Different effects on rat arterial pressure and heart rate when losartan is injected into the third or fourth ventricle

Cardiovascular responses to central losartan (LOS), a non-peptide angiotensin II (ANG II) receptor antagonist, were investigated by comparing the effects of LOS injection into the 3rd and 4th cerebral ventricles (3rdV, 4thV) on mean arterial pressure (MAP) and heart rate (HR). Adult male Holtzman rats were used (N=6 animals per group). Average basal MAP and HR were 114±3 mmHg and 343±9 bpm (N=23), respectively. LOS (50, 100 or 200 nmol/2 μl) injected into the 3rdV induced pressor (peak of 25±3 mmHg) and tachycardic (peak of 60±25 bpm) responses. LOS injected into the 4thV had no effect on MAP, but it induced bradycardia (peak of -35±15 bpm). KCl (200 nmol/2 μl) injected into the 3rdV or into the 4thV had no effect on either MAP or HR compared to 0.9% saline injection. The results indicate that LOS injected into the third ventricle acts on forebrain structures to induce its pressor and tachycardic effects and that bradycardia, likely dependent on hindbrain structures, is obtained when LOS is injected into the fourth ventricle.

TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE E MODERADA COM FOSINOPRIL. COMPARACAO DE EFEITOS ADVERSOS COM OUTROS ANTI-HIPERTENSIVOS

Purpose - To evaluate the adverse reactions of fosinopril with other antihypertensives used as monotherapy. Methods - Out-patients (n = 2,568) with diagnostic of mild to moderate hypertension, diastolic blood pressure (DBP) 95-115 mmHg, with no antihypertensive treatment for 15 days, were included to treatment initially with fosinopril (F) 10mg, once daily, for six weeks. After this period, patients with DBP >95mmHg had the dosage, once daily, increased to 20 mg, while the others were maintained with the same dosage for six more weeks. Adverse reactions of 822 patients treated as monotherapy were grouped as absent, musculoskeletal, cardiovascular, cough, gastrointestinal, neurological, genital-urinary dysfunctions and dermatological and compared with 1,568 with F. Monotherapy consist in α-methyldopa (100 patients); β-blocker (129); calcium blocker (106); diuretic (394); and another ACE inhibitors (93). Results - At the end of the period without treatment, the blood pressure (BP), 165 ± 16/105 ± 7 mmHg decreased significantly at 6(th) week to 144 ± 15/91 ± 9 mmHg (p < 0.05 vs week 0) with further lowering to 139 ± 13/86 ± 7 mmHg till the end of 12(th) week. BP response (DBP ≤90 mmHg) was obtained in 89% of the patients with F. Absence of adverse reactions were ≥70% in patients with F compared to other drugs. Conclusion - Fosinopril has demonstrated therapeutic efficacy and less adverse reactions compared to antihypertensives used previously as monotherapy.

Effects of intracerebroventricular injections of losartan or PD123319 on arterial pressure and heart rate of sodium replete and sodium deplete rats

Angiotensin II (Ang II) non-peptide antagonists were injected i.c.v. (6.25-200 nmol, n = 5-8 rats/group): In sodium replete rats, losartan (AT1 receptor antagonist) induced an increase in mean arterial pressure (MAP) and in heart rate (HR) by 3rd ventricular (3rdV) injection, and a weaker pressor response and bradycardia by 4th ventricular (4thV) injection. PD123319 (AT2 receptor antagonist) induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and no alteration in HR by 4thV injection. In sodium deplete (furosemide plus removal of ambient sodium for 24 h) rats, losartan induced an increase in MAP and no alteration in HR by 3rdV injection, and no alteration in MAP and bradycardia by 4thV injection. PD123319 induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and bradycardia by 4thV injection. Thus, there was no fall in MAP by central injections of Ang II antagonists. Intravenous injection of losartan, but not of PD123319, induced a fall in MAP in both sodium replete and sodium deplete animals. Therefore, losartan and PD123319 can have similar effects on MAP and HR when injected intracerebroventricularly, although some differences are also present. The bradycardia is consistent with an withdrawal of Ang II inhibitory action on baroreflex.

Functional evidence that the central renin-angiotensin system plays a role in the pressor response induced by central injection of carbachol

We investigated the effects of losartan, an AT 1-receptor blocker, and ramipril, a converting enzyme inhibitor, on the pressor response induced by angiotensin II (ANG II) and carbachol (a cholinergic receptor agonist). Male Holtzman rats (250-300 g) with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The injection of losartan (50 nmol/l μl) into the LV blocked the pressor response induced by ANG II (12 ng/l μl) and carbachol (2 nmol/l μl). After injection of ANG II and carbachol into the LV, mean arterial pressure (MAP) increased to 31 ± 1 and 28 ± 2 mmHg, respectively. Previous injection of losartan abolished the increase in MAP induced by ANG II and carbachol into the LV (2 ± 1 and 5 ± 2 mmHg, respectively). The injection of ramipril (12 ng/l μl) prior to carbachol blocked the pressor effect of carbachol to 7 ± 3 mmHg. These results suggest an interaction between central cholinergic pathways and the angiotensinergic system in the regulation of arterial blood pressure.

