardiomyopathy, and nephropathy were the main toxic manifestations found when male spontaneously hypertensive rats (SHR) and genetically related Wistar-Kyoto (WKY) rats were given 1 mg/kg doxorubicin iv once a week for 12 weeks. Each of these alterations was more severe in SHR. The most profound effects on body weight were observed from the 7th to the 12th week of dosing. During this period the body weight of SHR declined to preinjection control levels. Weight loss also occurred in WKY given doxorubicin, but was not as profound. Pretreatment with 25 mg/kg ICRF-187 ip attenuated the doxorubicin-induced loss in body weight in both types of animals. The frequency and severity of cardiac and renal lesions were graded on a score of 0 to 4. Alterations were found in hearts of all SHR and four of five WKY given doxorubicin alone. Cytoplasmic vacuolization and myofibrillar loss were more severe in SHR (average score, 2.6) than in WKY (average score, 1.0). At the end of the study mean arterial pressure was also decreased in SHR which had received doxorubicin alone. Pretreatment with ICRF-187 significantly attenuated the severity of the lesions in both SHR (average score, 1.0) and WKY (average score, 0); mean arterial pressure was higher in SHR treated with ICRF-187 and doxorubicin than in saline-treated SHR. Renal alterations, including glomerular vacuolization and tubular dilatation, were found in both strains of rats (average scores, 4.0 in SHR and 3.0 in WKY). ICRF-187 also reduced the severity of renal lesions (average scores, 2.0 in SHR and 1.0 in WKY). Thus, although ICRF-187 significantly alters myocardial, renal, and body weight effects of doxorubicin in both strains of rats, these toxic effects are more severe in SHR than in WKY. SHR provide an useful animal model for the critical examination of agents with potential protective activity against doxorubicin-induced toxicity.

Animals↗
PubMed1988

Examination of minoxidil-induced acute cardiotoxicity in miniature swine.

Minoxidil, a vasodilating antihypertensive agent, was given orally in doses of 1, 3 or 10 mg/kg to miniature swine on 2 consecutive days. Mean arterial pressure decreased and heart rate increased most consistently after the 10 mg/kg dose. However, all 3 doses of minoxidil induced myocardial hemorrhages and/or left ventricular papillary muscle necrosis within 24 h after the second dose. Necrosis, characterized by hypercontraction of muscle cells and myofibrillar damage, occurred in 1 of 8 pigs given 1 mg/kg, 3 of 13 given 3 mg/kg and 7 of 14 given 10 mg/kg of minoxidil. The pharmacological effects of minoxidil, hypotension and reflex tachycardia, probably led to ischemia and necrosis in left ventricular papillary muscles. Gross hemorrhages involving the left atrium and to a lesser extent the left ventricle were found in 4 of 8 pigs given 1 mg/kg, 9 of 13 given 3 mg/kg and 11 of 14 given 10 mg/kg of minoxidil. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasation of erythrocytes and infiltration of areas around small arteries and arterioles with acute and chronic inflammatory cells. The hemmorhagic areas were concentrated along the epicardial surfaces, and to a lesser extent along the endocardial surfaces. Atrial lesions induced by minoxidil preferentially involve the left atrium in pigs and the right atrium in dogs. These differences may be related to the anatomic patterns of coronary circulation in the 2 species.

Administration, Oral↗
PubMed1988

Pretreatment with ICRF-187 allows a marked increase in the total cumulative dose of doxorubicin tolerated by beagle dogs.

To study the influence of ICRF-187 on the functional and morphological effects of very large cumulative doses of doxorubicin, adult beagle dogs were given doxorubicin (1.75 mg/kg i.v.) either alone or 15 min after ICRF-187 (25 mg/kg, i.v.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg, i.v.) or 0.9% saline without doxorubicin. Of eight animals receiving doxorubicin alone, two died after a total dose of 12.25 mg/kg and three died after 14 mg/kg; three others were in poor condition at the time of euthanasia after 14 mg/kg. Of eight animals receiving both ICRF-187 and doxorubicin, one died after 35 mg/kg, two died after 43.75 mg/kg and one died after 52.5 mg/kg; two dogs were euthanatized after 43.75 mg/kg because of difficulties encountered in giving i.v. injections, and two dogs survived a total dose of 52.5 mg/kg. All control dogs survived. None of the treatment or control groups developed consistent echocardiographic changes or alterations in mean arterial pressure. Dogs given ICRF-187 and doxorubicin developed PQ interval prolongation after 300 days and ventricular premature beats after 500 days. Each animal receiving doxorubicin alone had severe myocardial lesions (lesion score 3+). Of the animals given ICRF-187 and doxorubicin, one that received 35 mg/kg doxorubicin had no lesions; of four given 43.75 mg/kg, three had no lesions and one had minimal lesions (lesion score 1+); of three given 52.5 mg/kg, one had minimal (lesion score 1+) and two had moderate (lesion score 2+) lesions. Control animals had no myocardial lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Reduction of chronic doxorubicin cardiotoxicity in beagle dogs by bis-morpholinomethyl derivative of razoxane (ICRF-159).

