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Background: The kidney and cardiovascular system are closely related to each other during the modulation of the cardiovascular homeostasis. However, the search for new alternatives for the treatment and diagnosis of cardiovascular diseases does not take into account this relationship, so their evaluation results and the advantages offered by their global and integrative analysis are wasted. For example, a variety of receptors that are overexpressed in both pathologies is large enough to allow expansion in the search for new molecular targets and ligands. Nanotechnology offers pharmacological targeting strategies to kidney, heart, and blood vessels for overcoming one of the essential restrictions of traditional cardiovascular therapies the ones related to their unspecific pharmacodynamics distribution in these critical organs. Recent Findings: Drug or contrast agent nano-targeting for treatment or diagnosis of atherosclerosis, thrombosis, renal cancer or fibrosis, glomerulonephritis, among other renal, cardiac and blood vessels pathologies would allow an increase in their efficacy and a reduction of their side effects. Such effects are possible because, through pharmacological targeting, the drug is mainly found at the desired site. Review Purpose: In this mini-review, active, passive, and physical targeting strategies of several nanocarriers that have been assessed and proposed for the treatment and diagnosis of different cardiovascular diseases, are being addressed.

The renin-angiotensin system (RAS) during fetal or neonatal stages has been involved in lung growth and differentiation process. We studied the effects of maternal exposure to enalapril during late gestation (G13-G21) on lungs from their offsprings. Pregnant rats were administered with enalapril (2,85 mg/kg/day) and lungs analyzed at postnatal ages, significant difference between P0 and P30. Enalapril-treatment did not modify ACE activity in mothers, but decreased significantly in P0 treated-pups suggesting direct placental drug transference. sACE expression increased with age in both groups. AT1 receptors expression was high and localized in alveolar, bronchiole and endothelium cells. We detected larger but fewer alveoli with decreased septation at earlier postnatal stage in enalapril-treated pups. Quantification of immunopositive nuclei demonstrated that in treated pups the proliferation impairs in newborn lungs and thus progressively increased during two postnatal weeks, at difference with controls animals, where the highest proliferation levels were at P0 and then decreased significantly. In coincidence, high α-smooth muscle actin staining at the tips of developing secondary septal structures was observed at P15, evidencing an active elastogenesis. In summary, decreased ACE activity produced histomorphological changes and an impaired cellular proliferation at the saccular stage; however an active proliferation and elastogenesis, at later stages, suggest that the developing lung has the capacity to recover once treatment was stopped. Alterations in RAS function could contribute to the abnormalities in lung development tissue indicating that the system is one intrinsic factor necessary to differentiation and alveolarization process. However, other local factors could be involved in this mechanism.

Drug encapsulation in nanocarriers such as polymeric nanoparticles (Nps) may help to overcome the limitations associated with cannabinoids. In this sense, our work aimed to highlight the use of electrospraying technique for the development of carrier Nps of anandamide (AEA), an endocannabinoid with attractive pharmacological effects but underestimated due to its unfavorable physicochemical and pharmacokinetic properties added to its undesirable effects at the level of the central nervous system. We characterized physicochemically and evaluated in vitro biological activity of anandamide/ε-polycaprolactone nanoparticles (Nps-AEA/PCL) obtained by electrospraying in epithelial cells of human proximal tubule (HK2), to prove the utility of this method and to validate the biological effect of Nps-AEA/PCL. We obtained particles from 100 to 900 nm of diameter with a predominance of 200 a 400 nm. Their zeta potential was -20±1.86 mV. We demonstrated the stable encapsulation of AEA in Nps-AEA/PCL, as well as its dose-dependent capacity to induce the expression of iNOS and NO levels and to decrease the Na+/K+ ATPase activity in HK2 cells. Obtaining Nps-AEA/PCL by electrospraying would represent a promising methodology for a novel AEA pharmaceutical formulation development with optimal physicochemical properties, physical stability and biological activity on HK2 cells. Fil: Martín Giménez, Virna Margarita. Universidad Católica de Cuyo - Sede San Juan; Argentina Fil: Russo, Marcos Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Narda, Griselda Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; Argentina Fil: Fuentes, Lucía B.. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Mazzei, Luciana Jorgelina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Gamarra Luques, Carlos Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina Fil: Kassuha, Diego Enrique. Universidad Católica de Cuyo - Sede San Juan; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina

Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others. This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies. We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes. Fil: Martín Giménez, Virna Margarita. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Noriega, Sandra. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Kassuha, Diego Enrique. Universidad Catolica de Cuyo - Sede San Juan. Facultad de Cs. de la Alimentación, Bioquímicas y Farmacéuticas. Instituto de Investigación En Ciencias Químicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fuentes, Lucia Beatriz. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia; Argentina Fil: Manucha, Walter Ariel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina

