THE PATHO-PHYSIOLOGY OF CHRONIC ARTERIAL HYPERTENSION: A HYPOTHESIS

An important unresolved problem in hypertension is how an elevated blood pressure from any cause may eventually become self-sustaining and apparently independent of the initiating event. Folkow has suggested that this results from arteriolar narrowing due to a physiological response or ‘structural adaptation’ to the higher pressure, but it is suggested here that the histological appearances within the arterioles in chronic hypertension are much more in keeping with a pathological process, and not vastly different from those observed after intimal damage to larger arteries in experimental atherosclerosis. From this, it is proposed that the arteriolar narrowing is secondary to the endothelial damage which arises when a maintained cardiac output is forced through a constricted arteriolar bed, so increasing substantially the shearing stress on their walls.     

ON THE RELATIONSHIP BETWEEN CARDIAC OUTPUT AND PERIPHERAL ARTERIAL RESISTANCE

The concept of ‘whole body auto-regulation’ is a somewhat unsatisfactory explanation of the increased peripheral arterial resistance which follows a rise in cardiac output in ‘volume’ forms of hypertension. This analysis suggests that the resistance change may be due to the sodium retention and increased cardiac output having a direct effect to alter haemodynamics of flow through the arterioles in such a way as to damage their walls, and so lead to the gradual development of structural arteriolar narrowing. Studies are presented in the DOCA/salt hypertensive rat consistent with this proposal.     

HORMONES AS LONG-TERM ERROR SIGNALS FOR THE SYMPATHETIC NERVOUS SYSTEM: IMPORTANCE OF A NEW PERSPECTIVE

1. A hormonal-sympathetic reflex model for long-term control of arterial pressure is presented. It is hypothesized that the hormonal-sympathetic reflex regulates arterial pressure during chronic dietary salt loading by decreasing sympathetic tone. This sympathetic response is mediated by an increase in plasma vasopressin (AVP) and a decrease in plasma angiotensin (AngII). 2. Three new models of neurogenic salt-dependent hypertension are presented. All models are theoretically based on an impaired hormonal-sympathetic reflex. 3. In the first model, sympathetic responsiveness is ‘clamped’ by long-term α-adrenergic blockade with prazosin. Prazosin treated rats exhibit marked salt-dependent hypertension despite normal suppression of the renin-angiotensin system. 4. In the second model, the ability of the central nervous system to respond to salt-induced changes in AVP and AngII concentrations was prevented by long-term administration of antagonists selective for the AVP-V₁ and AT₁. This ‘clamp’ of the afferent hormonal signal resulted in salt-dependent hypertension identical in magnitude to that observed in prazosin treated rats. 5. In the third model, the long-term arterial pressure responses to increasing dietary salt were examined in sino-aortic denervated (SAD) rats. SAD rats exhibited salt-dependent hypertension, of lesser magnitude than that observed with ‘clamped’ afferent and efferent pathways of the hormonal-sympathetic reflex. 6. A primary role for hormonal ‘error signals’ is presented and the impact this perspective has on past and future investigations of central mechanisms of long-term arterial pressure regulation is discussed.     

REMODELLING OF THE VASCULAR SYSTEM IN RESPONSE TO HYPERTENSION AND DRUG THERAPY

1. Arterial remodelling is an important mechanism in the pathophysiology of hypertension and its complications, being involved in the decrease of vascular reserve, the autoregulation of cerebral blood flow and the development of atherosclerosis. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth-promoting substances. Based on these data, the effects of perindopril, a potent and long-lasting angiotensin-converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall have been studied in animal models of hypertension. Perindopril completely reversed the aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats and in spontaneously hypertensive rats. The effect of perindopril was consistent with the potent inhibition of vascular ACE, and emphasized the potential role of angiotensin II as a vascular growth modulator. Whether the time constant of remodelling is similar or not in the heart and large vessels remains an important question that requires further investigation.     

