Primacy of angiotensin converting enzyme in angiotensin-(1-12) metabolism.

Angiotensin-(1-12) [ANG-(1-12)], a new member of the renin-angiotensin system, is recognized as a renin independent precursor for ANG II. However, the processing of ANG-(1-12) in the circulation in vivo is not fully established. We examined the effect of angiotensin converting enzyme (ACE) and chymase inhibition on angiotensin peptides formation during an intravenous infusion of ANG-(1-12) in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). WKY and SHR were assigned to a short ANG-(1-12) infusion lasting 5, 15, 30, or 60 min (n = 4-10 each group). In another experiment WKY and SHR were assigned to a continuous 15-min ANG-(1-12) infusion with pretreatment of saline, lisinopril (10 mg/kg), or chymostatin (10 mg/kg) (n = 7-13 each group). Saline or lisinopril were infused intravenously 15 min before the administration of ANG-(1-12) (2 nmol·kg(-1)·min(-1)), whereas chymostatin was given by bolus intraperitoneal injection 30 min before ANG-(1-12). Infusion of ANG-(1-12) increased arterial pressure and plasma ANG-(1-12), ANG I, ANG II, and ANG-(1-7) levels in WKY and SHR. Pretreatment with lisinopril caused increase in ANG-(1-12) and ANG I and large decreases in ANG II compared with the other two groups in both strains. Pretreatment of chymostatin had no effect on ANG-(1-12), ANG I, and ANG II levels in both strains, whereas it increased ANG-(1-7) levels in WKY. We conclude that ACE acts as the primary enzyme for the conversion of ANG-(1-12) to smaller angiotensin peptides in the circulation of WKY and SHR and that chymase may be an ANG-(1-7) degrading enzyme.

Multiphoton imaging of the glomerular permeability of angiotensinogen.

Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration.

Effects of proangiotensin-12 infused continuously over 14 days in conscious rats.

The carboxyl terminal-extended form of angiotensin I, proangotensin-12, was recently identified in rat tissues including the small intestine, cardiac ventricles, and kidneys. Single administration of proangiotensin-12 exerts vasoconstrictor and pressor effects, probably by conversion to angiotensin II; however, there are currently no data available about the subacute effects of proangiotensin-12. In the present study, we examined the effects of prolonged infusion of proangiotensin-12 in conscious rats. Continuous, subcutaneous infusion of 240 pmol/kg/min of proangiotensin-12 gradually elevated blood pressure over 14 days, as did the same dose of angiotensin II. The pressor effects of proangiotensin-12 were abolished by oral administration of losartan, an angiotensin II type 1 receptor blocker, or perindopril, an angiotensin converting enzyme (ACE) inhibitor. Meanwhile, angiotensin II-induced elevation of blood pressure was inhibited by losartan but not by perindopril. Both the plasma aldosterone level and heart weight/body weight ratio were increased by the prolonged infusion of proangiotensin-12, but these increases were attenuated by losartan and perindopril. The present results suggest that proangiotensin-12 infused continuously over 14 days exerts pressor effects accompanied with the elevation of plasma aldosterone and cardiac hypertrophy in an ACE- and angiotensin II type 1 receptor-dependent manner.

Fisiopatología de la prorrenina y la renina. Cincuenta años en busca de los inhibidores directos de la renina. Sus ventajas y sus limitaciones / Physiopathology of prorenin and renin. Fifty years in search of direct renin inhibitors. Their benefits and limitations

La renina es la enzima que limita la síntesis de angiotensina II y la activación del sistema renina-angiotensina (SRA), por lo que desde hace más de 50 años se ha intentado desarrollar fármacos activos por vía oral capaces de inhibir directamente la renina. Recientemente se ha demostrado que prorrenina y renina son moléculas activas que interactúan con un receptor específico, (P)RR, y que su estimulación activa diversas vías de señalización independientes de las activadas por la angiotensina II. Aliskiren, el primer inhibidor directo de la renina (IDR) no peptídico, activo por vía oral, ha mostrado eficacia y seguridad en el tratamiento de la hipertensión arterial. Este artículo revisa el desarrollo de los IDR, el papel fisiopatológico de la prorrenina y la renina, la estructura y las vías de señalización acopladas a la activación del (P)RR, el mecanismo de acción y las posibles diferencias, ventajas y/o desventajas de los IDR con respecto a otros fármacos que inhiben el SRA, como los inhibidores de la enzima de conversión y los antagonistas de los receptores AT1 (AU)

Renin is an enzyme that limits angiotensin-II synthesis and activates the renin-angiotensin system (RAS). Therefore, for almost 50 years, multiple attempts were made to develop orally active direct renin inhibitors (DRIs). Recently, it has been demonstrated that both prorenin and renin are active molecules that interact with a specific receptor, (P)RR, and that stimulation of this receptor leads to the activation of signal transduction pathways independent of angiotensin-II activity. Aliskiren, the first non-peptide orally active DRI, has been found to be safe and effective in the treatment of hypertension. The present article reviews the development of DRIs, the pathophysiological roles of prorenin and renin, the structure of and the signal transduction pathways involved in activation of the (P)RR, and the mechanisms of action of, the possible differences between, and the comparative advantages and disadvantages of DRIs and other RAS inhibitors, mainly angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers (AU)

Gene therapy of amyotrophic lateral sclerosis.

