The terms 'autacoid', 'hormone' and 'chalone' and how they have shifted with time.

The increase of knowledge in a particular field (endocrinology) can be understood if one follows how certain key concepts were constructed and transformed over time. To explore such construction and transformation (shifts in meaning), we studied the use of the concepts 'autacoid' and 'chalone' in a period of one century (1916-2016), since the introduction of these concepts by the British professor of physiology Sir Sharpey-Schäfer. We could identify that the use of 'autacoid' shifted from a very broad category encompassing both stimulating and inhibiting hormones, in the period 1916-1960, to a much more specific use of the term for locally produced bioactive molecules, from the 1960s onwards. Histamine was the first compound seen as an 'autacoid', followed by prostaglandins, ATP, ADP and bradykinin, and from 1993 onwards, compounds such as 'palmitoylethanolamide' were also classified as 'autacoids'. For 'chalone', a comparable shift was noticed around the 1960s, when the concept suddenly changed from the category of inhibiting hormones into a substance that is produced within a tissue, inhibiting mitosis of the cells of that tissue. For both concept shifts, we could not find any argument. Around 1980, authors started to relate autacoids to various promising indications in the field of inflammation and immune modulation. The Nobel laureate Rita Levi-Montalcini gave an extra dimension to the concept autacoid in 1993, and introduced a new class of compounds modulating mast cells, the ALIAmides (from Autacoid Local Inflammation Antagonist), of which palmitoylethanolamide was the prototype. Our exploration demonstrates that biomedical concepts can be constructed and defined differently as time goes by, while concept transformations seem to emerge without arguments.

Characterization of local vascular effects of the nitric oxide inhibitor NG-monomethyl-L-arginine on dorsal hand veins.

Infusion of NG-monomethyl-L-arginine (L-NMMA; 6.4 µmol/min) into hand veins can cause a 20% increase in vein size in specific subjects. This study explored potential underlying mechanisms in healthy male participants. Ten healthy male participants received in phenylephrine (PE)-preconstricted veins a dose-response curve (DRC) to L-NMMA (0.2-6.4 µmol/min) without and with coinfusion of the endothelium-dependent dilator histamine, a DRC to L-arginine with and without coinfusion of L-NMMA, a DRC to NG-monomethyl-D-arginine (D-NMMA), and a DRC to L-NMMA in prostaglandin F(2α)-(PGF(2α))-preconstricted veins. Participants were classified as L-NMMA responders (R) and nonresponders (NR). Infusion of L-NMMA resulted in a maximum venodilation of 38% ± 11% (R) versus 10% ± 5% (NR; P = .005). In PGF(2α)-preconstricted veins, L-NMMA caused venodilation to 26% ± 34% (NS) in responders. Results suggest that endothelial nitric oxide synthase-mediated formation of nitric oxide (NO) from L-NMMA in doses >3.2 µmol/min and continuous PE-induced α-adrenergic stimulation resulting in release of very small amounts of NO from L-NMMA contribute to the observed L-NMMA-induced increase in vein size. Venous reactivity to L-NMMA resulting in a phenotype as R or NR is most likely genetically predetermined, which requires further study.

Identification of 9-cis-retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion.

The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat ß-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4α mRNA expression, ∼8- and 80-fold, respectively: defects in Pdx-1 or HNF4α cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas ß-cells generate 9cRA, and mouse models of reduced ß-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have ß-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.

Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy.