Could hypertension possibly be adaptive?‡

1. We believe that the ultimate goal of cardiovascular regulatory mechanisms is not the regulation of arterial blood pressure (BP), but the maintenance of tissue blood flows commensurate with metabolic requirements. Thus, elevated BP can potentially contribute to optimizing tissue blood flows under select circumstances; for example, when there are primary defects in autoregulation of tissue blood flows. 2. The hypothesis that a primary defect in autoregulation of tissue blood flows may be responsible for the development of hypertension is presented. It is argued that, in this context, at least part of the rise in BP may be reflexly driven by a ‘metaboreflex’, a homeostatic mechanism acting to regulate tissue blood flows. 3. We argue that in the context of primary defects in autoregulation of tissue blood flows, the ability to generate and sustain a hypertensive phenotype increases the lifespan of species (i.e. if it were not for this adaptive hypertensive phenotype, death due to circulatory failure would occur much earlier). 4. Experimental and clinical evidence that indirectly supports the hypothesis is reviewed briefly and a means for testing this hypothesis is suggested.     

Altered norepinephrine synthesis of splanchnic vessels in neurogenic hypertension

Sino-aortic denervation (SAD) in the rabbit produced neurogenic hypertension which at first was characterized by induced cardiac output and later by increased peripheral vascular resistnace. Tyrosine hydroxylase activity and catecholamine concentration of proximal mesenteric artery were greater than those of distal mesenteric ‘vessels’ in normal rabbits. 1 hr after SAD, NE synthesis, the activity of tyrosine hydroxylase assayed in vitro, was increased in proximal mesenteric artery and decreased in distal mesenteric ‘vessels’ . 11 and 30 days after SAD, NE synthesis in vivo and the activity of tyrosine hydroxylase assayed in vitro was increased in distal mesenteric ‘vessels’ and decreased in proximal mesenteric artery. Sympatho-adrenal regulation of increased splanchnic vascular resistance is concluded to be an important factor in the initiation and maintenance of neurogenic hypertension in the rabbit.     

THE EFFECT OF ADRENAL DENERVATION ON ACTH-INDUCED HYPERTENSION IN SHEEP

SUMMARY 1. The effect of surgical denervation of the adrenal gland on ACTH-induced hypertension in the sheep has been examined. ACTH (80 iu/day) was administered for 5 days to eight sheep before and after bilateral surgical denervation of the adrenal.
2. In intact sheep, ACTH-induced hypertension is associated with a significant increase in cardiac output and heart rate. Adrenal denervation obtained by sectioning of the lumbar sympathetic and splanchnic nerves supplying the adrenal gland did not alter the magnitude or time course of the hypertension, or the increase in heart rate.
3. Adrenal denervation did not affect the increase in plasma sodium, the fall in plasma potassium, the initial urinary sodium retention, the increase in water turnover or the changes in blood corticosteroids which are seen during ACTH administration to intact sheep. However, in these adrenally denervated sheep ACTH treatment did not significantly change cardiac output.
4. This study suggests an important role for a factor or factors from the adrenal cortex in causing ACTH-induced hypertension.     

ENHANCEMENT OF ENDOTHELIUM-DEPENDENT RELAXATION IN THE AORTA FROM STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS AT DEVELOPMENTAL STAGES OF HYPERTENSION

1. Endothelium-dependent relaxation (EDR) in aortic rings from young (8 weeks) and adult (16 weeks and 20 weeks) stroke-prone spontaneously hypertensive rats (SHRSP) was investigated in comparison with age-matched Wistar-Kyoto rats (WKY). 2. At 8 weeks, acetylcholine (3×10^?-⁹-^?10^?-⁵ mol/L) and ionomycin (4×10^?8-10^?6 mol/L)-induced EDR in SHRSP aortae was significantly enhanced compared to that in WKY aortae. Mechanical denudation of the endothelium completely abolished, and pretreatment of aortae with N^G-monomethyl L-arginine (1 mmol/L), an inhibitor of nitric oxide formation, greatly reduced the relaxation in both strains. Indomethacin (10^?5 mol/L), a cyclo-oxygenase inhibitor that blocks the production of endothelium-derived contracting factors, did not significantly alter the relaxation by acetylcholine at this age. There was no difference in endothelium-independent relaxation of denuded aortae by sodium nitroprusside (10^?9-10^?6 mol/L) and 8-bromoguanosine 3‘, 5‘-cyclic monophos-phate (10^?6-10^?3 mol/L). 3. In adult SHRSP with established hypertension, however, the acetylcholine (10^?8-^?10^?5 mol/L)-induced relaxation markedly diminished at any of the concentrations tested compared to that observed in 8 week old SHRSP and WKY at 8–20 weeks of age. This finding differed from other observations where the relaxation in SHRSP was impaired only at higher concentrations of acetylcholine. Indomethacin pretreatment of aortae from 20 week old SHRSP restored acetylcholine-induced EDR to a level comparable with that in age-matched WKY. 4. These results suggest that the aorta from young SHRSP releases more endothelium-derived relaxing factors in response to acetylcholine and ionomycin, but the relaxation greatly diminishes in adult SHRSP with established hypertension. This may be due to counteraction of endothelium-derived contracting factors released from the endothelium with functional changes resulting from the long duration of the hypertension.     