Two-year experiments were performed to evaluate the neurotrophic effect of hypoxia-inducible factors (vascular endothelial growth factor and angiogenin) expressed in recombinant human adenoviruses in amyotrophic lateral sclerosis. Randomized placebo-controlled trial demonstrated safety and good tolerability of the recombinant antiviral drugs. The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates differential approach to the selection of patients and continuous monitoring of gene therapy.

Cardiovascular response to renin substrate microinjection into the central nucleus of the amygdala of rats.

Central nucleus of the amygdala is involved in cardiovascular regulation. Although most components of the renin-angiotensin system have been found to be distributed in amygdala, renin expression in brain has remained controversial. This work was undertaken to elucidate the extent of renin presence in this nucleus. A cannula was implanted bilaterally into the central nucleus of the amygdala. Mean arterial pressure and heart rate were directly measured via indwelling femoral artery cannula post bilateral intra central nucleus of the amygdala microinjection of renin substrate. Renin substrate microinjection dose-dependently increased mean arterial pressure and heart rate, whereas captopril, saralasin and losartan pretreatment inhibited these effects. The results suggest the presence of local renin or similar proteases in this nucleus.

Microinjection of renin-angiotensin system peptides in discrete sites within the rat periaqueductal gray matter elicits antinociception.

The intracerebroventricular administration of renin substrate or angiotensin II evokes antinociception in rodents, but the brain sites where most of the renin-angiotensin system peptides act are not yet known. This study describes the antinociceptive effects of microinjecting porcine renin substrate tetradecapeptide (RS) or angiotensins I (AI), II (AII) or III (AIII) into different regions of the periaqueductal gray matter (PAG), using the rat tail flick test. All the above peptides were effective following administration into several PAG regions. Their antinociceptive effects were strongly evoked from the caudal ventrolateral and ventral PAG, including the dorsal raphe nucleus. A dose-dependent antinociception following administration into the ventrolateral PAG was demonstrated for all peptides studied. The effect of AII from the ventrolateral PAG was inhibited by the previous local administration of saralasin, a non-selective angiotensin receptor antagonist. Moreover, the peak effects of RS and AI occurred later than those of AII and AIII. The time-course of antinociception suggests that longer-chain peptides are locally processed to biologically active smaller-chain peptides. This study shows for the first time the antinociceptive effect of RS, AI, AII and III in well-defined PAG regions, an effect that is receptor mediated for AII.

Óxido nítrico: un campo abierto para la angiología y la cirugía vascular / Nitric oxide: open field to angiology and vascular surgery

Objetivo. El objetivo es promover la formación continua de los profesionales de la cirugía vascular y angiología mediante una recopilación de las últimas publicaciones sobre el tema. Desarrollo. Abordamos la bioquímica, formación, regulación, acciones, posibles usos y la relevancia clínica de la molécula de óxido nítrico, compuesto sintetizado por la mayoría de las células de los mamíferos y que presenta efectos vasomotores locales y sistémicos de importancia para la mayoría de las patologías y tratamientos del ámbito de la cirugía vascular y de la angiología. Conclusión. Se han identificado las diversas áreas de actuación para su uso y se ha sugerido la terapia manipuladora de la respuesta endógena del compuesto mencionado, con el fin de obtener mejores resultados en los ámbitos de la medicina citados anteriormente (AU)

A study of the renin inhibitor H142 in man.

The inhibitor of human renin, H142, was studied in nine male volunteers. On three occasions, in random order, volunteers were infused with 5% dextrose or with H142 at 1.0 or 2.5 mg/kg per h for 30 min while supine and thereafter with dextrose for 1 1/2 h. There was a marked reduction in plasma active renin concentration as assayed by an enzyme-kinetic method, with parallel falls in the circulating concentrations of angiotensins (ANG) I and II, all of which rebounded transiently to values above basal after the H142 infusion was stopped. In contrast, total renin concentration as measured by radio-immunoassay rose while ANG I and II fell, subsiding when H142 was discontinued. There was a slight but significant increase in plasma noradrenaline as renin became inhibited; plasma adrenaline was unchanged. H142 produced a slight fall in systolic blood pressure (SBP) and a clearer, highly significant, dose-related fall in diastolic blood pressure (DBP). There was a modest but significant increase in the heart rate. These studies confirm H142 as an effective inhibitor of human renin in vivo.

Angiotensin II concentration in cerebrospinal fluid after intraventricular injection of angiotensinogen or renin.

To determine if the brain enzyme which has renin-like activity in vitro can form angiotensin in vivo, angiotensin II concentration in cerebrospinal fluid (CSF) was measured before and at various intervals after injection of partially purified renin substrate (angiotensinogen) into the third cerebral ventricle of anesthetized dogs. The injection increased CSF angiotensinogen concentration 3-fold, but despite this, CSF angiotensin II concentration, which was undetectable (less than 6.25 fmol/ml) before injection, did not change. Arterial blood pressure was also unchanged after the injection. In contrast, both CSF angiotensin II concentration and arterial pressure increased after an inventricular injection of renin. These results demonstrate that angiotensin II is formed centrally after administration of exogenous renin but not after injection of angiotensinogen. The results thus fail to demonstrate renin activity in the brain in vivo.