Addition of morpholinomethyl substituents to razoxane (ICRF-159) produced a compound (bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-propane (MM-159) considerably more water-soluble than razoxane. The increased solubility allowed MM-159 to be examined for protective activity against chronic doxorubicin (DXR) cardiotoxicity. Adult beagle dogs of either sex were given, i.v. at 3-week intervals, either DXR (1.75 mg/kg) alone or DXR 15 min after MM-159 (25 mg/kg). Control animals received MM-159 (25 mg/kg) or saline without DXR. The experiment was terminated 3 weeks after the ninth injection (total DXR dose, 15.75 mg/kg). Of the eight animals given DXR alone, five died after receiving seven to eight injections (12.25-14 mg/kg DXR) and the remaining three were killed after eight injections because they were in poor condition. Marked ascites was noted in four of these eight dogs. When frequency and extent of myocardial lesions (vacuolation and myofibrillar loss) were assessed on a scale from 0 to 4+, severe lesions (3+) were present in all eight dogs given DXR alone, but no abnormalities (lesion score 0) were found in the hearts of three of eight dogs given MM-159 and DXR and the five remaining animals in this group had minimal (1+; four dogs) or mild (2+; one dog) alterations. DXR reduced the erythrocyte count, hemoglobin, and hematocrit when administered alone, but not in combination with MM-159. Such protection against DXR hematologic effects was not noted previously when dogs were pretreated with ICRF-187, the d-isomer of razoxane, despite the fact that pretreatment with ICRF-187 was as effective as MM-159 in reducing chronic DXR cardiotoxicity. It remains to be determined whether there are other differences in biological activity between MM-159 and ICRF-187.

Animals↗
PubMed1986

Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits.

The long-term protective effect of ICRF-187 against chronic daunorubicin cardiotoxicity was examined. Rabbits were given 3.2 mg daunorubicin/kg, with or without pretreatment with 25 mg ICRF-187/kg, once every 3 weeks over an 18-week period (6 doses). The experiment was terminated 3 months after the last treatment. At this time, all seven rabbits given daunorubicin alone had evidence of myocardial alterations ranging from minimal (2 animals) to mild (5 animals). Pretreatment with ICRF-187 caused a significant reduction in both the incidence and the severity of cardiac lesions. Hearts from the majority (5 of 7) of animals given the combination of ICRF-187 and daunorubicin were normal; myocardial alterations were minimal in the remaining rabbits treated with ICRF-187. In previous studies ICRF-187 was found to cause a reduction in cardiotoxicity 1-3 weeks after the final anthracycline dose. The results of the present study demonstrate that pretreatment with ICRF-187 provides prolonged protection against the cardiomyopathy, as opposed to producing only a delay in the appearance of cardiac alterations.

Animals↗
PubMed1986

Effect of selenium deficiency on the chronic toxicity of adriamycin in rats.

The effect of selenium deficiency on the chronic toxicity of adriamycin was examined in rats fed diets adequate in vitamin E. Selenium-deficient and selenium-supplemented diets were fed to rats for 10 wk, after which groups of 10 rats fed each diet were given weekly intravenous injections of adriamycin in saline at doses of 0, 0.5 or 1.0 mg/kg body weight for 12 wk. All rats were killed at 24 wk. Even though the cardiac glutathione peroxidase activity in the selenium-deficient group was less than 1% of that of the selenium-supplemented group, the severity of the adriamycin-induced cardiomyopathy was similar in both groups. However, the selenium-deficient rats were more sensitive to the growth-inhibiting effect of the higher dose of adriamycin than the selenium-supplemented rats. Moreover, the lower dose of adriamycin caused a mild nephropathy in 70% of the deficient rats but affected only 10% of the supplemented rats. Selenium status may have to be considered when adriamycin is used as a chemotherapeutic agent.

