Citations

Exercise is associated with release of catecholamines and vasoactive intestinal polypeptides. Recurrent exposure to catecholamines modifies the sensitivity of adrenoceptors. To test the hypothesis that exercise training may affect the sensitivity of the epicardial coronary arteries, we performed studies on isolated coronary arteries from male dogs capable of running on a treadmill. The animals were separated randomly into two groups: sedentary and exercise training. After 11 wk, rings of left circumflex and left anterior descending coronary arteries were studied in vitro. Contractions to alpha 1-adrenergic agonists (norepinephrine and phenylephrine) were not affected by exercise training. During contractions with prostaglandin F2 alpha, endothelium-dependent relaxations to alpha 2-adrenergic agonists (norepinephrine and UK 14304) were not reduced significantly by exercise training. The concentration-relaxation curves to beta-adrenergic agonists (norepinephrine, isoproterenol, and epinephrine) were shifted to the right after training. The concentration-response curves to vasoactive intestinal polypeptide, but not that to substance P, were shifted to the right in rings with endothelium from exercise-trained animals. These findings demonstrate a decrease in responsiveness of canine vascular smooth muscle to beta-adrenergic agonists and to vasoactive intestinal polypeptide after exercise training.

Experiments were designed to determine the effect of oxygen-derived free radicals in isolated canine basilar arteries. Rings with and without endothelium were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution bubbled with 95% O2-5% CO2 (temperature = 37 degrees C; pH = 7.4). A radioimmunoassay technique was used to measure production of prostaglandins and thromboxane B2. Xanthine oxidase (1-9 mU/ml, in the presence of 10(-4) M xanthine) and hydrogen peroxide (10(-6) to 10(-4) M) caused concentration-dependent contractions. The removal of endothelium reversed these contractions into relaxations. Contractions to xanthine oxidase and hydrogen peroxide were inhibited in the presence of superoxide dismutase (150 U/ml), catalase (1,200 U/ml), indomethacin (10(-5) M), and SQ 29548 (10(-6) M) but not in the presence of deferoxamine (10(-4) to 10(-3) M) and dimethyl sulfoxide (10(-4) M). NG-monomethyl-L-arginine (3 x 10(-5) M) augmented the contractions to hydrogen peroxide. Xanthine oxidase stimulated production of 6-ketoprostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and thromboxane B2. The stimulatory effect was prevented by the removal of endothelial cells. These studies suggest that xanthine oxidase causes endothelium-dependent contractions mediated by: 1) hydrogen peroxide-induced stimulation of the endothelial metabolism of arachidonic acid via the cyclooxygenase pathway, leading to activation of prostaglandin H2-thromboxane A2 receptors, and 2) inactivation of basal production of nitric oxide by superoxide anions.

The effect of removing the airway epithelium on the responses of canine airways of decreasing diameter to contractile and relaxing agonists was explored. Three orders of canine bronchus were studied: second order (lobar bronchus), third order (segmental bronchus), and fourth order (subsegmental bronchus). Paired rings of tissue, with and without epithelium, were placed in organ chambers in physiological salt solution gassed with 95% O2–5% CO2 and maintained at 37 degrees C. For second- and third-order bronchi, epithelium removal caused significant left-ward shifts of the concentration-effect curves for 5-hydroxytryptamine, histamine, and acetylcholine. In fourth-order bronchi, there was no significant shift for any of the contractile agonists. Isoproterenol (during contractions evoked by acetylcholine) induced concentration-dependent relaxations that were significantly greater in bronchi with than in those without epithelium. This effect was most prominent in fourth-order bronchi. These results suggest that 1) the canine airway epithelium releases a relaxing factor, 2) in larger airways the major effect is reduction of contractile responses, and 3) in smaller airways the major effect is enhancement of relaxing responses.

