The noradrenaline stimulus has two components, one excitor, the other inhibitory. Neuronal noradrenaline is the excitor component and plasma noradrenaline is the inhibitory. The balance of effect between the two, the noradrenergic balance, is the controlled variable of the sympathetic system and determines the effect of noradrenaline. Neuronal noradrenaline stimulates tissues by diffusion from their sympathetic nerve endings, plasma noradrenaline does so by diffusion from their microcirculations. Changes in microcirculatory flow, by altering the flow mediated effect of plasma noradrenaline, are mainly responsible for altering the noradrenergic balance in the peripheral tissues; changes in CSF flow are speculated to be mainly responsible for doing the same in the brain, by altering the balance between synaptic noradrenaline in the brain and nonsynaptic noradrenaline in the subarachnoid CSF. When plasma noradrenaline alters the noradrenergic balance it triggers afferent sympathetic activity that alerts hypothalamic neurons to the event and they restore the balance and tissue homeostasis, within milliseconds, by adjusting the level of efferent sympathetic activity they project back to the affected tissue. Because the restoration is so rapid the effect of plasma noradrenaline is normally unobservable and dismissed as not having occurred. Because the hypothalamus is not involved with the responses of isolated canine lateral saphenous vein segments to noradrenaline, the effects of plasma noradrenaline in that preparation are not countered by reactive efferent activity and, consequently, are readily apparent in it. Quantitatively, they have been found to be a function of microcirculatory flow and noradrenaline concentration and, qualitatively, to be inhibitory, dilator, pro inflammatory and neurodegenerative. In life, due to a progressive increase in plasma noradrenaline concentration and, more so, in microcirculatory flow, the noradrenergic balance moves progressively in favour of the neurodegenerative and inflammatory effects of plasma noradrenaline. These observations are the basis of an hypothesis that ageing is caused by a genetically programmed shift in balance away from the growth and anti-inflammatory effects of neuronal noradrenaline, early in life, towards the neurodegenerative and pro-inflammatory effects of plasma noradrenalin, later in life. Death is believed to occur when plasma noradrenaline has damaged the structure of the sympathetic system so much that it can no longer create the minimum quantity of neurotransmitter needed to maintain the level of noradrenergic balance and homeostasis necessary for life.

Experiments on canine lateral saphenous vein segments have shown that noradrenaline causes potent, flow dependent effects, at a threshold concentration comparable to that of plasma noradrenaline, when it stimulates a segment by diffusion from its microcirculation (vasa vasorum). The effects it causes contrast with those neuronal noradrenaline causes in vivo and that, in the light of the principle that all information is transmitted in patterns that need contrast to be detected – star patterns need darkness, sound patterns, quietness – has generated the hypothesis that plasma noradrenaline provides the obligatory contrast tissues need to detect and respond to the regulatory information encrypted in the diffusion pattern of neuronal noradrenaline. Based on the implications of that hypothesis, the controlled variable of the peripheral noradrenergic system is believed to be the maintenance of a set point balance between the contrasting effects of plasma and neuronal noradrenaline on a tissue. The hypothalamic sympathetic centres are believed to monitor that balance through the level of afferent sympathetic traffic they receive from a tissue and to correct any deviation it detects in the balance by adjusting the level of efferent sympathetic input it projects to the tissue. The failure of the centres to maintain the correct balance is believed to be responsible for inflammatory and genetic disorders. When the failure causes the balance to be polarised in favour of the effect of plasma noradrenaline that is believed to cause inflammatory diseases like dilator cardiac failure, renal hypertension, varicose veins and aneurysms; when it causes it to be polarised in favour of the effect of neuronal noradrenaline that is believed to cause genetic diseases like hypertrophic cardiopathy, pulmonary hypertension and stenoses and when, in pregnancy, a factor causes the polarity to favour plasma noradrenaline in all the maternal tissues except the uterus and conceptus, where it favours neuronal noradrenaline, that is believed to cause preeclampsia. Finally, the shift in the balance caused by the slow physiological increase in plasma noradrenaline concentration in life is believed to be responsible for ageing.

