Integration of baroreflex and autoregulation control of bronchial blood flow in awake dogs.

AIM: Baroreflex control of the bronchial circulation is unresolved. Early studies suggested that baroreflexes dilate or have no effect, but recent studies in awake dogs suggested baroreflexes did not normally engage tonic vasoconstrictor efferents but during excitement systemic pressure rises may also trigger local sensory-motor dilator reflexes. We examined the postulate that bronchial flow is normally regulated at rest during controlled changes in pressure gradient (Pg) by integration of tonic autonomic activity with autoregulation. METHODS: Twelve greyhounds were instrumented under general anaesthesia by surgical implantation of pulsed Doppler flow transducers on the right bronchial artery (BA). After recovery baroreflex effects were evoked by raising and lowering aortic pressure using a lower thoracic aortic balloon in 11 animals, and in six of these after cholinoceptor plus adrenoceptor blockade. RESULTS: The right BA bed showed pressure-passive responses and the time-dependent bronchial bed effects in the autonomically intact state (INT) were largely similar to those in the blocked state (TAB). When results were replotted as pressure-flow relationships and analysed using covariance, the regression line over the pressure range 70-135 mmHg for TAB demonstrated a significant slope (P < 0.05), a linear regression elevated 120% (P = 0.006) above and parallel to INT (Y(Q) = 0.034 + 0.00033(X(Pg) - 104.6). The regression fell on the line of equal proportional change. CONCLUSION: Baroreflexes do not functionally engage the autonomic outflow to the bronchial circulation. Under controlled conditions of systemic Pg change, the bronchial circulation is normally controlled by the integration of resting autonomic tone, myogenic autoregulation and pressure-passive effects.

Influence of bronchial C fibre receptors on respiration in cats: possible role in humans.

In order to find out whether the bronchial C fibre receptors influence respiration in cats, as the J receptors do, two drugs known to stimulate them consistently, i.e. phenyl diguanide (PDG) and capsaicin were injected into the left atrium (LA). The influence of these drugs, in suprathreshold doses, was seen on the intrapleural pressure (IPP), frequency of respiration (f(R)), systemic blood pressure (BP) and cardiac frequency (f(H)). PDG LA produced an inhibitory influence on respiration of a majority of cats, accompanied by a fall in BP and f(H). With capsaicin, a stimulation of respiration and a notable increase in BP (sometimes preceded by a fall also of f(H)) was seen. After blocking the epicardial/cardiac receptors with xylocaine, a local anaesthetic, the effects of PDG LA on the above variables were blocked, whereas, those of capsaicin survived--which they did, also after a bilateral vagotomy. Similar responses were obtained from injecting the drugs into the distal part of the aorta i.e. a notable stimulation of respiration by capsaicin, which survived vagotomy and hardly any effect, by PDG. It is concluded that activation of bronchial C fibre receptors does not influence respiration or BP in cats.

Autonomic control of bronchial circulation in awake sheep during rest and behaviour.

1. We tested the hypothesis that the pattern and the intensity of autonomic mechanisms causing vasoconstriction in the resting bronchial circulation of awake dogs also exists in awake sheep. It was also postulated that sighing behaviour and the associated bronchovascular dilatation induced by non-adrenergic, non-cholinergic (NANC) mechanisms observed in the dog exist in sheep. 2. Bronchial arterial blood flow to lower airways of both lungs of awake sheep was measured continuously using pulsed Doppler flow probes mounted on the bronchial artery at prior thoracotomy. 3. Cumulative and factorial analysis of responses to randomized combinations of autonomic alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors and cholinoceptor autonomic blockade suggests that resting vasoconstrictor activity is less in sheep than in dogs. At normal aortic pressure, the autonomic activity of these receptor groups in the sheep lowers bronchial blood flow and conductance by 30%, whereas in the awake dog, the corresponding autonomic effect is 50%. 4. Tonic autonomic control of bronchial conductance can be partitioned in sheep to show significant and separate alpha- and beta-adrenoceptor vasoconstrictor activity at a ratio of 1.8:1, an effect normally offset by a weaker vasodilator alpha-/beta-adrenoceptor interaction. In contrast to the situation in awake dogs, cholinoceptors do not play a role in awake sheep. 5. Nitric oxide (NO) synthase inhibition in sheep using NG-nitro-L-arginine following blockade of alpha- and beta-adrenoceptors and cholinoceptors causes hypertension, but minor changes, if any, in pulmonary pressures or heart rate. Bronchial flow and conductance, however, fall from a higher resting conductance by approximately 50%, suggesting that, normally, resting bronchial flow conductance is dominated by strong tonic NO vasodilator effects that interact with weaker tonic autonomic vasoconstrictor effects. 6. Superimposed (respiratory) behaviours of sighing, sneezing and coughing, which involve negative swings in intrathoracic pressure and the movement of inspired air, evoke large active bronchovascular dilator effects. These appear to be largely NANC in origin and appear to be dependent, in part, on mechanisms associated with NO release. It is postulated that the C-fibre axon reflex using substance P, calcitonin gene-related peptide and neurokinin A may be involved. Vocalization and eructation do not evoke bronchovascular effects.