Responses to arachidonate were examined in rings with and without epithelium of lobar, segmental, and subsegmental canine bronchi. Arachidonate evoked epithelium-dependent relaxations, which were less pronounced in subsegmental bronchi and abolished by indomethacin and meclofenamate. Nordihydroguairetic acid (NDGA) and nafazatrom reduced epithelium-dependent relaxations only in lobar but unmasked epithelium-independent relaxations to arachidonate in all bronchi. Prostaglandin E2 and prostacyclin relaxed all tissues similarly. In lobar bronchi without epithelium, basal release of prostaglandin E2 was reduced by indomethacin but unaffected by NDGA. Arachidonate augmented prostaglandin E2 release more in subsegmental than in lobar bronchi with epithelium; in bronchi without epithelium the rise was absent (lobar) or attenuated (subsegmental). Arachidonate augmented the release of 6-ketoprostaglandin F1 alpha more in lobar bronchi with than without epithelium; this was inhibited by indomethacin, but not NDGA. Thus arachidonate releases prostaglandin E2 (possibly produced by cyclooxygenase inaccessible to inhibitors and activated by lipoxygenase products) but not prostacyclin from the epithelium. Heterogeneity in response to arachidonate is not due to different sensitivity to, or production of, prostaglandins.

Experiments were designed to determine whether the airway epithelium affects the membrane potential of the underlying smooth muscle. The effect of epithelium removal (by gentle rubbing) on the responsiveness of isolated canine bronchi was studied. Simultaneous recordings of mechanical and electrical activity were made in paired circumferential strips (with and without epithelium) of third-order bronchi. Changes in tension were recorded with a force transducer, and changes in membrane potential were measured with a microelectrode. The cell membrane potential and resting tension of the bronchial smooth muscle were stable over a 150-min period and were not affected by removal of the epithelium. In the presence of antagonists at muscarinic and adrenergic receptors, the resting tension and membrane potential were comparable in preparations with and without epithelium. By contrast, the anticholinesterase, echothiophate, caused depolarization in bronchi without epithelium. Exposure to high potassium induced similar levels of depolarization and contraction in tissues with and without epithelium. No significant differences in threshold for depolarization or for mechanical activation in the membrane potential-tension relationship were noted in the presence or absence of epithelium. In the presence of echothiophate, removal of the epithelium augmented the contraction of the bronchi to acetylcholine; the depolarization of the cell membrane induced by the cholinergic transmitter was significantly larger than in control tissues, even when matched contractions were compared. These observations indicate that the respiratory epithelium generates an inhibitory substance that dampens depolarization and contraction of bronchial smooth muscle caused by acetylcholine.

Ten normal subjects performed a 90-s isometric exercise [20, 30, and 40% of maximal voluntary contraction (MVC) of the flexor muscle of the right index finger or quadriceps muscle of the right leg. Contralateral forearm and calf blood flows (strain gauge plethysmography) and arterial blood pressure (auscultation) were measured simultaneously. Each exercise caused a decrease in forearm vascular resistance and a progressive increase in calf resistance. These changes were greatest with the 40% MVC. With finger exercise at 20 and 40% MVC, the percentage decreases in forearm vascular resistance from control were 12.3 and 22.7%, respectively (P less than 0.01). Similar decreases (9.5 and 24.9%, respectively; P less than 0.01) were noted with exercise of the quadriceps muscle. By contrast, the corresponding increases in calf vascular resistance were greater (P less than 0.01) with quadriceps exercise (13.3 and 55.4%, respectively) than with finger exercise (6.0 and 36.0%). Arrest of the circulation to the exercising muscles just before the exercise ended caused an abrupt increase in forearm vascular resistance and a decrease in calf resistance. These studies provide further evidence of the heterogeneity of responses of forearm and calf resistance vessels to certain cardiovascular stimuli.