OBJECTIVE: This study was aimed at obtaining a profile of lipids and proteins with a paracrine function in normal and diabetic vitreous and exploring whether the profile correlates with retinal pathology. RESEARCH DESIGN AND METHODS: Vitreous was recovered from 47 individuals undergoing vitreoretinal surgery: 16 had nonproliferative diabetic retinopathy (NPDR), 15 had proliferative diabetic retinopathy, 7 had retinal detachments, and 9 had epiretinal membranes. Protein and lipid autacoid profiles were determined by protein arrays and mass spectrometry-based lipidomics. RESULTS: Vitreous lipids included lipoxygenase (LO)- and cytochrome P450 epoxygenase (CYP)-derived eicosanoids. The most prominent LO-derived eicosanoid was 5-hydroxyeicosate traenoic acid (HETE), which demonstrated a diabetes-specific increase (P = 0.027) with the highest increase in NPDR vitreous. Vitreous also contained CYP-derived epoxyeicosatrienoic acids; their levels were higher in nondiabetic than diabetic vitreous (P < 0.05). Among inflammatory, angiogenic, and angiostatic cytokines and chemokines, only vascular endothelial growth factor (VEGF) showed a significant diabetes-specific profile (P < 0.05), although a similar trend was noted for tumor necrosis factor (TNF)-alpha. Soluble VEGF receptors R1 and R2 were detected in all samples with lowest VEGF-R2 levels (P < 0.05) and higher ratio of VEGF to its receptors in NPDR and PDR vitreous. CONCLUSIONS: This study is the first to demonstrate diabetes-specific changes in vitreous lipid autacoids including arachidonate and docosahexanoate-derived metabolites indicating an increase in inflammatory versus anti-inflammatory lipid mediators that correlated with increased levels of inflammatory and angiogenic proteins, further supporting the notion that inflammation plays a role the pathogenesis of this disease.

Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury.

Inflammation and angiogenesis are intimately linked, and their dysregulation leads to pathological angiogenesis in human diseases. 15-lipoxygenase (15-LOX) and lipoxin A(4) receptors (ALX) constitute a LXA(4) circuit that is a key feature of inflammatory resolution. LXA(4) analogs have been shown to regulate vascular endothelial growth factor (VEGF)-A-induced angiogenic response in vitro. 15-LOX and ALX are highly expressed in the avascular and immune-privileged cornea. However, the role of this endogenous LXA(4) circuit in pathological neovascularization has not been determined. We report that suture-induced chronic injury in the cornea triggered polymorphonuclear leukocytes (PMN) infiltration, pathological neovascularization, and up-regulation of mediators of inflammatory angiogenesis, namely VEGF-A and the VEGF-3 receptor (FLT4). Up-regulation of the VEGF circuit and neovascularization correlated with selective changes in both 15-LOX (Alox15) and ALX (Fpr-rs2) expression and a temporally defined increase in basal 15-LOX activity. More importantly, genetic deletion of 15-LOX or 5-LOX, key and obligatory enzymes in the formation of LXA(4), respectively, led to exacerbated inflammatory neovascularization coincident with increased VEGF-A and FLT4 expression. Direct topical treatment with LXA(4), but not its metabolic precursor 15-hydroxyeicosatetraenoic acid, reduced expression of VEGF-A and FLT4 and inflammatory angiogenesis and rescued 15-LOX knockout mice from exacerbated angiogenesis. In summary, our findings and the prominent expression of 15-LOX and ALX in epithelial cells and macrophages place the LXA(4) circuit as an endogenous regulator of pathological angiogenesis.

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions.

The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MPhis). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MPhis converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MPhi mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MPhis in tissue homeostasis, inflammation resolution, wound healing, and host defense.

Endogenous urea as an autacoid: extrarenal and renal focuses.

The present position article complies with selected own and literature data concerning the characterization of endogenous urea at extrarenal level in animal and human organism in functional aspect. With key pharmacological experiments, both under in vivo and in vitro conditions, we apply urea in concentrations corresponding to physiological and pathological ones. We established that endogenous urea (without use as an exogenous applied drug) possesses important properties. It is assumed that urea is an endogenous non-specific beta-adrenergic receptor antagonist (ENBARA), non-selective, non-competitive, reversible and non-toxic. Based on these data we develop a concept for endogenous beta-adrenergic receptor antagonists (EBARA). In agreement with proofs of RJ Lefkowitz' group in the 90-ies that "beta arrestines 1 and 2 antagonize three of four agonist-activated beta-adrenergic receptors" we accept that they act as relatively endogenous specific beta-adrenergic receptor antagonists (RESBARA). As regards for the last four beta-agonist-activated adrenergic receptor we propose that is controlled via ENBARA. That is why a new role of urea is to be in the list of endocoids (autacoids).

The role of autacoids and the autonomic nervous system in cardiovascular responses to radio-frequency energy heating.