THE PHYSIOLOGY OF PRE-ECLAMPSIA

1. Pre-eclampsia is a multisystem disorder of human pregnancy with a genetic predisposition. It occurs more commonly in first pregnancies and primarily affects maternal renal, cerebral, hepatic and clotting functions while elevating blood pressure. The foetus is affected through placental insufficiency arising from abnormal ‘placentation’, that is, failure of adequate trophoblast invasion of maternal vasculature, and possibly from abnormal autacoid production. 2. Pre-eclampsia is caused by the placenta; delivery of the placenta is the only known cure. Its manifestations are considered secondary to organ hypoperfusion which arises as a result of vasoconstriction, intravascular coagulation and reduced maternal blood volume. 3. Current hypotheses propose that pre-eclampsia is due to widespread maternal endothelial cell damage, perhaps secondary to a cytotoxic factor released by the placenta. This hypothesis has gained wide acceptance, but scientific evidence is lacking. 4. Defining the abnormal balance of vasoactive factors in pre-eclampsia has proved a difficult task. There is enhanced pressor reactivity to infused angiotensin 11 (AII) despite reduced plasma concentrations of AII, renin and aldosterone. Prostacylclin production appears reduced, and the balance of thromboxane/prostacyclin favours vasoconstriction and platelet aggregation. There is no convincing evidence for enhanced endothelin or reduced nitric oxide production. Plasma concentrations of atrial natriuretic peptide are paradoxically elevated in the face of plasma volume contraction. An intriguing observation, which remains unexplained, is why some vascular beds are affected predominantly in one patient (eg. hepatic ischaemia) while another has a similar degree of hypertension but involvement of a different organ system (eg. renal insufficiency yet normal liver function). 5. Volume homeostasis is disturbed with redistribution of intravascular volume to the interstitial fluid space due to increased capillary permeability and in some cases reduced plasma oncotic pressure. This redistribution is not always clinically apparent as peripheral oedema. Whether this change in volume is compensated for by venoconstriction and maintenance of adequate cardiac output is undetermined. 6. Improved understanding of the pathophysiology of pre-eclampsia is necessary to allow better clinical management of this serious disorder.     

Microcirculation in the brain: viewpoint of autoregulation]

The cerebral blood flow (CBF) is autoregulated to a steady flow within certain ranges. CBF increases and cerebrovascular resistance (CVR) decreases dramatically with breakthrough of autoregulation when systemic arterial blood pressure exceeded the upper limit of the range. Many kinds of components in the brain as well neurogenic factors affect the autoregulation. The breakthrough of autoregulation does not occur in the presence of nitric oxide (NO) synthesis inhibitors, angiotensin converting enzyme inhibitor, prostanoids (PG) administered in the brain, sympathetic denervation, and sinoaortic denervation. The abolishment of breakthrough of autoregulation may be due to an increased tolerance of cerebral vessels to hypertension and the inhibition of the release of a vasodilator substance such as NO or PG. It appears that the tone of brain microvessels is controlled towards dilation by cholinergic innervation originating from the nucleus basalis of Meynert, glutamatergic or GABAergic mediated GABAA receptor, and by a mediator such as NO, bradykinin, PGs. Also, it is likely that candidates for constricting factors in intraparenchymal microvessels are norepinephrinergic from the superior cervical ganglion, serotonergic involved in 5-HT1D beta- and 5-HT2B-specific receptor subtypes, GABAergic mediated GABAB receptor, thromboxane, PG F2 alpha and the angiotensin system. The autoregulation of CBF is maintained by these neurogenic factors to prevent brain ischemia and hyperemia.     

