ABSTRACT
Doxorubicin (DXR) is a common antineoplastic agent whose clinical utility is limited by development of a dose-related cardiomyopathy. Recent studies demonstrating DXR toxicity in skeletal muscle suggest that this compound may in fact be a general depressant of muscle function. Although previous studies have reported possible indirect actions of DXR on blood vessels, we have investigated the direct effects of this agent on vascular smooth muscle. Chronic, low-dose treatment of rats with intraperitoneal DXR (12 mg/kg total dose over 4 weeks) had no significant effect on body or heart weight, left ventricular water or calcium content, or aortic water or calcium content. Contractile responses to norepinephrine of thoracic aortic strips taken from DXR-treated rats were attenuated by this treatment, and sensitivity (EC50) of these strips to norepinephrine was significantly reduced compared to controls. These results suggest that DXR may have physiological effects on vascular smooth muscle function at doses which produce no signs of toxicity in cardiac muscle.
Subject(s)
Calcium/metabolism , Doxorubicin/pharmacology , Muscle, Smooth, Vascular/drug effects , Norepinephrine/pharmacology , Animals , Aorta/drug effects , Body Weight/drug effects , Dose-Response Relationship, Drug , Male , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/metabolism , Rats , Rats, Inbred StrainsABSTRACT
The vascular effects of several purine compounds were evaluated using isolated arteries from bovine heart and tongue. At almost all concentrations tested, adenosine, AMP, ADP, ATP, guanosine, GMP, GDP and inosine produced significant relaxation of the lingual artery. In general, these compounds were much less effective in the coronary artery. Dipyridamole and nitrobenzylthioinosine (NBMPR), compounds which block the cellular uptake of nucleosides, partially prevented the actions of these compounds in the lingual artery but not in the coronary artery. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a potent inhibitor of adenosine deaminase also altered the relaxant effect of adenosine. These results suggest that at least part of the action of purine compounds on the vascular smooth muscle of the lingual artery is a result of an intracellular effect.
Subject(s)
Blood Vessels/drug effects , Purine Nucleosides/pharmacology , Purine Nucleotides/pharmacology , Adenine/analogs & derivatives , Adenine/pharmacology , Animals , Arteries/drug effects , Cattle , Coronary Vessels/drug effects , Dipyridamole/pharmacology , Drug Interactions , In Vitro Techniques , Thioinosine/analogs & derivatives , Thioinosine/pharmacology , Tongue/blood supplyABSTRACT
Surgical specimens of human vas deferens, mounted isometrically in vitro, were tested for their reactivity to norepinephrine, the major neurohumoral control mechanism in this tissue, under a variety of conditions. There was no significant difference in reactivity (measured as amplitude and frequency of contraction) between vasa obtained under either spinal or local anesthesia. Similarly, the age of the donor (range, 20 to 79 years) had no effect on either measure of reactivity. Prostaglandins A1 (10(-7) gm/ml) and E2 (10(-9) gm/ml), Escherichia coli (10(5) organisms/ml), and E. coli endotoxin (10(-7) gm/ml) did not affect norepinephrine responses, suggesting that the role of these compounds in problems of fertility is not related to an alternation in sperm transport through the vas. Nitrofurantoin (10(-5) gm/ml) also had no effect on reactivity to norepinephrine, providing further evidence that low sperm counts in patients taking this drug are more appropriately attributed to a direct effect on spermatogenesis than to an effect on sperm transport.
Subject(s)
Escherichia coli , Nitrofurantoin/pharmacology , Norepinephrine/pharmacology , Prostaglandins A/pharmacology , Prostaglandins/pharmacology , Vas Deferens/drug effects , Endotoxins/pharmacology , Enterotoxins/pharmacology , Humans , Male , Muscle Contraction/drug effects , Prostaglandins E/pharmacology , Vas Deferens/physiologyABSTRACT
The vascular effects of ethanol were evaluated using isolated arteries from bovine brain, eye, and kidney. Ethanol induced contraction in all vessels, but only at concentrations in excess of lethal blood levels in man. At a concentration approximating that found in the blood during intoxication (43 mM), ethanol had no effect on renal vascular responses to norepinephrine, serotonin, or histamine. The response of ocular vessels to norepinephrine and histamine was significantly diminished by 43 mM ethanol, suggesting a possible mechanism underlying the "bloodshot" eyes found in acute intoxication. Cerebral vascular responses to vasoactive agents were generally unaffected by 43 mM ethanol, indicating that regional differences in brain perfusion are probably not a cause of the behavioral changes found during intoxication.