Preeclampsia is an inflammatory condition, involving the pregnant mother and complicated by the presence of a growing child and a disfunctional placenta; such is its complexity that so far no one has been able to fully elucidate its pathophysiolgy. Varicose veins are an inflammatory condition also, but far simpler and localised, whose pathophysiology has recently been virtually fully established by a combination of clinical observation, animal experiment and analysis of stripped veins. They have indicated the immediate cause of inflammation is stimulation of a tissue by increased levels of plasma noradrenaline, at basal concentration, diffusing into it from its microcirculation. The hypothesis offered here applies that information and proposes the changes in the uteroplacental tissues in preeclampsia are a result of a decreased level of microcirculatory noradrenaline stimulation, and the changes in the maternal tissues are a result of an increased level. The dichotomy means any treatment likely to benefit the mother in preeclampsia is likely to harm the child and vice versa. That may explain why the spectacular therapeutic advances of the past 50–60 years have had, relatively, so little impact on the treatment of preeclampsia. However, experiments aimed at finding tissue specific drugs to treat different aspects of HIV and individual types of cancer offer some slight hope that in the long term it may be possible to at least alleviate preeclampsia, if not cure it.

This paper proposes that plasma noradrenaline plays a central role in the physiology and pathophysiology of the macrocirculation, the heart, veins and arteries. The proposal stems, in the final analysis, from the finding that noradrenaline dilates the canine lateral saphenous vein when it is released from its microcirculation, the vasa venarum. The concentration threshold of the effect is estimated to be at least eight times lower than the threshold of the constrictor effect of intralumenal noradrenaline. Combined with other evidence, the finding indicates that, contrary to opinion, plasma noradrenaline has an effective β1-agonist hormonal effect on the macrocirculation, at normal concentrations. It also indicates that noradrenaline has a bi-polar effect. The reason it has that effect is that noradrenaline is a primary biological stimulus and like all primary stimuli investigated to date, it can be expected to have two cross-inhibitory components, commonly referred to as excitor and lateral inhibitory. When examined, neuronal noradrenaline shows the features characteristic of excitor components in general and plasma noradrenaline shows those characteristic of inhibitory components. The most significant of the latter is that inhibitory components are the most potent physiological modulators of excitor components. A striking example of that modulation effect occurs in smooth muscle contraction where muscles contracted by neuronal noradrenaline stimulation appear to be incapable of relaxing without stimulation by plasma noradrenaline-hence the proposition that vascular stenosis and cardiospasm are caused by a pathological loss of plasma noradrenaline stimulation. By triggering turbulence, cholesterol plaques increase the arterial microcirculatory flow and so increase the β1-agonist effect of plasma noradrenaline. This paper proposes that this cholesterol driven increase in the microcirculatory effect of plasma noradrenaline is the cause of the arteriosclerotic syndrome, a proposition that is consistent with the success of beta-blockade in treating manifestations of the syndrome. The paper concludes by examining a variety of conditions, including dissecting aneurysms, dilator cardiac failure, angina, myocardial infarction, hypertension, eclampsia and cirrhosis and pointing out that all of them, like varicose veins, show evidence consistent with having been caused by a turbulence induced increase in a β1-agonist stimulatory effect of microcirculatory plasma noradrenaline.

Objective: To investigate the structure and function of the venous valve agger, a fibroelastic structure located at the base of every valve in veins that are responsive to noradrenaline (NA).Design: Constant flow perfusion studies of the responses of in situ and in vitro canine lateral saphenous vein segments to NA and electrical stimulation, supplemented by histological studies of the segments.Setting: University Departments of Physiology and Histology.Materials: Segments of canine lateral saphenous vein. In vitro = 84, in situ = 60 plus.Results: The agger is a crescentic fibroelastic sleeve, spanning the vein wall very obliquely through which the local vasa venarum network drains. It has a dedicated musculature which, when the tone rises, contracts and stretches the fibroelastic of the agger and opens the drainage channels to reflux. Each agger has four muscles, two each of which insert on the concave and convex margins of the agger. They pull in opposite directions when they contract.Conclusions: The agger forms part of a complex that, in conjunction with its dedicated musculature, a reversible transmural pressure gradient and physiological turbulence in the valve sinuses, positively facilitates drainage from the local segment of the vasa venarum network when venous tone is normal; and when venous tone is elevated it pumps and sucks blood from the lumen of the vein to perfuse the vasa venarum network. When the plasma NA in the perfusate diffuses from the network, it causes a localized venodilator feedback effect that restores the elevated tone of the vein to normal. The feedback effect is potent, being estimated to reduce the venonstrictor effect of neuronal NA by about 50% when flow is laminar and considerably more when flow is turbulent. There is evidence that plasma NA may constitute the lateral inhibitory component of the NA chemostimulus of the smooth muscle cell, neuronal NA constituting the excitor component. A chronic breakdown in agger function is believed to be the cause of varicose veins.

