The renin-angiotensin and the kallikrein-kinin systems

The renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS) each encompasses a large number of molecules, with several participating in both systems. The RAS generates a family of bioactive angiotensin peptides with varying biological activities. These include angiotensin-(1-8) (Ang II), angiotensin-(2-8) (Ang III), angiotensin-(3-8) (Ang IV), and angiotensin-(1-7) [Ang-(1-7)]. Ang II and Ang III act on type 1 (AT(1)) and type 2 (AT(2)) angiotensin receptors, whereas, Ang IV and Ang-(1-7) act on their own receptors. The KKS also generates a family of bioactive peptides with varying biological activities. These include hydroxylated and non-hydroxylated bradykinin and kallidin peptides and their carboxypeptidase metabolites des-Arg(9)-bradykinin and des-Arg(10)-kallidin. Whereas bradykinin and kallidin act mainly via the type 2 bradykinin (B(2)) receptor, des-Arg(9)-bradykinin and des-Arg(10)-kallidin act mainly via the type 1 bradykinin (B(1)) receptor. The AT(1) receptor forms heterodimers with the AT(2) and B(2) receptors and there is cross talk between the AT(1) and epidermal growth factor receptors. The B(2) receptor also interacts with angiotensin converting enzyme and nitric oxide synthase. Both angiotensin and kinin peptides are metabolised by many different peptidases that are important determinants of the activities of the RAS and KKS, and several of which participate in both systems.     

Cross-talk of the renin-angiotensin and kallikrein-kinin systems

The renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems play a key role in multiple physiological and pathophysiological conditions, including growth and development, inflammation, blood pressure regulation and control of renal function. In many instances, kinins and angiotensin II work together, e.g., during development, whereas they oppose each other's actions in the regulation of vascular tone and renal function. The RAS and KKS systems also interact at multiple levels, so that changes in the activity of one system greatly impact the activity of the other. The purpose of this brief review is to highlight recent knowledge regarding interactions at the cellular and molecular levels between the two systems, with an emphasis on the coordinate developmental regulation of these phylogenetically conserved vasoactive systems.     

Effects of a prostacyclin analog iloprost on kidney function, renin-angiotensin and kallikrein-kinin systems, prostanoids and catecholamines in man

Iloprost (ZK 36 374), a stable analog of carbaprostacyclin, was infused for 72 h to nine patients with advanced obliterative arterial disease. Iloprost caused a marked vasodilation and a compensatory increase in cardiac output. The glomerular filtration rate increased by 45% and tubular reabsorption of sodium and water were reduced by 80% and 107%, respectively. The urine excretion rate increased by 122%. Tubular handling of potassium and calcium were not influenced by iloprost but magnesium reabsorption was stimulated. The renin-angiotensin system was not activated while serum angiotensin converting enzyme activity was decreased. Kallikrein excretion in urine was increased 4.4-fold but plasma kininogen, a substrate for kallikrein in producing vasoactive kinins, was unaffected by the drug. Plasma levels of 6-keto-PGF_1α and TxB₂ were decreased and their excretion in urine increased. Plasma catecholamines were not changed by iloprost. Several of the changes persisted for at least the first postinfusion day. The results indicate that iloprost increases urine excretion rate by increasing glomerular blood flow and by inhibiting sodium and water reabsorptions. The kinin-forming system, but not the renin-angiotensin system or plasma catecholamines, may be activated. The decrease in plasma level of prostanoids can be, at least partly, due to their increased excretions in urine.     

Effects of a prostacyclin analog iloprost on kidney function, renin-angiotensin and kallikrein-kinin systems, prostanoids and catecholamines in man

Iloprost (ZK 36 374), a stable analog of carbaprostacyclin, was infused for 72 h to nine patients with advanced obliterative arterial disease. Iloprost caused a marked vasodilation and a compensatory increase in cardiac output. The glomerular filtration rate increased by 45% and tubular reabsorption of sodium and water were reduced by 80% and 107%, respectively. The urine excretion rate increased by 122%. Tubular handling of potassium and calcium were not influenced by iloprost but magnesium reabsorption was stimulated. The renin-angiotensin system was not activated while serum angiotensin converting enzyme activity was decreased. Kallikrein excretion in urine was increased 4.4-fold but plasma kininogen, a substrate for kallikrein in producing vasoactive kinins, was unaffected by the drug. Plasma levels of 6-keto-PGF1 alpha and TxB2 were decreased and their excretion in urine increased. Plasma catecholamines were not changed by iloprost. Several of the changes persisted for at least the first postinfusion day. The results indicate that iloprost increases urine excretion rate by increasing glomerular blood flow and by inhibiting sodium and water reabsorptions. The kinin-forming system, but not the renin-angiotensin system or plasma catecholamines, may be activated. The decrease in plasma level of prostanoids can be, at least partly, due to their increased excretions in urine.     