IMPORTANCE OF THE 'CROSSOVER' CONCEPT IN EXERCISE METABOLISM

1. The ‘crossover’ concept is a model of substrate supply during exercise which makes the following predictions. 2. Lipid is the major fuel (approximatel. 60%) for non-contracting skeletal muscle and the body at rest. 3. Energy flux, as determined by exercise intensity, is the major factor in determining the balance of substrate utilization during exercise. Thus, moderate and greater exercise intensities increase contraction-induced muscle glycogenosis and glycolysis, increase recruitment of fast-twitch muscle fibres, increase sympathetic nervous system activity and down-regulate mitochondrial fatty acid uptake. 4. Glycogen and glucose utilization scales exponentially to relative exercise power output with a greater gain in glycogen than in glucose use at high power. The relationship between free fatty acid flux and power output is an inverted hyperbola. Consequently, at high power outputs, the role of lipid oxidation is diminished. 5. Factors such as endurance training, energy supply, as influenced by dietary manipulation, and prior exercise play secondary roles in determining the balance of substrate utilization durin. exercise. 6. Comparisons of the metabolic responses in subjects engaged in activities requiring vastly different metabolic rates or comparisons of subjects of different gender, age or training status require normalization of dat. to total energy flux.     

THE SYMPATHETIC NERVOUS SYSTEM AND LONG-TERM REGULATION OF ARTERIAL PRESSURE: WHAT ARE THE CRITICAL QUESTIONS?

1. The role of the sympathetic nervous system in long-term control of arterial pressure remains unclear despite decades of intense research. 2. Previous studies have shown that denervation of arterial baroreceptors does not chronically increase arterial pressure. As baroreceptors are thought to provide the primary ‘error signal’ to the autonomic nervous system, this has been interpreted as evidence against neural control of arterial pressure over long periods of time. 3. The possibility that other ‘error signals’ are important in the long-term control of sympathetic activity (and arterial pressure) is introduced. 4. The following ‘Critical Questions’ are presented for subsequent discussion: (i) is the sympathetic nervous system a ‘major player’ in the long-term control of arterial pressure; (ii) why doesn't arterial pressure remain at hypertensive levels after arterial baroreceptor denervation; and (iii) which ‘error signals’ are most important in the long-term control of sympathetic outflow?     

Role of the serotonin transporter in pulmonary arterial hypertension

Pulmonary arterial hypertension is a disease in which pulmonary arterial pressure is raised, leading to right heart failure. Survival is poor despite current therapeutic strategies. The ‘serotonin hypothesis of pulmonary arterial hypertension’ arose in the 1960s following an ‘epidemic’ of pulmonary arterial hypertension in women taking the indirect serotinergic agonist aminorex as an anorexigen. In the 1980s, the hypothesis was revisited following the occurrence of pulmonary arterial hypertension associated with the use of fenfluramines as anorexigens; these are also indirect serotinergic agents. Research has identified changes in serotonin synthesis, serotonin receptor activation and serotonin uptake via the serotonin transporter in experimental and clinical pulmonary arterial hypertension. This review will discuss our current understanding of this serotonin hypothesis with particular reference to the role of the serotonin transporter.     

EFFECT OF ACTH ADMINISTRATION ON THE HAEMODYNAMIC RESPONSE TO ARGININE-VASOPRESSIN IN SHEEP

1. Blood pressure, heart rate and cardiac output were studied in intact conscious sheep during AVP infusion at 0.1, 0.25, 0.5 and 10 μg/min for 30 minutes to determine whether pressor responsiveness to AVP was altered in ACTH-induced hypertension. 2. Prior to ACTH treatment, AVP produced rises in blood pressure associated with a fall in heart rate and cardiac output. 3. During ACTH treatment, pressor responsiveness to AVP and decrease in cardiac output were unchanged, but reflex bradycardia was reduced. 4. ACTH-induced hypertension in sheep is not associated with enhanced pressor responsiveness to AVP.     

Drug-device combination products in the twenty-first century: epinephrine auto-injector development using human factors engineering

Introduction: The systematic application of human factors engineering (HFE) principles to the development of drug-device combination products, including epinephrine auto-injectors (EAIs), has the potential to improve the effectiveness and safety of drug administration.

Areas covered: A PubMed search was performed to assess the role of HFE in the development of drug-device combination products. The following keywords were used in different combinations: ‘human factors engineering,’ ‘human factors,’ ‘medical products,’ ‘epinephrine/adrenaline auto-injector,’ ‘healthcare’ and ‘patient safety.’ This review provides a summary of HFE principles and their application to the development of drug-device combination products as advised by the US FDA. It also describes the HFE process that was applied to the development of Auvi-Q, a novel EAI, highlighting specific steps that occurred during the product-development program.

