Alan S. Nies

Mechanism of adriamycin cardiotoxicity: Evidence for oxidative stress

Abstract Adriamycin is a widely used anticancer agent but the cumulative dose-dependent cardiotoxicity severely limits the use of Adriamycin in the treatment of neoplastic diseases. Recent evidence suggests that Adriamycin forms reactive free radical species which may oxidize cellular components and produce the cardiomyopathy. Sulfhydryl donors and antioxidants have been effective in preventing acute Adriamycin cardiotoxicity in animal models presumably by scavenging the free radicals generated by Adriamycin. The sulfhydryl donors, namely cysteamine and N-acetyl cysteine, do not interfere with Adriamycins antitumor activity. The results from these studies give considerable hope that the chronic cardiotoxicity from Adriamycin may be attenuated in people, thereby givinh additional therapeutic benefit from this antitumor agent.

Factors modifying the early nondiuretic vascular effects of furosemide in man. The possible role of renal prostaglandins.

Animal experiments have suggested that salt-balance, prostaglandin synthesis, and renal function are important determinants of the nondiuretic vascular effects of furosemide. To investigate the influence of these factors in humans, we studied 10 normal volunteers and five anephric patients. The volunteers were studied on three occasions: when on a 10 mEq/day sodium diet, on a 250 mEq/day sodium diet, and on a 10 mEq/day sodium diet with indomethacin, 200 mg/day. The anephric patients were studied immediately after dialysis. Plethysmographic methods were used to measure venous capacitance and blood flow in the calf before, and at 5, 10, and 15 minutes after furosemide, 80 mg, iv. Blood was obtained before and 15 minutes after furosemide for determination of plasma renin activity by radioimmunoassay and of plasma 6-keto-prostaglandin F1 alpha by chromatography-mass spectrometry. We found that furosemide significantly increased venous capacitance in the calf of the normal volunteers on a low salt diet. Indomethacin, high salt intake, or lack of renal function was sufficient to inhibit this effect. Plasma renin activity increased only in the group that had the increase in venous capacitance. Limb blood flow decreased gradually in the 15 minutes following administration of furosemide in the normal volunteers, regardless of salt balance or indomethacin, but remained unchanged in the anephric patients. Plasma 6-keto-prostaglandin F1 alpha was less than 30 pg/ml in all samples. Indomethacin concentration averaged 1.3 micrograms/ml in volunteers on the drug. To determine whether indomethacin, salt intake or renal function affected another venodilator, we studied an additional group of normal and uremic volunteers who received 0.6 mg nitroglycerin sublingually.(ABSTRACT TRUNCATED AT 250 WORDS)

Canine gastric mucosal vasodilation with prostaglandins and histamine analogs.

The effect of direct intragastric artery infusion of prostaglandins E2 and I2, arachidonic acid, dimaprit (histamine H2 agonist), and 2′,2′-pyridylethylamine (histamine H1 agonist) on gastric mucosal blood flow was examined in dogs to elucidate the relationship between gastric secretory state and mucosal blood flow in dogs. These compounds were chosen because of their diverse effect on gastric acid secretion. Gastric fundus blood flow was measured both electromagnetically with a flow probe around the left gastric artery which supplies the fundus almost exclusively, and by the radioactive microsphere technique. Intraarterial infusion of all the compounds resulted in gastric mucosal vasodilation even though PGE2, PGI2, and arachidonic acid inhibit gastric acid secretion, dimaprit stimulates gastric acid secretion, and 2′,2′-pyridylethylamine does not affect gastric acid secretion. There was total agreement in the blood flow measurements by the two different techniques. Our data suggest that gastric acid secretion and gastric vasodilation are independently regulated. In addition, the validity of the studies in which the aminopyrine clearance indicates that prostaglandins are mucosal vasoconstrictors needs to be questioned because of the reliance of those measurements on the secretory state of the stomach.

Prostaglandin production by intact isolated gastric parietal cells.

An enriched population of isolated gastric parietal cells was obtained from canine gastric mucosa. Parietal cells incubated with [14C]arachidonic acid produced radiolabelled PGF2 alpha, PGE2, PGD2 and 6-keto PGF1 alpha (acid hydrolysis product of PGI2). The prostaglandin synthesis was inhibited by indomethacin. Prostaglandin production, as measured by gas chromatography-mass spectrometry demonstrated that PGF2 alpha was produced in the highest quantity followed by PGE2 and 6-keto PGF 1 alpha. This demonstrates that isolated prietal cells are capable of producing prostaglandins. Since prostaglandins have a potent effect on gastric acid secretion, local prostaglandin synthesis could modulate parietal cell function.

Prostaglandins and the control of the circulation

Clinical Pharmacology and Therapeutics (1986) 39, 481–488; doi:10.1038/clpt.1986.84

Age does not alter human vascular and nonvascular β2-adrenergic responses to isoproterenol

β‐Adrenoceptor‐mediated functions appear to diminish with aging, but the exact scope of these changes is unknown, because most studies have been limited to β1‐adrenergic cardiac phenomena. To evaluate both a vascular and a nonvascular β2‐adrenergic response in the aged, we have studied 12 healthy elderly and 12 healthy young subjects infused with increasing doses of isoproterenol and compared the change in peripheral vascular resistance, measured by venous occlusion plethysmography, and insulin release. In both groups vascular resistance fell and insulin concentrations increased. These changes were equivalent in both groups, and we therefore infer no significant decline in either of these β2‐adrenergic functions in the elderly.