Evidence suggests that Angiotensin II plays an important role in the complex process of renal organogenesis. Rat kidney organogenesis starts between E13-14 and lasts up to 2 weeks after birth. The present study demonstrates histologic modifications and changes in receptor localisation in animals born from mothers treated with Angiotensin II, Losartan or PD123319 (1.0 mg/kg/day) during late pregnancy. Angiotensin II-treated animals exhibited very well developed tubules in the renal medulla in coincidence with higher AT(1) binding. Control animals exhibited angiotensin AT(2) binding in the outer stripe of the outer medulla, while in the Angiotensin II-treated animals binding was observed to the inner stripe. In Angiotensin II-treated 1-week-old animals, the nephrogenic zone contained fewer immature structures, and more developed collecting tubules than control animals. Treatment with Losartan resulted in severe renal abnormalities. For newborn and 1-week-old animals, glomeruli exhibited altered shape and enlarged Bowman spaces, in concordance with a loss of [(125)I]Angiotensin II binding in the cortex. Blockade with PD123319 led to an enlarged nephrogenic zone with increased number of immature glomeruli, and less glomeruli in the juxtamedullary area. Autoradiography showed a considerable loss of AT(1) binding in the kidney cortex of PD123319-treated animals at both ages. The present results show for the first time histomorphological and receptor localisation alterations following treatment with low doses of Losartan and PD123319 during pregnancy. These observations confirm previous assumptions that in the developing kidney Angiotensin II exerts stimulatory effects through AT(1) receptors that might be counterbalanced by angiotensin AT(2) receptors.

We described the daily rhythms of parameters involved in melatonin production in the pineal of viscacha. Norepinephrine showed the highest levels at night. A peak in β1-adrenoceptor mRNA was observed at the end of the light phase. Serotonin exhibited higher values during the light period. AA-NAT mRNA showed the highest expression at Zeitgeber time 0 (ZT0), reaching a minimum at night. AA-NAT activity and melatonin content exhibited a nocturnal peak at ZT16, a lower diurnal increase during the light period and minimal level at ZT8. HIOMT activity showed a peak at ZT16. The daily pattern in norepinephrine content was similar to that of AA-NAT activity and melatonin levels. Our data suggest that the melatonin synthesis in viscacha might be activated via adrenergic induction; the differences observed in the daily rhythms of AA-NAT activity and its mRNA suggest that post-transcriptional mechanisms may be involved, and other Zeitgeber and other mechanisms might also control melatonin production.

Melatonin is synthesized primarily in the pineal gland. Lithium affects the circadian rhythms that may explain its therapeutic effectiveness in the treatment of bipolar disorder. The objective of this study was to investigate the effect of lithium on the biochemical parameters involved in melatonin synthesis in the pineal gland of viscacha. Viscachas were daily intraperitoneally injected with lithium chloride or saline solution for one month. Pineal mRNAs encoding β1-adrenoceptor and arylalkylamine-N-acetyltransferase enzyme (AA-NAT) were studied by in situ hybridization. Pineal melatonin concentrations were determined by radioimmunoassay, and AA-NAT and hydroxyindol-O-methyltransferase (HIOMT) activities were investigated by radiometric assays. The only parameters that decreased significantly were the expression of AA-NAT mRNA and pineal melatonin levels. Our data suggest that lithium treatment may decrease melatonin synthesis in the viscacha pineal gland by a complex mechanism that involves cur...

The metabolic syndrome (MS) is a deadly metabolic abnormality-associated to obesity. The pulmonary microvasculature is a sink of circulating neutrophils; as well as this is highly sensitive to small changes in the systemic oxidative/inflammatory profile, as occur in chronic inflammatory diseases, such as obesity. Previously, we have characterized a MS-mouse model in which animals were fed for 16 weeks a 22% p/p chicken-fat rich diet and 10 % fructose in the drinking water. These animals show several features of MS including obesity, central adiposity, insulin resistance (IR), hypertension, dyslipidemia and streatohepatitis. Using this model we envisioned to test whether MS predisposes to pulmonary retention/activation of neutrophils and how it affects whole-body IR. To accomplish this goal we studied MS and control mice (B6 mice fed for 16 weeks with low-fat diet/tap water). MS mice had more IR than control mice. MS mice had also higher concentration of circulating inflammatory mediators than control mice. The lung tissue of MS mice was lighter and expressed more inflammation mediators (TNF-α; IL-6 and inducible nitric oxide) than the control lung. The lung of MS mice had more neutrophils (NIMP-14 + cells), myeloperoxidase (MPO) activity and chlorotyrosine than control mice. ICAM-1 expression in MS mice’s lung tissue was higher than control mice. In relation to control mice, intratracheal instillation (ITI) 2.5 ug lipopolysaccharide (LPS)/mouse to MS mice caused more retention/activation of neutrophils, ICAM-1 expression, MPO activity, chlorotyrosine, circulating inflammatory mediators and also worsened IR. These effects where damped by ITI of 5 nmol of 5,5-dimetil-1-pirrolina N-oxido/mouse. Our data suggest that retention/activation of neutrophils in the lung may be a potential therapeutic target to reduce IR and other complications of obesity. Supported by PROICO 2-3214 & PICT-2014-3369 (toDCR), PROICO 10-0414 (ToSEGM) and PIP2015-2017-112215-0100603CO (To DCR, SEA & SEGM).