Adrenergic and cholinergic regulation of bronchial vascular tone.

The autonomic nervous system plays a vital role in the regulation of vasomotor tone. Previous studies of systemic arteries and veins have shown that the classic autonomic neurotransmitters, norepinephrine and acetylcholine, act on smooth muscle, adrenergic nerve endings, and endothelial cells in the blood vessel wall to regulate vasomotor tone. Similar studies with isolated tissues indicate that bronchial arteries are innervated by adrenergic neurons and that norepinephrine activates postjunctional alpha 1-adrenoceptors to cause smooth muscle contraction. Isolated canine bronchial arteries fail to relax in response to beta-adrenoceptor agonists, and they do not contract when exposed to acetylcholine. This lack of responsiveness may be species-specific, however, since isolated bronchial arteries from other species respond to these agonists. Acetylcholine causes endothelium-dependent relaxation of bronchial arteries in vitro; this response is mediated by endothelial M3-muscarinic receptors. The role of the endothelium in mediating responses to adrenergic agonists, as well as the prejunctional effects of norepinephrine and acetylcholine on adrenergic nerve endings, remain to be explored in isolated bronchial arteries.

Intrapulmonary bronchial circulation during hemorrhage.

Experiments were conducted on 119 anesthetized and artificially ventilated rats to evaluate effects of a physiological stimulus (hemorrhage) to the sympothoadrenal system on the bronchial circulation. In the presence of a sufficient dose of a vasopressin V1-receptor antagonist, moderate (81 mmHg on average, 33 rats) or severe hypotension (69 mmHg, 28 rats) was produced by controlled hemorrhage (11 or 9 rats, respectively), or by treatment with phenoxybenzamine (0.1 mg/kg, i.v., 12 rats, or 1.0 mg/kg, 10 rats), or the highly selective alpha 1-adrenoceptor antagonist, bunazosin (0.01 mg/kg i.v., 10 rats, or 0.1 mg/kg, 9 rats). During hypotension, the intrapulmonary bronchial blood flow (microsphere method) was decreased in a dose-dependent manner in the two antagonist-treated groups. However, these decreases were only of a moderate degree compared to the severe decrease in the hemorrhage group. Although the bronchovascular resistance was not significantly changed after treatment with either antagonist, this variable was greatly elevated during severe hemorrhagic hypotension, reaching 240 +/- 51% (P less than 0.001 with either antagonist study) of its baseline level. Changes in the pulmonary arterial and left atrial pressures, plasma vasopressin concentration, and renin activity were found to be less influential on these responses in 58 rats. Overall, we concluded that the sympathoadrenal mechanism powerfully increased the resistance and decreased the blood flow of the intrapulmonary bronchial circulation.

Neural control of lower airway vasculature. Involvement of classical transmitters and neuropeptides.

1. SP- and CGRP-IR fibres of presumably sensory origin were abundantly located around the vasculature and glands in the laryngotracheal and bronchial mucosae of the pig. A sparse presence of CGRP- and SP-IR nerves in the tracheobronchial smooth muscle layer as well as an atropine-sensitive bronchoconstrictor response to electrical field stimulation suggested that neuropeptides locally released from sensory nerves may be related to vascular or exocrine gland function rather than to bronchial smooth muscle control. In the tracheal mucosa, many VIP-positive perivascular nerve fibres, likely to be of local parasympathetic origin, were present, whereas very few or no such fibres were found in the bronchial mucosa or in the pulmonary vascular bed. A dense innervation of the tracheobronchial and pulmonary vasculature by NPY/DBH-containing perivascular fibres suggested that the sympathetic control of these vascular beds may not only involve NA as transmitter. 2. Mainly sensory axon reflex mechanisms occurred upon systemic capsaicin injection in the pig after pretreatment with a combination of autonomic blocking agents, as revealed by plasma elevations of CGRP- and NKA-LI but not NPY-LI or catecholamines. Repeated capsaicin injections, in the presence of autonomic blocking agents, caused a marked reduction in the elevation of plasma CGRP- and NKA-LI with a clear-cut fall in the bronchial vascular response, suggesting development of tachyphylaxis for local sensory mechanisms. 3. Vasodilatory vagal mechanisms involved different neurotransmitters in the lower airway vasculature of the pig. Thus, local blood flow in the laryngo-tracheal circulation was regulated by cholinergic and non-cholinergic parasympathetic mechanisms and a small capsaicin-sensitive sensory component, while the vagal control of the bronchial circulation seemed to mainly involve capsaicin-sensitive sensory nerves. VIP and ACh were more potent as vasodilators in the laryngo-tracheal compared to the bronchial circulation. Exogenous SP was the most potent vasodilator peptide in the lower airway mucosa. SP and CGRP mimicked capsaicin-induced vasodilatation in the laryngo-tracheal and bronchial circulations. In the pulmonary circulation, vagal activation evoked atropine-sensitive vasoconstriction, probably due to sympathetic reflexes, but not vasodilatation. 4. Both NA and NPY had potent vasoconstrictor effects in the airway mucosa.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic and cholinergic responsiveness of isolated canine bronchial arteries.