Effect of beta-adrenergic blockade on circulating catecholamines and dopamine-beta-hydroxylase activity during exercise in normal subjects

We investigated the effects of beta-adrenergic blockade with propranolol (P) on circulating catecholamines at rest and during isometric and dynamic exercise. By means of a radioenzymatic assay, we measured plasma norepinephrine (NE) and epinephrine (E) concentrations in nine normal, sedentary men, aged 22 to 34 years. Measurements were made during resting conditions, at 3 minutes of 30% maximal isometric handgrip exercise (IHE), and during submaximal and maximal dynamic treadmill exercise. Measurements were repeated one week later after the subjects received P in doses ranging from 40 to 80 mg four times a day (plasma P levels at the time of exercise ranged from 96 to 303 ng/ml with a mean of 178 ng/ml). We also measured serum dopamine-beta-hydroxylase (DBH) activity to detect changes in chronic sympathetic tone. Changes in NE from rest to exercise were significant (p less than 0.01) at all exercise loads with or without P. Changes in E from rest to exercise were significant (p less than 0.01) at all exercise loads with or without P except for submaximal dynamic exercise during the control study (p greater than 0.05). For NE, there were no significant differences between the control and P values either at rest or during any form of exercise. For E, there were no significant changes between the control and p values at rest or at maximal dynamic exercise, although there were mild increases (p less than 0.05) with IHE and submaximal dynamic exercise. DBH activity increased significantly (p less than 0.01) from rest to exercise for all exercise points with and without P, but there were no significant differences between the control and p values either at rest or during any form of exercise. In conclusion, we have demonstrated that competitive blockade of beta-adrenergic receptors at the tissue level does not alter neural release of NE or DBH and has little effect on adrenal release of E.

Interaction between furosemide-induced renal vasodilation and the prostaglandin system

The effect of intravenous furosemide, 5 mg/kg, on renal hemodynamics as it relates to the prostaglandin cascade was examined in dogs. In 11 dogs the vasculature to the kidney was isolated and a femoral to renal arterial and a renal to femoral venous shunt was performed. With the use of a protein-free salt solution to perfuse the kidney for 3 minutes, the renal cortex was enriched with tritiated arachidonic acid. After blood perfusion to the kidney was re-established, the renal effluent radioactivity was followed before and after furosemide administration. Furosemide produced two types of response. In six dogs there was renal vasodilation, diuresis, and a three and one-half fold increase in renal venous radioactivity. In five dogs that were in renal failure, furosemide administration caused no change in renal effluent radioactivity. On thin-layer chromatography most of the released radioactivity by the kidney after furosemide administration traveled as arachidonic acid. In a separate seven dogs, we measured the total unesterified arachidonic acid concentration in the plasma before and after furosemide by the use of gas chromatography-flame ionization. Even though in these dogs furosemide caused a significant increase in renal blood flow and diuresis, renal venous plasma levels of arachidonic acid were unaltered. Our data suggest that furosemide causes a release of arachidonic acid from the kidney from a small pool at fast turnover lipid stores and that the stimulus for arachidonic acid release after furosemide depends on a intra-renal mechanism whereby the diuresis is coupled to the increase in renal blood flow.

The balance between vascular alpha‐ and beta‐adrenoceptors is not changed in the elderly

It has been suggested that β‐adrenoceptor‐mediated functions are diminished with aging and that these responses are reduced to a greater extent than are α‐adrenoceptor‐mediated responses. The resulting imbalance in the elderly may produce an increased vascular resistance from the unopposed α‐adrenoceptor stimulation in the peripheral vasculature. To evaluate this hypothesis, we studied 12 healthy elderly and 12 healthy young subjects during a graded infusion of epinephrine and compared blood pressure response, vascular resistance, and calf blood flow as determined by venous occlusion plethysmography. In both groups, heart rate increased, blood flow to the leg increased, and vascular resistance fell in response to epinephrine infusion, but in the elderly the systolic blood pressure failed to rise as it did in the young subjects. From these data we conclude that the overall vascular response to epinephrine does not change with age and that the balance between β‐adrenoceptor‐mediated vasodilation and α‐adrenoceptor‐mediated vasoconstriction is therefore unchanged in the elderly.

Beta‐2 adrenergic blockade evaluated with epinephrine after placebo, atenolol, and nadolol

Vascular β2‐adrenergic blocking effects of the water‐soluble drugs atenolol (β1‐selective) and nadolol (nonselective) were evaluated. Twenty‐four healthy young men were studied in three dosing groups (eight subjects per group) before and after 1 wk on placebo, atenolol (50 mg twice a day), or nadolol (40 mg twice a day). Maximal treadmill exercise heart rates were reduced to a similar degree by atenolol (−48 ± 3 bpm) and nadolol (−48 ± 4 bpm) but were not affected by placebo. Trough blood levels were 226 ± 9 ng/ml for atenolol and 43 ± 9 ng/ml for nadolol. Calf blood flow was measured with a plethysmograph and calf vascular resistance was calculated from blood pressure and flow. β2‐Adrenergic blockade was determined at rest with epinephrine infused intravenously in graded doses from 0.001 to 0.032 µg/kg/min. Mean arterial pressure and calf vascular resistance rose markedly after nadolol but not after atenolol or placebo. Marked bradycardia developed after nadolol, probably by baroreceptor stimulation. Thus at an equivalent, substantial degree of β1‐adrenergic blockade, nadolol blocks vascular β2‐adrenergic receptors and atenolol does not. Measurement of the peripheral vascular response to epinephrine infusion is an effective means of assessing the impact of β‐adrenergic blockers on vascular β2‐adrenergic receptors.