The vizcacha is a photoperiodic rodent living in the southern hemisphere. The adult males exhibit an annual reproductive cycle characterized by a gonadal regression period during winter with, in some animals, an almost complete loss of spermatogenesis. In this study, we investigated whether biochemical parameters involved in melatonin synthesis in the vizcacha pineal gland exhibited an annual rhythm in parallel with the annual reproductive cycle. By use of in situ hybridization, an annual variation of mRNA encoding s 1 -adrenoceptor was shown, with a maximum during autumn and winter. In situ hybridization for mRNA encoding AA-NAT enzyme also exhibited an annual rhythm with the lowest and highest levels in May and August, respectively. Likewise, in August the activity of arylalkylamine N-acetyltransferase enzyme also reached a maximum. Finally, dertermination of the serum concentrations of melatonin by use of radioimmunoassay showed an increase during winter. Moreover, our results are in concordance with s...

Angiotensin II (Ang II) elicits a variety of physiological effects through specific Ang II receptors in numerous tissues. In addition, Ang II is a modulator of cellular growth and exerts a positive or negative effect on cell growth depending on which receptor subtype is activated. Expression of the intrarenal AT2 receptors occurs at its highest levels in the fetal kidney, with a rapid decline after birth. In the present paper, we performed a study on the signaling mechanism of Ang II receptors in rat fetal (E20) kidney, a rich source of AT2 receptors, where both Ang II receptor subtypes are present. Ang II induces Tyr-dephosphorylation of proteins in rat fetal kidney membranes. The response is dose-dependent, with a reduction of 20% with respect to the control (100%), signal that is completely reversed by Ang II AT2 competitor PD123319. Orthovanadate, the inhibitor of phospho-Tyr-phosphatases (PTPase), reverts Ang II effect, suggesting the involvement of a protein tyrosine phosphatase. The peptide analog of Ang II, CGP42112, exhibits an agonist effect, which is dose-dependent. Thus, in rat fetal (E20) kidney, the Ang-induced protein Tyr-dephosphorylation of several proteins is mediated by AT2 receptors, mechanism that involves an orthovanadate sensitive PTPase.

The renin-angiotensin system (RAS) has been implicated in pulmonary hypertension and pulmonary fibrosis. In the present study, we examined the effects of maternal exposure to captopril (2.85 mg/kg/day) during late pregnancy (G13-G21) on postnatal rat lung development. Treatment with captopril during late pregnancy caused a significant decrease in ACE activity in P0 rats. Body weight decreased at P0 (p

The development of knock-out mice for Angiotensin II (Ang II) AT(2) receptors, which exhibited altered exploratory behavior, prompted us to investigate the cerebellum and brainstem. We evaluated the effect of stimulation/inhibition of Ang II receptors on hindbrain development, in offspring (postnatal days P0, P8) of pregnant rats treated during late pregnancy (Ang II, Losartan or PD123319, 1 mg/kg/day). Receptor localization by autoradiography showed in P0 and P8 hindbrains, that most structures expressed AT(2) subtype: cerebellar cortex, cerebellar nuclei, genu facial nucleus, inferior colicullus, inferior olive. In the cerebellar cortex, [(125)I]Ang II AT(2) binding was predominant, while low AT(1) binding was observed in adjacent layers of the cerebellar cortex. Blockade of AT(2) receptors with PD123319 increased binding in cerebellar nuclei (p

Seasonal changes in reproductive activity in the adult male vizcacha (Lagostomus maximus maximus), a South American rodent, were investigated. Monthly, for 2 yr, the animals were killed and decapitated during the night near their burrows in the vicinity of San Luis, Argentina. The testes, epididymides, and pineal glands were removed and used for biochemical and structural studies. Significant changes associated with seasonal cycles were found. 1) In July-August (winter in South America), a short hibernal period of sexual quiescence, decline in testicular and epididymal weights, arrest of spermatogenesis, and decrease of serum testosterone were observed. The gonads regressed during this period, with regression most pronounced in August. 2) During September-November (spring), a recovery period--without arrest of spermatogenesis--was observed, with significant expression of gonadal activity during April-May (autumn). In this season, gonadal weight was increased and spermatogenesis was complete. These results indicate an increase in sexual activity as well as in the ability to secrete testosterone. A gradual reduction of testicular activity appeared in June-July (early winter). Conversely, in this period, the pineal hydroxyindole-O-methyl transferase activity decreased in contrast to the highest values observed in winter. Our findings indicate that the male adult vizcacha under natural conditions exhibits an annual reproductive cycle. A possible relationship between increased pineal activity and gonadal regression is also suggested.