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.

Immunohistochemical demonstration of enkephalin-containing nerve fibers in guinea pig and rat lungs.

Met-enkephalin (Met-Enk) and Leu-enkephalin (Leu-Enk), the opioid peptides originally isolated from the brain, are believed to act as inhibitory neuromodulators at various synaptic sites. In this immunohistochemical study, we have investigated the localization and distribution of Met- and Leu-Enk immunoreactivities in airways and pulmonary vessels of guinea pigs and rats. Immunoreactivities to both peptides were found in nerve fibers and nerve terminals distributed mainly to the trachea and major bronchi, and were especially prevalent in the smooth muscle layer, in the lamina propria, and around tracheal and bronchial glands, but not in the epithelium. Few immunoreactive nerve fibers were detected in smaller bronchi, bronchioles, and alveoli. Enkephalin-immunoreactive nerve fibers were also localized in the walls of pulmonary and bronchial vessels. Within airway microganglia, immunoreactivity was observed in a few nerve terminals, but not in ganglion cell bodies. Met- and Leu-Enk immunoreactive nerve fibers showed similar distribution patterns, though minor differences were noted between the two species: Enk-immunoreactive nerve fibers in the smooth muscle layer were more abundant in guinea pigs than in rats, whereas those in mucous glands were richer in rats than in guinea pigs. These results document the presence of Met- and Leu-Enk immunoreactivity in nerve fibers supplying guinea pig and rat airways and pulmonary vessels, and provide a morphologic basis for the view that enkephalins are likely neurotransmitters or neuromodulators in the lung.

Vagal vasodilatory mechanisms in the pig bronchial circulation preferentially involves sensory nerves.

The present study shows that in contrast to the upper trachea, where the parasympathetic vasodilatory components of both cholinergic and non-cholinergic nature are dominating, the vagal blood flow regulation in the peripheral airways of the pig supplied by the bronchial artery is entirely carried out by local release of vasodilatory mediators from capsaicin-sensitive sensory nerves. Also inhalation of the vapour phase from the major airway irritant cigarette smoke was associated with a marked increase in bronchial blood flow possibly via local axon reflexes. Capsaicin, substance P (SP) and calcitonin gene-related peptide (CGRP) caused vasodilatation in both the trachea and bronchi while vasoactive intestinal polypeptide (VIP) was most active in the trachea. These functional data were supported by immunohistochemical studies showing the presence of SP- and CGRP-containing nerves of presumably sensory origin around bronchial blood vessels while VIP-positive perivascular fibres of local parasympathetic origin were found mainly in the trachea.

Cholinergic properties of the bronchial artery and contribution of the endothelium.

Using selective agonists and antagonists, both muscarinic and nicotinic receptors were identified in the bovine bronchial artery. The helical bronchial artery strips contracted to acetylcholine and methacholine and responses to both were blocked by atropine. Nicotine contractions were blocked by both atropine and hexamethonium. Longitudinal strips responded poorly to both acetylcholine and nicotine. Sixty-five percent of pre-contracted bronchial arterial strips with intact endothelium relaxed in the presence of low concentrations of acetylcholine (1 X 10(-9)M to 1 X 10(-7)M), while those strips without endothelium did not. The presence or absence of endothelium was shown histologically, as was the identification of cholinergic fibers located in the adventitia and outer layers of the tunica media of the bronchial artery. These data confirm the hypothesis of vagal innervation of the bronchial artery and also suggest a role for the endothelium in modulating this artery's response to acetylcholine stimulation in obstructive airway diseases.