This paper argues that varicose veins are caused by a feedback malfunction. The feedback in question regulates the tone of the vein by dilating it as needed, using noradrenaline (NA), tapped from the circulating pool, for the purpose. The drug, though conventionally classified as a venoconstrictor, dilates the vein when it diffuses from the vasa venarum of the vein into the vein’s media; the drug having reached the vasa by reflux from the vein lumen. A varicosity is created when a factor increases the volume of reflux, and, therefore, the quantity of NA, perfusing a unit of the vasa network, selectively. The resultant, exaggerated, localised, dilator effect that the NA has on a section of the vein, constitutes the varicosity radix. In brief, a varicosity, when first created, is seen as being an exaggerated, but appropriate, dilator response of a section of a normal vein to an inappropriate, corrupted, feedback signal. The acute varicosity is believed to transform into the permanent type seen in varicose veins if the factor responsible for it persists long enough.

This paper advances the hypothesis that the rearrangement of the actin cytoskeleton that takes place during contraction in the SMC is a mechanical reflection of the spatiotemporal pattern of the cell's polarized stimulus. In that sense the cell is responding more like a motile non-muscle cell than like a skeletal muscle cell. The paper reviews how diffusion patterns are generated and modified and suggests how the patterns are detected by the cell and transduced into cytoskeletal movement. Evidence is presented suggesting the actin cytoskeleton is composed of conical-shaped myofibrils (contractile units) measuring half a cell in length and containing filament-free spaces at their centres filled with cell inclusions. It is argued that the SMC contracts by involving variable combinations of the myofibrils in sequence and that the cell takes advantage of that fact to translocate various contractile elements between the myofibrils during contraction, thus economizing on its needs for those elements. Among the elements translocated are thought to be myosin, SR and mitochondria.

The first section of this paper reviews the clinical, histochemical and histological features of the varicosity in the early stage of human varicose veins. The second section demonstrates that many of those features have been duplicated in acute experiments where noradrenaline perfused the vasa venarum of an isolated in situ canine vein segment, the drug having reached the vasa by reflux from the lumen of the segment (radial reflux). It also explains how perfusion of the vasa for an extended period would duplicate other distinctive features of the early-stage human varicosity, such as its permanence, the hypoxia of its tissues and the hypertrophy of the smooth muscle in its wall. The findings further support the hypothesis that varicose veins arise from chronic perfusion of the vasa venarum of a normal vein by circulating noradrenaline contained in pathologically high volumes of radial venous reflux. The main cause of the high volume of reflux seems to be turbulent luminal flow in the case of secondary varicose veins and a real or relative structural deficiency of the fibroelastic of the valve aggers in the case of primary ones.

Objective: A general investigation of the vasa venarum network in a segment of canine peripheral vein, isolated between cannulae in an amputated hindlimb. Technique: The vasa venarum were perfused with ink by reflux from the lumen of the segment. The technique worked only when the vein segment was actively constricted and its flow made turbulent. Results: Vasa venarum were found to have the potential to drain, by unvalved channels, directly into their parent segment, into neighbouring veins, into the vasa networks of neighbouring arteries, veins and lymphatics, and into the postcapillary networks of every tissue in the hindlimb. The network contained dedicated arteriovenous anastomoses which drained by valved channels into the parent segment. A feature of the perfusion technique was the production of acute experimental varices. Conclusions: The drainage of the vasa venarum is far more complex than it is believed to be at present. The demonstration that reflux is possible from a vein with competent valves and is associated with the production of varices may have clinical implications.