Local renin-angiotensin systems: the unanswered questions

The concept of local renin-angiotensin systems has been introduced almost 20 years ago to explain the beneficial blood pressure-independent effects of ACE inhibitors and AT(1) receptor antagonists in cardiovascular diseases. In the past decade, research has focussed on the local effects of angiotensin II rather than on the mechanism(s) of its local generation. This review addresses several of the unanswered questions with regard to tissue angiotensin II generation, focussing in particular on the heart and vascular wall: (1) what is the origin of the renin that is required to generate angiotensin II locally, (2) where does tissue angiotensin generation occur (intra- versus extracellular), (3) what is the importance of alternative (non-renin, non-ACE) angiotensin-generating enzymes, (4) do ACE inhibitors and AT(1) receptor antagonists exert local effects that are renin-angiotensin system independent (thereby incorrectly leading to the conclusion that they interfere with the local generation or effects of angiotensin II), and (5) to what degree do differences in tissue angiotensin generation underlie the association between cardiovascular diseases and renin-angiotensin system gene polymorphisms?     

The in vitro cross-effects of inhibitors of renin-angiotensin and fibrinolytic systems on the key enzymes of these systems

The effects of hypotensive agents (captopril, enalaprilat, and lisinopril) on the activities of components of the fibrinolytic system (FS) and the effects of antifibrinolytic agents (6-aminohexanoic acid (6-AHA) and tranexamic acid (t-AMCHA)) on the activities of angiotensin converting enzyme (ACE) were studied in vitro. Enalaprilat did not affect the FS activity. Captopril considerably inhibited the amidase activities of urokinase (u-PA), tissue plasminogen activator (t-PA), and plasmin ([I]₅₀ (2.0?2.6) ± 0.1 mM), and the activation of Glu-plasminogen by t-PA and u-PA ([I]₅₀ (1.50?1.80) ± 0.06 mM), which may be due to the presence of a mercapto group in the inhibitor molecule. Lisinopril did not affect the amidase activities of FS enzymes, but stimulated Glu-plasminogen activation by u-PA and inhibited activation fibrin-bound Glu-plasminogen by t-PA ([I]₅₀ (12.0 ± 0.5) mM). Presumably, these effects can be explained by the presence in lisinopril of a Lys side residue, whose binding to lysine-binding Glu-plasminogen centers resulted, on the one hand, in the transformation from its closed conformation to a semi-open one and, on the other hand, in its desorption from fibrin. Unspecific inhibition of the activity of ACE, a key enzyme of the renin-angiotensin system, in the presence of 6-AHA and t-AMCHA ([I]₅₀ 10.0 ± 0.5 and 7.5 ± 0.4 mM, respectively) was found. A decrease in the ACE activity along with the growth of the fibrin monomer concentration was revealed. The data demonstrate that, along with endogenous mediated interaction between FS and RAS, relations based on the direct interactions of exogenous inhibitors of one system affecting the activities of components of another system can take place.     

The kallikrein-kinin system in the rat hypothalamus

Summary High molecular weight kininogen (HKg) and T kininogen (TKg) were detected and localized by immunocytochemistry in adult rat hypothalamus. In addition, kininogens were measured by their direct radioimmunoassay (RIA) or by indirect estimation of kinins released after trypsin hydrolysis and high pressure liquid chromatography (HPLC) separation of bradykinin (BK) and T kinin. A specific HKg immunoreactivity demonstrated with antibodies directed against the light chain (LC) of HKg was colocated with SRIF in neurons of hypothalamic periventricular area (PVA) projecting to external zone (ZE) of median eminence (ME). Heavy chain (HC) immunoreactivity which could be related to HKg or to low molecular weight kininogen (LKg) was detected in some other systems: i) parvocellular neurons of suprachiasmatic (SCN) and arcuate nuclei containing SRIF, ii) magnocellular neurons (mostly oxytocinergic) of paraventricular (PVN) and supraoptic (SON) nuclei, iii) neurons of dorsomedian and lateral hypothalamic areas. TKg immunostaining was restricted to magnocellular neurons of PVN, SON, accessory nuclei (mostly vasopressinergic) and to parvocellular neurons of SCN (vasopressinergic). TKg projections are directed towards the internal zone (ZI) of ME, but very few immunoreactive terminals are detectable in neurohypophysis. TKg staining parallels with vasopressin during water deprivation, and is undetectable in homozygous Brattleboro rats. In some magnocellular neurons, TKg and HC (related to HKg or LKg) are coexpressed. TKg, was also detected in hypothalamus and cerebellum extracts by direct RIA, and BK and T kinin were identified after trypsin hydrolysis. HKg and LKg can act as precursor of BK which can play a physiological role as releasing factor, neuromodulator — neurotransmitter, — or modulator of local microcirculation in hypothalamus. The three kininogens are also potent thiolprotease inhibitors which could modulate both the maturation processes of peptidic hormones and their inactivation and catabolism.     