A pharmacological evaluation for diuretic activity of the ethanol extract of Alternanthera pungens was carrried out. Urinary excretion of water, pH, density and sodium concentration were investigated in isotonic saline loaded rats. The extract showed an effective diuretic activity, in comparison with furosemide, increasing significantly the renal loss of sodium. These results indicate that this plant has a diuretic behaviour similar to furosemide, a high-ceiling diuretic agent. © 1997 John Wiley & Sons, Ltd.

Angiotensin II (Ang II) elicits a variety of physiological effects through specific Ang II receptors in numerous tissues. In addition, Ang II is a modulator of cellular growth and exerts a positive or negative effect on cell growth depending on which receptor subtype is activated. Expression of the intrarenal AT2 receptors occurs at its highest levels in the fetal kidney, with a rapid decline after birth. In the present paper, we performed a study on the signaling mechanism of Ang II receptors in rat fetal (E20) kidney, a rich source of AT2 receptors, where both Ang II receptor subtypes are present. Ang II induces Tyr-dephosphorylation of proteins in rat fetal kidney membranes. The response is dose-dependent, with a reduction of 20% with respect to the control (100%), signal that is completely reversed by Ang IIAT2 competitor PD123319. Orthovanadate, the inhibitor of phospho-Tyr-phosphatases (PTPase), reverts Ang II effect, suggesting the involvement of a protein tyrosine phosphatase. The peptide analog of Ang II, CGP42112, exhibits an agonist effect, which is dose-dependent. Thus, in rat fetal (E20) kidney, the Ang-induced protein Tyr-dephosphorylation of several proteins is mediated by AT2 receptors, mechanism that involves an orthovanadate sensitive PTPase.

The viscacha (Lagostomus maximus maximus) is a seasonal rodent living in the Southern Hemisphere. The adult males exhibit an annual reproductive cycle characterized by a gonadal regression period during winter. In this study, we investigated the effects of bilateral enucleation and captivity on their annual reproductive cycle. Testicular volume relative to body weight was recorded monthly in intact and bilaterally enucleated animals placed under natural photoperiod, water, and food ad lib. and constant temperature. Testes and accessory organs were evaluated by qualitative and quantitative light microscopic studies. The intact animals showed an annual reproductive cycle with complete gonadal atrophy in the first year. In the second year, testicular regression was observed but attenuated in regard to that recorded in the first winter period, indicating that adaptive changes might be involved. Bilateral enucleation in the viscacha dampened and extended the period of its annual reproductive cycle. The results suggest that both conditions, constant captivity and enucleation, produced stimulatory effects on the reproductive system of this rodent. Furthermore, local control mechanisms might be responsible for the morphological differences observed in testes, epididymis, and seminal vesicles from both groups, which exhibited similar levels of serum testosterone. Finally, an intact retinohypothalamic-pineal axis and/or photoperiodic input would be necessary to maintain the reproductive cycle amplitude and timing in viscacha.

Recently, it has become clear that many of the intracellular signals mediated by Ang II receptors are similar to the signaling pathways activated by receptor tyrosine kinases. In the present paper, we are reporting a full characterization of Ang II receptors in rat fetal membranes. We assayed binding of the Ang II antagonist [ 125 I]Sar 1 Ile 8 Ang II and the AT 2 specific competitor [ 125 1]CGP42112. Both ligands exhibited a rapid equilibrium and a high specificity for Ang II receptors. Competition studies confirmed the presence of both receptor subtypes, with a predominance of AT 2 receptors and the following order of potency: CGP42112>Ang II>Losartan>PD123177. Immunoblotting studies of tyrosine phosphoproteins showed that Ang II (10 −6 M) mediates a rapid reduction in tyrosine phosphorylation of several proteins with apparent molecular masses in the range of 30–45 kDa. Increasing concentrations of Ang II (10 −9 –10 −6 M) showed a dose–response behavior, suggesting a clear physiological role of the observed effect. The response, blocked by Losartan and PD123177, seems to be mediated by both receptor subtypes. These results clearly indicate that both Ang II receptors mediate tyrosine dephosphorylation in early stages of development and support a role of these receptors in growth and development.