Objective: To investigate the effects of flow from the vein lumen into the vasa venarum (radial reflux) and the factors regulating it. Design: In vivo and in vitro animal study. Setting: University Department of Physiology. Materials: Segments of canine vein were perfused in vitro ( n = 84) and in situ ( n = 60). Main outcome measures: Specimens were studied by conventional histology using light microscopy. Results: Radial reflux caused dilatation of constricted segments and when associated with turbulent flow resulted in the formation of acute short-lived varices, marked dilatation of sinusoidal venules at the medioadventitial junction of the segments and of sinusoidal venules in the paradventitial tissue. Conclusion: During laminar flow radial reflux operated as a feedback to regulate venoconstrictor tone. During turbulent flow it caused more widespread vascular changes and inhibited adrenergic activity. The changes are of particular interest because they mimicked those that characterize the early stage of varicose veins.

A hypothesis is presented on the origin of PSD, the dilatation which occurs in an artery distal to a site of stenosis. The fact that turbulent flow is associated with both PSD and with experimentally induced varicosities suggested that similar mechanisms are involved. That is the basis for a proposal that PSD originates as an active dilator response of the artery wall to circulating NE released in excess from a section of the vasa vasorum (VV) network of the affected artery. Turbulence is believed to be the cause of that excess through multiplying the volume of blood and, consequently, the amount of circulating NE flowing from an artery to its VV. There is published evidence that turbulence does increase flow to the VV of an artery and evidence is presented that if norepinephrine is injected rapidly into a small canine muscular artery, with the aim of creating turbulence in the artery, the injection is promptly followed by localised dilator effects in the artery which, overall, is constricted by the drug.

The use of beta-blockers in the treatment of angina, claudication or hypertension is a therapeutic paradox. All those conditions feature increased constrictor tone, so it appears to make little sense to treat them with drugs which block the action of vasodilators. The paradox would disappear, however, if vasodilators could be shown to have the ability to increase constrictor tone in certain circumstances. This paper argues that they have. It presents evidence that isoprenaline, a potent dilator of the dog's saphenous vein, is a powerful constrictor of the vein when it is released from the vasa vasorum of the vein. Indeed, on a molar basis, it appears to be a more powerful constrictor of the vein than exogenous noradrenaline is. Since there is no reason to suppose that isoprenaline is unique among dilators in demonstrating this type of bimodal behaviour, it is possible to justify the proposal that compounds which are normally classified as endogenous dilators may, when released from the pathological vasa vasorum which neoproliferate in atherosclerosis, be responsible for the constrictor effects associated with claudication, and some forms of hypertension and angina. If true then beta-blockade would not be a paradoxical choice of treatment for those conditions.

It is proposed that pathological varicosities begin as acute dilator responses of normal veins to noradrenaline released from the vasa vasorum of the vein; the noradrenaline is part of a circulating pool formed by overflow following adrenergic nerve activity. In health, a minimal quantity of noradrenaline routinely flows by reflux to the vasa where it has a negative feedback, venodilator effect. However, when the volume of reflux becomes excessive, the noradrenaline in it abolishes venoconstrictor tone, thereby creating a varicosity. Excessive venous reflux over a short period causes no significant hypoxic damage to the vein wall or any other tissues and any damage associated with it regresses when the excess reflux ceases. However, if excessive reflux is persistent then a time comes when irreversible hypoxic structural changes occur in the vein wall and in other tissues affected by the reflux. The structural pathology associated with varicose veins reflects the effect of the long-term tissue hypoxia associated with that condition.