Animals↗
PubMed1986

Mechanism of the protective activity of ICRF-187 against alloxan-induced diabetes in mice.

ICRF-187, (+)-1,2-bis(3,5-dioxopiperazine-1-yl)propane, has been shown to protect against alloxan diabetes (el-Hage et al., 1981). Since alloxan-induced pancreatic beta cell damage is thought to be mediated through the generation of highly reactive oxygen radicals by a metal catalyzed reaction involving both superoxide anion and hydrogen peroxide, in the present study the protective activity of ICRF-187 was compared with that of free radical scavengers, microsomal enzyme inhibitors and chelating agents. The free radical scavengers DMSO, vitamin E and WR2721 markedly reduced alloxan-induced hyperglycemia. ICRF-187 was found not to interact with superoxide anions, and there is no evidence to indicate that any of the known biological effects of ICRF-187 are mediated through free radical scavenging activity. SKF-525 and cimetidine, known inhibitors of drug metabolizing enzymes, also protected against the diabetogenic action of alloxan. Since it was found that ICRF-187 did not alter hexobarbital sleeping time, this compound must protect by a mechanism other than microsomal enzyme inhibition. Since the chelating agents EDTA and DETAPAC were found to protect against alloxan diabetes, ICRF-187 or its hydrolytic products, which are structurally similar to EDTA, could function as chelating agents. Transitional metals such as iron, zinc and copper were found to bind preferentially to a hydrolysis product of ICRF-187. Chelation of iron by ICRF-187 or its hydrolytic products could decrease in vivo formation of reactive oxygen radicals and provide a means for protecting against chronic anthracycline cardiotoxicity and alloxan diabetes.

Alloxan↗
PubMed1985

Comparison of the severity of the chronic cardiotoxicity produced by doxorubicin in normotensive and hypertensive rats.

A comparison was made of the severity of chronic doxorubicin cardiotoxicity in adult male spontaneously hypertensive rats (SHR) and in genetically related normotensive Wistar-Kyoto rats (WKY). Groups of SHR and WKY were given 12 weekly iv injections of doxorubicin at 0.25, 0.5, or 1.0 mg/kg. When the study was concluded, mean arterial pressure was 127 to 161 nm Hg in doxorubicin-treated SHR compared with 74 to 87 mm Hg in similarly treated WKY. Lesions, consisting mainly of cytoplasmic vacuolization and myofibrillar loss, were noted in the hearts from both types of rats given the 1.0-mg/kg dose and were considerably more severe in SHR than in WKY (average scores 3.8 and 2.0). Renal lesions (glomerular vacuolization and dilatation of tubules with accumulations of proteinaceous material) were of comparable severity in both types of rats at the 9- and 12-mg/kg cumulative doses; however, they were more severe in SHR at the 6-mg/kg cumulative dose. Moderate cardiac alterations were present in all SHR (average score 1.6) given 0.5 mg doxorubicin/kg; at the same dose, lesions were minimal in two and absent in three WKY. In a second study, groups of rats were killed 1 week after 3,6,9, or 12 weekly iv injections of doxorubicin (1.0 mg/kg). Myocardial lesions were noted initially in SHR after six doses and in WKY after nine doses. Three of five SHR were dead by the 12th dose. These results indicate that spontaneously hypertensive rats are much more sensitive than normotensive rats to the cardiotoxic effects of doxorubicin.

Animals↗
PubMed1985

Influence of the diabetic state on isoproterenol-induced cardiac necrosis.

Isoproterenol-induced myocardial necrosis was examined in male mice with alloxan-induced and genetically transmitted diabetes. Ten days after alloxan treatment, mice exhibited an elevation in blood glucose concentrations, weight loss, polyuria and decreased heart rates (510 +/- 15 v. 675 +/- 11 beats/min) compared with matched control mice. Similarly, genetically diabetic mice exhibited lower heart rates than the corresponding age-matched controls (383 +/- 30 v. 603 +/- 30 beats/min). In comparison to matched controls, both groups of diabetic mice had a significant decrease in the severity of the cardiac necrosis which was induced by the administration of isoproterenol. The reduction in isoproterenol-induced cardiac lesions was similar in mice with chemically induced diabetics and mice with genetically transmitted diabetes. Biochemical studies of ventricular slices revealed no change in basal cAMP levels and no differences in isoproterenol-induced changes in cAMP levels in mouse hearts from both models of diabetes. Insulin treatment corrected the chemically induced diabetic state and restored the cardiotoxic potential of isoproterenol.

Animals↗