Multifactorial control of water and saline intake: Role of α2-adrenoceptors

Water and saline intake is controlled by several mechanisms activated during dehydration. Some mechanisms, such as the production of angiotensin II and unloading of cardiovascular receptors, activate both behaviors, while others, such as the increase in blood osmolality or sodium concentration, activate water, but inhibit saline intake. Aldosterone probably activates only saline intake. Clonidine, anα2-adrenergic agonist, inhibits water and saline intake induced by these mechanisms. One model to describe the interactions between these multiple mechanisms is a wire-block diagram, where the brain circuit that controls each intake is represented by a summing point of its respective inhibiting and activating factors. The α2-adrenoceptors constitute an inhibitory factor common to both summing points.

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1.0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n=10). Myocardial histology was analysed in 3 μm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Pharmacological evidence for β2-adrenoceptor in right atria from stressed female rats

The purpose of the present study was to demonstrate a physiological response to TA2005, a potent β2-adrenoceptor (β2-AR) selective agonist, in right atria isolated from stressed female rats under the influence of the estrous cycle. We obtained concentration-response curves to the agonist in the presence and in the absence of selective antagonists in right atria isolated from female rats submitted to three daily foot-shock sessions (30 min duration, 120 pulses of 1.0 mA, 1.0 s, applied at random intervals of 5- 25 s) and sacrificed at estrus or diestrus. Our results showed that the pD2 values of TA2005 were not influenced by estrous cycle phase or foot-shock stress. However, in right atria from stressed rats sacrificed during diestins, the concentration-response curve to TA2005 was biphasic, with a response being obtained at concentrations of 0.1 nM, whereas during estrus no response was observed at doses lower than 3 nM. ICI118,551, a β2-AR antagonist, abolished the response to nanomolar concentrations of TA2005 in right atria from stressed rats at diestrus, with no changes in agonist pD2 values in right atria from control rats (7.47 ± 0.09, p > 0.05) but a 3-fold decrease in pD2 values of TA2005 in right atria from foot shock stressed rats (7.90 ± 0.07, p ≤ 0.05). Concentration-response curves to TA2005 in the presence of ICI118,551 were best fitted by a one-site model equation. The β1-AR antagonist, CGP20712A, shifted to the right only the second part of the concentration-response curves to the agonist, unmasking the putative β2-AR-mediated response to the agonist in tissues isolated from stressed rats at diestrus. Under this condition, concentration-response curves to the agonist were best fitted by a two-site model equation, pD2 and maximum response of TA2005 interaction with β1- and putative β2-adrenoceptor components were calculated. Schild analyses gave a pK(B) value for CGP20712A that was typical for the interaction with β1-AR in each experimental group, pK(B) values for ICI118,551 could not be obtained in stressed rats sacrificed at diestins since Schild plot slopes were lower than 1.0. In right atria from control rats, ICI118,551 pK(B) values were similar to reported values for the interaction of the antagonist with β1-AR. These results confirm that a heterogenous β1-AR population mediating the chronotropic response to catecholamines can be demonstrated in right atria from foot shock stressed female rats sacrificed at diestins. The stress-induced response seems to be mediated by the β2-AR subtype. Right atria from rats sacrificed during estrus are protected against stress-induced alterations on the homogeneity of β-AR population.

Conformational basis for the biological activity of TOAC-labeled angiotensin II and bradykinin: Electron paramagnetic resonance, circular dichroism, and fluorescence studies

N-Terminally and internally labeled analogues of the hormones angiotensin (AII, DRVYIHPF) and bradykinin (BK, RPPGFSPFR) were synthesized containing the paramagnetic amino acid 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4- carboxylic acid (TOAC). TOAC replaced Asp 1 (TOAC 1-AII) and Val 3 (TOAC 3-AII) in AII and was inserted prior to Arg 1 (TOAC 0-BK) and replacing Pro 3 (TOAC 3-BK) in BK. The peptide conformational properties were examined as a function of trifluoroethanol (TFE) content and pH. Electron paramagnetic resonance spectra were sensitive to both variables and showed that internally labeled analogues yielded rotational correlation times (TC) considerably larger than N-terminally labeled ones, evincing the greater freedom of motion of the N-terminus. In TFE, τ C increased due to viscosity effects. Calculation of τ Cpeptide/τ CTOAC ratios indicated that the peptides acquired more folded conformations. Circular dichroism spectra showed that, except for TOAC 1-AII in TFE, the N-terminally labeled analogues displayed a conformational behavior similar to that of the parent peptides. In contrast, under all conditions, the TOAC 3 derivatives acquired more restricted conformations. Fluorescence spectra of All and its derivatives were especially sensitive to the ionization of Tyr 4. Fluorescence quenching by the nitroxide moiety was much more pronounced for TOAC 3-AII The conformational behavior of the TOAC derivatives bears excellent correlation with their biological activity, since, while the N-terminally labeled peptides were partially active, their internally labeled counterparts were inactive [Nakaie, C. R., et al., Peptides 2002, 23, 65-70]. The data demonstrate that insertion of TOAC in the middle of the peptide chain induces conformational restrictions that lead to loss of backbone flexibility, not allowing the peptides to acquire their receptor-bound conformation. © 2004 Wiley Periodicals, Inc.