243,901), but an understanding of its role in control of airway function in health and disease has been difficult because of the lack of specific antagonists.It was the purpose of this study to synthetise analogues of NKA and to test them for pharmacological antagonism of NKA-induced contraction of guinea-pig tracheal smooth muscle.We have previously reported that NKA analogue in which glycine 8 was replaced by aminoisobutyric acid (Aib) is an antagonist of NKA, but not Substance P, activity on tracheal smooth muscle from guinea-pig (Abu Shanab et al, Biochem.Soc.Trans.1990: 18, 286).We now report the effect on biological activity of deletions at the N-terminus.NKA was purchased from Biosyn Ltd. (Belfast, N. Ireland) and the peptides [Ala s, Aib s, Leu 1~ NKA (4-10), [Ala ~, Aib 8, Leu 1~ NKA (2-10) and [Ala s, Aib s, Leu 1~ NkA, hereafter referred to as peptides 1, 2 and 3 respectively, were synthetised by solid phase methods.Isometric contraction of isolated guinea-pig tracheal rings in response to exogenous NKA (10 -1~ to lO-6M) was recorded as described previously (Abu Shanab et al, Biochem.Soc.Trans.1990: 18, 286) and the effect of the peptide analogues on the NKA doseresponse relationship examined.In the presence of peptide 3 (10 -8 to 10-6M) NKA evoked contractions were reduced at all doses producing acharacteristic shift in the NKA dose-response curve suggestive of classical non-competitive antagonism, although contractions to substance P (SP; 10 -8 to 10-6M) were unaltered by analogue.In contrast, peptide 2 (104 to 1 ff6M) caused a dose-dependent shift to the right of the NKA doseresponse curve with no depression of the maximum NKA response.Peptide 2 showed no pharmaclogical antagonism to SP.A schild regression plot for peptide 2 antagonism of NKA evoked contractions yielded a straight line of slope -0.4 with an interscept (PA2) of 7.7 on the abscissa.Unlike peptides 2 and 3, peptide 1 (10-6M) itself caused contraction of the tracheal preparation.In conclusion, peptide analogues that selectively antagonise the activity of NKA on tracheal smooth muscle have been produced by replacement of Gly s in a NKA ,,~icgue that also had the substitutions Ala s and Leu 1~ Removal G~ the N-terminal residue did not abolish this selectivity although the nature of the antagonism was altered.Removal of a further two amino acid residues from the Nterminus resulted in the generation of agonist activity.

When noradrenaline, either endogenous or exogenous, is released from the venae venarum of a dog's lateral saphenous vein which is constricted by noradrenaline, it dilates the vein. By limiting the release of the drug to just a section of the vein's venae venarum network it is possible to dilate the normal vein segmentally, that is, cause varicosities. This has led to the suggestion that pathological varicosities begin as localised physiological dilator responses of the vein wall to circulating endogenous noradrenaline, released from the vein's venae venarum. Under ambulatory conditions small quantities of noradrenaline probably flow almost continually from the lumen of the vein to different parts of its venae venarum network and serve to adjust constrictor tone downwards. When there is turbulence in the vein lumen the volume of reflux becomes excessive and causes so much adjustment that constrictor tone is abolished. The vein, in effect, then exhibits a frank dilator effect, visible as a varicosity, localised to the level in the vein at which the turbulence occurs. If a high volume of hypoxic blood reflux continues for a critical period then the wall of the varicosity suffers secondary degenerative structural changes which make the varicosity permanent.

Experiments have shown that noradrenaline can dilate the lateral saphenous vein of the dog when that vein has been constricted by noradrenaline, at the same concentration, in the first place. This dilator action of noradrenaline occurs when the drug stimulates the constricted vein through its outer surface after it is released from the vein's vasa vasorum network. There is evidence suggesting that this effect is not uique to noradrenaline and that the effect of any agonist stimulating a blood vessel through its lumenal surface may be reversed following its release from vasa vasorum. This phenomenon may be important in the context of the known relationship there is between the severity of the symptoms of atherosclerosis and the degree to which vasa vasorum proliferate de novo in the adventitia of blood vessels affected by that disease. It is suggested that in athersclerosis endogenous vasodilators have their actions reversed by release from these pathological vasa. This would result in the vasodilators of exercise having a constrictor action on the coronary vessels and becoming the immediate cause of angina. If vasodilators do indeed cause angina then the use of β-blockade in this condition becomes a rational rather than an empirical method of treatment. An hypothesis is advanced to explain the phenomenon of drug action reversal.