Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in balloon-injured rat carotid arteries.

PURPOSE: To determine whether perivascular delivery of paclitaxel prevents luminal narrowing after balloon injury by inhibiting intimal hyperplasia. MATERIALS AND METHODS: Immediately after balloon injury of the entire left common carotid artery, three slow-release formulations of paclitaxel or control formulations without drug were applied around a distal segment of the artery. The noninjured right carotid arteries were evaluated as a control. The animals were maintained for 14 and 28 days (n = 5 in each group at each time interval). Histology, immunohistochemistry, and morphometric analysis were performed. RESULTS: Injured nontreated arteries exhibited a pronounced intimal hyperplasia (0.185 +/- 0.01 mm2 at 14 days and 0.189 +/- 0.01 mm2 at 28 days) and a marked reduction in luminal area (44% at 14 days and 43% at 28 days). Medial area and the number of medial cells increased by 44% and 45%, respectively, at 14 days, and by 22% and 37%, respectively, at 28 days. Injured arteries treated with perivascular paclitaxel did not show any intimal hyperplasia, and luminal area was increased in five of six groups and was unchanged in one group. These arteries had an increased medial area but they had fewer medial cells than noninjured arteries. Injured arteries treated with control implants without paclitaxel exhibited intimal hyperplasia and luminal narrowing. CONCLUSION: Perivascular slow release of paclitaxel totally inhibits intimal hyperplasia and prevents luminal narrowing after balloon injury. Because of its efficacy, perivascular paclitaxel represents a possible approach for prevention of restenosis in humans.

Autonomic nervous control of heart rate in muskrats during exercise in air and under water.

Neural control of the cardiac responses to exercise in air (running) and under water (diving) was studied in the muskrat (Ondatra zibethicus) by means of acute pharmacological blockade with the muscarinic blocker atropine and the beta-adrenergic blocker nadolol. Saline injection was used as a control. Controls running on a treadmill showed a marked increase in heart rate with exercise. Atropine-treated animals had a higher resting heart rate than controls, but heart rate still increased with running. Nadolol-treated animals had a lower resting heart rate than controls and displayed a less pronounced increase in heart rate with running than controls. Animals treated with a combination of atropine and nadolol had a resting heart rate similar to that of controls but their heart rate was unaffected by running. Thus, exercise tachycardia in muskrats is due to activation of the sympathetic system and also to a reduction in parasympathetic tone. Heart rate decreased markedly during voluntary submergence in controls but rose as muskrats swam submerged against increasing water flows. Nevertheless, diving bradycardia was still present. Free-diving bradycardia and the relative increase in heart rate with underwater exercise were abolished by atropine and unaffected by nadolol. Hence, unlike the cardiac response to exercise in air, the cardiac response to underwater exercise is due only to a reduction in parasympathetic tone. Injection of the beta-adrenergic agonist isoproterenol markedly increased heart rate in air but had little effect during voluntary and forced dives, indicating a marked decrease in the sensitivity of cardiac cells to adrenergic stimulation during submergence. These results strongly suggest that accentuated antagonism between the two branches of the autonomic nervous system occurs during diving so that parasympathetic influences on the heart predominate and inhibit any chronotropic response to adrenergic stimulation.

Effect of pharmacological blockade on cardiovascular responses to voluntary and forced diving in muskrats.

Neural control of free and forced diving bradycardia and peripheral resistance was studied in the muskrat (Ondatra zibethicus) by means of acute pharmacological blockade with the muscarinic blocker atropine, the alpha-adrenergic blocker phentolamine and the beta-adrenergic blockers nadolol and propranolol. Saline injection was used as a control. Heart rate in control animals increased before voluntary dives and dropped markedly as soon as the animals submerged. Heart rate started increasing towards the end of voluntary dives and reached pre-dive values within the first 5 s of recovery. Pre-dive and post-dive tachycardia were reduced in beta-blocked animals, emphasizing the role of the sympathetic system during the preparatory and recovery periods of voluntary dives. Diving bradycardia and the acceleration in heart rate before surfacing were abolished by atropine and unaffected by nadolol, demonstrating the importance of vagal efferent activity during diving. The results after blockade with nadolol suggest that there is an accentuated antagonism between the two branches of the autonomic nervous system during diving, so that parasympathetic influences on the heart predominate. Propranolol-treated muskrats had a higher diving heart rate than saline- and nadolol-treated animals, which may be due to a sedative effect caused by propranolol crossing the blood-brain barrier, a blockade of central catecholaminergic pathways or a peripheral neural effect, due to the anaesthetic properties of propranolol. Phentolamine did not affect diving bradycardia, indicating that diving bradycardia occurs independently of peripheral vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)