Among the potential effects of exposure to high levels of radio-frequency energy (RFE) (which includes microwaves), an increase in body temperature is the primary consequence. Release of autacoids and activity of the autonomic nervous system may influence (or be directly responsible for) some of the physiological changes that occur in conjunction with this hyperthermia. The main focus of this review is the interaction of autacoids and the autonomic nervous system with cardiovascular changes during heating. Differences between environmental and RFE-induced heating (such as rate of temperature change and degree of skin vs. core heating) may be important when considering these effects. Antihistamines exhibited no beneficial effect on circulatory collapse during RFE-induced heating. The serotonergic blocker methysergide decreased survival time in rats during terminal RFE exposure, despite no effects on heart rate (HR) or blood pressure. Although blockade of platelet-activating factor resulted in lower HR before RFE exposure, there was a lack of effect on the subsequent increase in HR during heating. Nitric oxide did not contribute to the hypotension that occurs due to rapid heating by RFE exposure. There have been either no or very limited studies of effects of prostaglandins, bradykinin, or angiotensin on RFE-induced heating responses. beta-Adrenoceptor antagonism with propranolol resulted in significantly decreased survival times and lower final colonic temperatures during RFE exposure. A lack of effects of nadolol on survival time and temperature, coupled with its poor ability to traverse the blood-brain barrier, suggests that central beta-adrenergic stimulation rather than peripheral stimulation may alter thermoregulation. Effects of the autonomic nervous system (as studied by adrenoceptor blockade) on potassium changes during heating have not been fully investigated. Such changes could be important in animals' responses to RFE and other modalities of heating, and should be studied in future.

Effects of cyclic AMP-elevating hormones and autacoids on LPS-activated rat peritoneal, bronchoalveolar and hepatic (Kupffer) macrophages.

Peritoneal, bronchoalveolar and hepatic (Kupffer) macrophages activated in vitro by endotoxin, exhibit alterations in nitric oxide production when certain hormones or other biologically active agents (autacoids) are present in the culture medium. They also show changes in acid beta-glucuronidase activities and morphological changes concerning cell size and general appearance. Agents known to elevate the intracellular levels of cyclic AMP, e.g. adrenalin, prostaglandin E2 and dopamine, increase the nitric oxide production in all three types of macrophage. The addition of H-89, an inhibitor of protein kinase A, abolishes the increase in nitric oxide production. Adrenalin also increases the extracellular activity of beta-glucuronidase. The results of this work suggest that cyclic AMP-elevating hormones and autacoids affect the functions of endotoxin-activated macrophages, such as the production of nitric oxide and the activity of acid beta-glucuronidase.

Anti-thrombotic activity of PDR, a newly synthesized L-Arg derivative, on three thrombosis models in rats.

The possibility of a newly synthesized L-arginine derivative, polyaspartoyl-L-arginine (PDR), as a novel anti-thrombotic agent and its mode of action were investigated. The anti-platelet effects of PDR in rats ex vivo, anti-thrombotic effects in three thrombosis models in rats and its effect on some autacoids (nitric oxide [NO], thromboxane [TXA2] and prostacyclin [PGI2]) were studied. PDR (i.g.) significantly inhibited ADP-, collagen- or thrombin-induced rat platelet aggregation. In arteriovenous shunt model and ferric chloride-induced arterial thrombosis model in rats, PDR (i.g.) significantly reduced the thrombus weight. In electrical stimulation-induced arterial thrombosis in rats, PDR (i.v.) dose-dependently prolonged the thrombus occlusion time (OT). PDR increased the concentration of NO in plasma. In contrast with aspirin (ASA), PDR did not influence on the TXA2 and PGI2 levels in plasma. In conclusion, PDR is provided with significant inhibitory effect on platelet aggregation and prevention effect on platelet related thrombosis, which is probably attributed to its inhibition on platelet function by L-arginine-NO pathway. The results demonstrate that PDR is a novel, oral and venous effective platelet aggregation inhibitor and has a possibility used as an anti-thrombotic agent.

EDHF, but not NO or prostaglandins, is critical to evoke a conducted dilation upon ACh in hamster arterioles.