The central and peripheral renin-angiotensin and noradrenergic systems in the spontaneous hypertensive rats (SHR)

The aim of this study was to evaluate the components of the renin-angiotensin system in the periphery and in the central nervous system (CNS) of the spontaneous hypertensive rats (SHR). On the other hand, the norepinephrine (NE) content of the different areas and of the mesenteric artery were also measured. Sixteen SHR and 9 Wistar Kyoto (WKY) control animals were used at about 6 months of age. Blood and cerebrospinal fluid (CSF) samples were collected. The brain was dissected into several areas and the mesenteric artery was excised. Plasma renin activity (PRA), plasma angiotensinogen concentration (P1AoC), brain renin (RC) and angiotensinogen concentrations (AoC) were evaluated by radioimmunoassay. NE was determined in all the tissues by a fluorimetric technique. PRA, P1AoC and NE concentration in the mesenteric artery were similar in both groups. An increase in the NE content of the cerebellum was detected in the SHR without changes in the other areas of the CNS. AoC was decreased in the CSF and in the brain stem of the SHR animals. RC was evaluated in the hypothalamus, brain stem, cerebral cortex and cerebellum of the same strain of rats. These results seem to indicate the some alteration of the peptidergic system in the CNS is present in the hypertensive animals.     

The occurrence of a multilayered structure in the sperm of a pteridophyte

Summary A multilayered structure, previously recorded only in bryophytes, is reported in spermatids of three species of Equisetum. It is interpreted as comprising four layers, recalling the Vierergruppe of Marchantia spermatids. Unlike the multilayered structure of bryophyte spermatids, a rather compact organelle, that of Equisetum forms a thin strip extending almost the whole diameter of the cell. As in bryophytes the upper layer of the Equisetum multilayered structure is composed of parallel microtubules, extending far beyond the underlying layers. The microtubular band is considered equivalent to the similar structure seen in a variety of plant spermatozoids, but in Equisetum it is much longer and composed of many more microtubules than reported from any other plant spermatozoid. The morphology of the multilayered structure is related to the large size and short, broad form of Equisetum spermatozoids.     

The renin-angiotensin system and sodium appetite

Intracranial renin is a potent stimulus to sodium appetite and thirst, the effects being mediated by local generation of angiotensin II. Intakes are persistent and lead to fluid retention during the first 24 h (Avrith and Fitzsimons, 1983). Increased circulating renin after captopril treatment in adrenalectomized rats (Elfont and Fitzsimons, 1981), or in renal hypertension following partial inter-renal aortic ligation (Costales et al., 1982), also leads to increased intakes of 2.7% NaCl and water. Fluid intakes after aortic ligation were independent of the severity of hypertension produced by this procedure. In both the examples given, additional stimulation resulting from the hypovolaemia itself is required for the full expression of increased sodium appetite, but in both cases angiotensin makes a significant contribution to sodium appetite as well as thirst. Therefore, as has been shown for thirst, angiotensin is one of a number of factors that act together to cause increased sodium appetite in hypovolaemia.     

The renin-angiotensin system in the rat brain

Summary The distribution of angiotensinogen containing cells was determined in the brain of rats using immunocytochemistry. Specific angiotensinogen immunoreactivity is demonstrated both in glial cells and neurons throughout the brain, except the neocortical and cerebellar territories. Positive neurons are easily and invariably detected in female brains, and haphazardly in male brain (sex hormone dependent). Angiotensinogen immunoreactivity in male brain neurons can be induced by water deprivation or binephrectomy in some areas and particularly in paraventricular nuclei. Finally, the highest concentrations of positive neurons are found in the anterior and lateral hypothalamus, preoptic area, amygdala and some well known nuclei of the mesencephalon and the brainstem.Our results confirm the wide distribution of angiotensinogen mRNA in the brain reported recently by Lynch et al. (1987). Thus the demonstration of angiotensinogen in neurons and glial cells allows a greater understanding of the biochemical and physiological data in accordance with multiple brain renin angiotensin systems.     

The renin-angiotensin system and the central nervous system.