Experiments were conducted in canine bronchi to determine whether the effect of epithelium removal on relaxations was affected by the contractile agent used to induce active force and the degree of contraction. Pairs of fourth-order bronchi with and without epithelium were suspended in organ chambers in physiological salt solution (95% O2-5% CO2, 37 degrees C). The bronchi were contracted to the concentration of acetylcholine or 5-hydroxytryptamine that resulted in a contraction that was 40 or 80% of the response to 10(-4) M of the agonist (ED40 or ED80). Epithelium removal reduced relaxations to isoproterenol and sodium nitroprusside during contraction to the ED80 but not the ED40 of acetylcholine. Responses to forskolin were not affected. Bronchi were significantly more sensitive to relaxing agonists in the presence of 5-hydroxytryptamine; there was no effect on epithelium removal or level of contraction. Thus 1) the influence of epithelium on bronchial relaxation is greatest during high degrees of cholinergic tone and 2) experimental conditions influence the effect of epithelium removal on relaxation.

The purpose of this study was to characterize the adrenergic and cholinergic responsiveness of isolated rings of canine bronchial arteries. Electrical stimulation of the vessels produced frequency-dependent contractions that were inhibited by phenoxybenzamine, tetrodotoxin, and phentolamine but not by atropine. Norepinephrine caused concentration-dependent contractions of the rings; the concentration-response curve to norepinephrine was shifted to the right by phentolamine and prazosin, whereas rauwolscine had no effect. Isoproterenol, norepinephrine, tyramine, and electrical stimulation (in the presence of phentolamine) failed to elicit relaxation in rings contracted with prostaglandin F2 alpha. Contracted rings relaxed to acetylcholine in an endothelium- and concentration-dependent manner. At concentrations up to 10(-4) M, acetylcholine did not evoke contractions in these tissues. Endothelium-dependent relaxation to acetylcholine was inhibited by atropine and 4-diphenyl-acetoxy-N-methyl piperidine methiodine but not by pirenzepine. These results suggest that alpha 1-adrenoceptors mediate contraction to norepinephrine, and M3-muscarinic receptors mediate endothelium-dependent relaxation to acetylcholine in the canine bronchial artery. Moreover, the smooth muscle of these vessels does not respond directly to beta-adrenergic- or cholinergic-receptor stimulation.

Experiments were designed to compare the reactivity of canine basilar arteries to endothelium-derived relaxing factor (EDRF) and nitric oxide. Preparations with endothelium activated by bradykinin were used to study relaxations induced with EDRF, whereas the inhibitory effect of nitric oxide was studied in preparations without endothelium. All experiments were performed in the presence of indomethacin. EDRF- and nitric oxide-induced relaxations were significantly augmented in the presence of superoxide dismutase plus catalase but were reduced in the presence of methylene blue, LY 83583, and hemoglobin. M & B 22984 did not affect relaxations to either EDRF or nitric oxide. These results indicate that in the canine basilar artery EDRF is not an oxygen-derived free radical. The similar responsiveness of the basilar artery to EDRF and nitric oxide is consistent with the proposal that in the canine basilar artery nitric oxide is the factor.

Experiments were designed to compare the sensitivity of venous and arterial smooth muscle to endothelin and to determine whether contractions to the peptide could be inhibited by endothelium-derived relaxing factor and nitric oxide. Rings of canine left anterior descending coronary, femoral, and mesenteric arteries and femoral and saphenous veins with and without endothelium were suspended for measurement of isometric force. In the presence of indomethacin, phentolamine, and propranolol, endothelin initiated concentration-dependent increases in tension in all rings. The veins were more sensitive to the peptide than were the arteries. Endothelin depolarized the smooth muscle of the saphenous veins and mesenteric arteries; the threshold concentration for depolarization was approximately 100 times lower in the veins (10(-10) M) than in the arteries (10(-8) M). Removal of the endothelium enhanced the sensitivity only of venous smooth muscle to endothelin. However, stimulation of the endothelium in the arteries with either acetylcholine or the calcium ionophore A23187 rapidly inhibited the maximal tension developed to the peptide. Nitric oxide inhibited contractions to endothelin in arteries and veins without endothelium; the inhibition was greater in the arteries than in the veins. These results indicate that venous smooth muscle is more sensitive than arterial smooth muscle to endothelin. In both blood vessels, endothelium-derived relaxing factor(s) can inhibit contractions to the peptide.