Vasomotor reactions upon focal stimulation of arterioles have been shown to be conducted along the vascular wall. Such a conduction, which is assumed to reflect the spread of electrical signals, may contribute to coordination of responses within a vascular segment. We aimed to identify which endothelial autacoid(s) act as mediators of the local and conducted dilator responses, respectively. To this end, arterioles in the hamster cremaster microcirculation were locally stimulated with endothelium-dependent [acetylcholine (ACh)] or endothelium-independent dilators [sodium nitroprusside (SNP)], and the resulting changes in diameter were measured using a videomicroscopy technique at the site of application and up to 1.4 mm upstream at distant sites. Experiments were also performed after blockade of nitric oxide (NO) synthase, cyclooxygenase, P-450 monooxygenase, or K(+) channels. Dilations upon ACh (71 +/- 3%) were conducted rapidly (<1 s) to upstream sites (at 1.4 mm: 37 +/- 5%). Although the NO donor SNP induced a similar local dilation (71 +/- 7%), this response was not conducted. Maximal amplitudes of ACh-induced dilations were not attenuated after inhibition of NO synthase and cyclooxygenase at the local and remote sites. However, additional treatment with a P-450 monooxygenase blocker (sulfaphenazole) strongly attenuated the local response (from 62 +/- 9 to 17 +/- 5%) and abrogated dilations at distant sites (at 0.67 mm: from 23 +/- 4% to 4 +/- 3%). Likewise, 17-octadecynoic acid strongly attenuated local and remote responses. Blockers of Ca(2+)-dependent K(+) channels (charybdotoxin or iberiotoxin) attenuated dilations at the local and remote sites after focal application at the ACh stimulation site. In marked contrast, treatment of the upstream site with these blockers was without any effect. We conclude that upon local stimulation with ACh, a cytochrome P-450 monooxygenase product is generated that induces local dilation via the activation of Ca(2+)-dependent K(+) channels and initiates conduction of the dilation. In contrast to the local site, neither activation of these K(+) channels nor the synthesis of NO or prostaglandins is necessary to dilate the arterioles at remote, distant sites. This suggests that endothelium-derived hyperpolarizing factor serves as an important mediator to initiate conducted dilations and, by doing so, may act as a key player in the coordination of arteriolar behavior in the microcirculatory network.

[Effect of vasotocin and prostaglandin E2 on absorption of water and ions in the large intestine of a grass fog]. / Vliianie vazototsina i prostaglandina E2 na vsasyvanie vody i ionov v tolstoi kishke travianoi liagushki.

In experiments on the frog Rana temporaria L. isolated colon, it has been shown that the rate of fluid absorption from the lumen is the highest when the lumen contains a hypotonic solution (22.5 mOsm/kg H2O), whereas the rate is lower in case of mucosal Ringer solution (225 mOsm/kg H2O). 10 nmole arginine-vasotocin rises the hypotonic fluid absorption, while 0.1 mumole prostaglandin E2 reduces the fluid absorption. Water content in the colon wall is the highest at mucosal hypotonic Ringer solution. 0.1 mumole prostaglandin E2 decreases hydration of the colon tissue. Secretion of prostaglandins E1 and E2 into the extracellular fluid of the colon has been established. The data obtained indicate participation of vasotocin and prostaglandin E2 in regulation of fluid absorption in the frog colon.

Endogenous morphine and codeine. Possible role as endogenous anticonvulsants.

Exogenously administered morphine can have both convulsive or anticonvulsive effects, depending on the dose and species. The levels of the endogenous opiate alkaloids morphine and codeine were significantly elevated in specific rat brain regions by the convulsive drug, pentylenetetrazole, as well as by the anticonvulsant drugs, carbamazepine and phenytoin. Morphine and codeine levels in peripheral tissues (heart, lung, spleen and adrenal) were unaffected by these drugs. Maximal increases in morphine levels were seen in the hypothalamus and striatum (2-10-fold), while lesser increases occurred in the midbrain and brain stem (2-4-fold). Codeine levels were also markedly increased in hypothalamus (5-10 fold), In contrast to morphine, codeine levels were also increased in the hippocampus (2-10-fold), but were unchanged in the striatum. These studies suggest that the endogenous alkaloids morphine and codeine are involved in the modulation of convulsions and that morphine and/or codeine may act as an endogenous anticonvulsant.

Down-regulation and recovery of endothelin-1 binding and signaling in rat cardiomyocytes.