One of several factors affecting the secretion of renin by the kidneys is the sympathetic nervous system. The sympathetic input is excitatory and is mediated by beta-adrenergic receptors, which are probably located on the membranes of the juxtaglomerular cells. Stimulation of sympathetic areas in the medulla, midbrain and hypothalamus raises blood pressure and increases renin secretion, whereas stimulation of other parts of the hypothalamus decreases blood pressure and renin output. The centrally active alpha-adrenergic agonist clonidine decreases renin secretion, lowers blood pressure, inhibits ACTH and vasopressin secretion, and increases growth hormone secretion in dogs. The effects on ACTH and growth hormone are abolished by administration of phenoxybenzamine into the third ventricle, whereas the effect on blood pressure is abolished by administration of phenoxybenzamine in the fourth ventricle without any effect on the ACTH and growth hormone responses. Fourth ventricular phenoxybenzamine decreases but does not abolish the inhibitory effect of clonidine on renin secretion. Circulating angiotensin II acts on the brain via the area postrema to raise blood pressure and via the subfornical organ to increase water intake. Its effect on vasopressin secretion is debated. The brain contains a renin-like enzyme, converting enzyme, renin substrate, and angiotensin. There is debate about the nature and physiological significance of the angiotensin II-generating enzyme in the brain, and about the nature of the angiotensin I and angiotensin II that have been reported to be present in the central nervous system. However, injection of angiotensin II into the cerebral ventricles produces drinking, increased secretion of vasopressin and ACTH, and increased blood pressure. The same responses are produced by intraventricular renin. Angiotensin II also facilitates sympathetic discharge in the periphery, and the possibility that it exerts a similar action on the adrenergic neurons in the brain merits investigation.     

Reactivity of alpha 1-antitrypsin mutants against proteolytic enzymes of the kallikrein-kinin, complement, and fibrinolytic systems

Increased extracellular proteolysis because of unregulated activation of blood coagulation, complement, and fibrinolysis is observed in thrombosis, shock, and inflammation. In the present study, we have examined whether the plasma kallikrein-kinin system, the classical pathway of complement, and the fibrinolytic system could be inhibited by alpha 1-antitrypsin reactive site mutants. Wild-type alpha 1-antitrypsin contains a Met residue at P1 (position 358), the central position of the reactive center. It did not inhibit plasma kallikrein, beta-factor XIIa, plasmin, tissue-type plasminogen activator (t-PA), or urokinase. In contrast, these serine proteases were inhibited by alpha 1-antitrypsin Arg358. For the inhibition of C1s, a double mutant having Arg358 and a Pro----Ala mutation at P2 (position 357) was required. This double modification was made because C1-inhibitor, the natural inhibitor of C1s, has Arg and Ala residues at positions P1 and P2. Plasminogen activator inhibitor 1, the natural inhibitor of t-PA, also has Arg and Ala residues at positions P1 and P2. In a purified system, alpha 1-antitrypsin Ala357-Arg358 was 150-fold less efficient against C1s than C1-inhibitor and 27,000-fold less efficient against t-PA than plasminogen activator inhibitor-1. In plasma, 2.3 microM alpha 1-antitrypsin Ala357-Arg358 reduced by 65% the formation of a complex between kallikrein and C1-inhibitor following activation of the intrinsic pathway of blood coagulation by kaolin. Furthermore, after supplementation by 2.0 microM alpha 1-antitrypsin Ala357-Arg358, zymographic analysis showed that the majority of the free t-PA of normal plasma formed a bimolecular complex with the double mutant. In contrast, 3.4 microM alpha 1-antitrypsin Ala357-Arg358 did not prevent the activation of the classical pathway of complement observed when normal serum is supplemented with anti-C1-inhibitor F(ab')2 fragment. These results demonstrate that alpha 1-antitrypsin Ala357-Arg358 has therapeutic potential for disorders with unregulated activation of the intrinsic pathway of blood coagulation and the fibrinolytic system; however, the double mutant is not an efficient inhibitor for the classical pathway of complement.     

Biodiversity and ecosystem services: a multilayered relationship

The relationship between biodiversity and the rapidly expanding research and policy field of ecosystem services is confused and is damaging efforts to create coherent policy. Using the widely accepted Convention on Biological Diversity definition of biodiversity and work for the U.K. National Ecosystem Assessment we show that biodiversity has key roles at all levels of the ecosystem service hierarchy: as a regulator of underpinning ecosystem processes, as a final ecosystem service and as a good that is subject to valuation, whether economic or otherwise. Ecosystem science and practice has not yet absorbed the lessons of this complex relationship, which suggests an urgent need to develop the interdisciplinary science of ecosystem management bringing together ecologists, conservation biologists, resource economists and others.