Expert opinion: For drug-device combination products, device labeling and usability are critical and have the potential to impact clinical outcomes. Application of HFE principles to the development of drug-delivery devices has the potential to improve product quality and reliability, reduce risk and improve patient safety when applied early in the development process. Additional clinical and real-world studies will confirm whether the application of HFE has helped to develop an EAI that better meets the needs of patients at risk of anaphylaxis.     

ACTH HYPERTENSION MODIFIES THE HAEMODYNAMIC EFFECTS OF PROSTACYCLIN INFUSIONS IN SHEEP

1. The haemodynamic effects of short-term prostacyclin infusions (0.05-0 50 /μg/kg per min) were investigated in conscious adult sheep. 2. Haemodynamic dose-response curves to prostacyclin were performed before, during and after production of ACTH-induced hypertension. 3. Prior to ACTH administration prostacyclin produced dose-dependent reductions in mean arterial pressure, total peripheral resistance and stroke volume and these were accompanied by increases in heart rate and cardiac output. 4. After 5 days of ACTH-induced hypertension prostacyclin produced similar effects on mean arterial pressure to those seen prior to ACTH but the effects on heart rate, cardiac output, stroke volume and total peripheral resistance were markedly increased. 5. These studies demonstrate that the responsiveness of the circulation to prostacyclin is altered in ACTH-induced hypertension.     

Sildenafil for pulmonary arterial hypertension: when blue turns into white

Pulmonary arterial hypertension is a life-threatening, rare disease characterised by vasoconstriction and vascular remodelling of pulmonary artery vessels. Pulmonary arterial hypertension can occur without an obvious cause or can be secondary. Until several years ago, therapeutic approaches were represented mainly by ‘conventional therapy’ (anticoagulants, calcium channel blockers, diuretics and digoxin, and oxygen therapy). But recently ‘specific therapies’ (i.e., therapies targeting specific pathogenic pathways) have become available; these are therapies represented by prostacyclin and its derivatives, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Sildenafil citrate is a phosphodiesterase-5 inhibitor and is the second oral pharmacological agent recently approved for the treament of pulmonary arterial hypertension. Sildenafil has demonstrated short- and long-term clincal efficacy in the treatment of various forms of pulmonary arterial hypertension, either alone or in combination with other agents, but its safety profile needs further assessment.     

ELECTRICAL BASIS OF PERISTALSIS IN THE MAMMALIAN UPPER URINARY TRACT

1. Peristalsis in the mammalian upper urinary tract (UUT) is mostly myogenic in origin, originating predominately in the proximal pelvicalyceal regions of the renal pelvis, an area that is enriched with specialized smooth muscle cells termed ‘atypical’ smooth muscle cells. Propagating peristaltic contractions are little affected by blockers of either autonomic nerve function or nerve impulse propagation; however, blockers of sensory nerve function or prostaglandin synthesis reduce both the frequency and the strength of the spontaneous contractions underlying peristalsis. 2. The electrical drive for these peristaltic contractions has long been considered to involve mechanisms analogous to the heart, such that ‘atypical’ smooth muscle cells generate spontaneous ‘pacemaker’ action potentials. These pacemaker potentials trigger the firing of action potentials and contraction in the muscular regions of the renal pelvis, which propagate distally to the ureter, propelling urine towards the bladder. 3. Recent intracellular microelectrode and single cell/channel patch-clamp studies have revealed that the ionic conductances underlying the action potentials recorded in the UUT are likely to involve the opening and slow closure of voltage-activated ‘L-type’ Ca2+ channels, offset by the time-dependent opening and closure of both voltage- and Ca2+-activated K+ channels. 4. In the present review we summarize the current knowledge of the ionic mechanisms underlying action potential discharge in the UUT, as well as present our view on how this electrical activity supports the initiation and conduction of UUT peristalsis.     

Neurotrophic factors as a therapeutic target for Parkinson's disease

Background: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. Objective: In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. Methods: Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: ‘Parkinson's disease’, ‘Neurotrophic factors’, ‘BDNF’ (Brain-derived neurotrophic factor), ‘GDNF’ and ‘Neurturin’. Original articles were reviewed, and relevant citations from these articles were also appraised. Conclusion: NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.