Down-regulation and recovery of endothelin (ET) receptors and of ET-dependent phosphoinositide-specific phospholipase C (PI-PLC) signaling was examined in cultured cardiomyocytes from neonatal rats. Three hours treatment with 5 nM ET-1 decreased surface receptors to 30%, and transduction to 19%, of their respective time-zero values. After extensive washing and a 3 h recovery period surface receptors returned to 74% of the time-zero value, with concomitant recovery of signal transduction to 75% of the time-zero value. The recovery of PI-PLC signaling in these cells is in contrast with a previous report, but consistent with recovery of the receptor complement.

Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats.

The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT(2) receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT(2) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 microL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109+/-4 to 130+/-4 mm Hg (n=8, P<0.01), whereas S-ODN-treated (n=8) and vehicle-treated (n=8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitial fluid cGMP decreased from 11.9+/-0.8 to 3.6+/-0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05+/-0.05 to 0.18+/-0.03 ng/mL (P<0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had approximately 40% less expression of AT(2) receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT(2) receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT(2) receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.

Changes in renal autacoids and hemodynamics associated with aging and isolated systolic hypertension.

The aging kidney is characterized by a decrease in renal blood flow and glomerular filtration rate mainly due to glomerulosclerosis. Nevertheless, even in the presence of these changes, the kidney maintains its functionality until advanced age. However, there is a tendency towards greater renal vasoconstriction in the elderly as compared with young individuals. This occurs either in physiological circumstances such as physical exercise, or in disease manifestations, such as the effective circulatory volume depletion that develops, for example, in heart failure. This tendency may be secondary to the reduction of renal autacoid modulatory capacity, particularly at the vasodilating prostaglandin level. In an acute experimental model we could demonstrate that, in the healthy elderly, the renal response to adrenergic activation by mental stress is characterized by a prolonged and pronounced vasoconstriction. In addition to this, in elderly patients affected by isolated systolic hypertension, we demonstrated an impairment of renal hemodynamic and humoral adaptation capacity in response to adrenergic activation and blood pressure increase. In the presence of sudden blood pressure increase, the kidney of these patients responds with a passive vasodilation and a glomerular filtration rate increase without any activation of humoral modulatory substances. The impairment in renal adaptation capacity may predispose these patients to renal injury, particularly in the presence of the many hypertensive peaks which characterize everyday life of elderly individuals. In conclusion, these results show that renal adaptation capacity of elderly patients with isolated systolic hypertension is completely lost. Further studies will elucidate whether antihypertensive treatment per se, or specific classes of antihypertensive drugs, are able to revert this impairment.

Changes in renal autacoids in aged human hypertensives.

The aging process determines several modifications of the kidney, that, however, do not provoke any dysfunction in normal conditions. But in the elderly--in the presence of stressful situations and particularly when adrenergic activation is present--the kidney is more vulnerable than in the young, and renal failure may arise. Variations typical of the aging kidney are accelerated when hypertension overlaps the physiological renal process, because both senescence and hypertension weight on the same structures, i.e. glomeruli. We studied renal hemodynamic adaptation capacity both in the healthy elderly and in patients affected by isolated systolic hypertension, in an acute experiment which requires the application of a mental stress-induced adrenergic activation. In hypertensive patients we have already demonstrated a total lack of renal adaptation capacity. In fact, while the elderly normotensives react with a prolonged and pronounced vasoconstriction, in those with isolated systolic hypertension, adrenergic activation induces a passive renal vasodilation and glomerular hyperfiltration. The anomalous adaptation capacity of renal hemodynamics is probably due to an impairment in the paracrine response of renal vasculature. Indeed in the hypertensive elderly, unlike in the normotensive one, no variations of autacoid production occur during the adrenergic activation. Following on from this, pattients affected by isolated systolic hypertension passively suffer the many hypertensive peaks which characterize their every day life. The altered renal autoregulation of the elderly with isolated systolic hypertension may explain the accelerated glomerulosclerosis and the greater incidence of renal damage and end-stage renal disease which characterize this condition. These aspects underline the primary role of the antihypertensive treatment of isolated systolic hypertension, not only for the prevention of cardiovascular mortality but also of renal damage and/or end-stage renal disease.