Influence of arginine vasopressin receptor and nitric oxide on the water, sodium intake and arterial blood pressure induce by angiotensin injected into third ventricle of the brain

As several structures of the central nervous system are involved in the control of hydromineral and cardiovascular balance we investigated whether the natriorhexigenic and pressor response induced by the injection of ANG II into the 3rd V could be mediated by vasopressinergic and nitrergic system. Male Holtzman rats weighing 200-250 g with cannulae implanted into the 3rd V were used. The drugs were injected in 0.5 μL over 30-60 sec. Controls were injected with a similar volume of 0.15 M NaCl. ANGII increased the water intake vs control. AVPA injected into 3rd V prior to ANGII decreased the dipsogenic effect of ANGII. L-arginine also decreased the water intake induced by ANGII. AVPA plus L-arginine inhibit the water intake induced by ANGII. 7NIT injected prior to ANGII potentiated the dipsogenic effect of ANGII. Pre-treatment with ANGII increased the sodium ingestion vs control. AVPA decreased the ANGII effect in sodium intake. L-arginine also decreased the natriorhexigenic effect of ANGII. The combination of L-arginine and AVPA inhibit the sodium intake induced by ANGII. 7NIT injected prior to ANGII potentiated the sodium intake induced by ANGII. ANGII induced an increase in Mean Arterial Pressure (MAP) vs control. AVPA and L-arginine induced a decreased in the pressor effect of ANGII. The combination of L-arginine and AVPA inhibit the pressor effect of ANGII. 7NIT injected prior to ANGII into 3rd V potentiated the pressor effect of ANGII. These data suggest that arginine vasopressin V 1 receptors and Nitric Oxide (NO) within the circumventricular structures may be involved in sodium intake and pressor response induced by the activation of ANGII receptors within the circumventricular neurons. These studies revealed the involvement of sodium appetite by utilizing the angiotensinergic, vasopressinergic and nitrergic system in the central regulation of blood pressure. © 2006 Asian Network for Scientific Information.

Nitrergic pathways and L-type calcium channel of MnPO influencing cardiovascular homeostasis

The median preoptic nucleus (MnPO) is one of most important site of the lamina terminalis implicated in the regulation of hydro electrolytic and cardiovascular balance. The purpose of this study was to determine the effect of L-Type calcium channel antagonist, nifedipine, on the increase of median arterial blood pressure (MAP) induce by angiotensin II (ANG II) injected into the MnPO. The influence of nitric oxide (NO) on nifedipine antipressor action has also been studied by utilizing N W-nitro-L-arginine methyl ester (L-NAME) (40 μg 0.2 μL -1) a NO synthase inhibitor (NOSI), 7-nitroindazole (7-NIT) (40 μg 0.2 μL -1), a specific neuronal NO synthase inhibitor (nNOSI) and sodium nitroprusside (SNP) (20 μg 0.2 μL -1) a NO donor agent. We have also investigated the central role of losartan and PD123349 (20 nmol 0.2 μL -1), AT 1 and AT 2, respectively (selective non peptide ANG II receptor antagonists), in the pressor effect of ANG II (25 pmol 0.2 μL -1) injected into the MnPO. Male Wistar rats weighting 200-250 g, with cannulae implanted into the MnPO were utilized. Losartan injected into the MnPO, prior to ANG II, blocked the pressor effect of ANGII. PD 123319 only decreased the pressor effect of ANG II. Rats pre-treated with either 50 μg 0.2 μL -1 or 100 μg 0.2 μL -1 of nifedipine, followed by 25 pmol 0.2 μL -1 of ANG II, decreased ANG II-pressor effect. L-NAME potentiated the pressor effect of ANG II. 7-NIT injected prior to ANG II into the MnPO also potentiated the pressor effect of ANGII but with less intensity than that of L-NAME. SNP injected prior to ANG II blocked the pressor effect of ANG II. The potentiation action of L-NAME and 7-NIT on ANG II-pressor effect was blocked by prior injection of nifedipine. The results described in this study provide evidence that calcium channels play important roles in central ANG II-induced pressor effect. The structures containing NO in the brain, such as MnPO, include both endothelial and neuronal cells, which might be responsible for the influence of nifedipine on the pressor effect of ANG II. These data have shown the functional relationship between L-Type calcium channel and a free radical gas NO in the MnPO, on the control of ANG II-induced pressor effect acting in AT 1 and AT 2 receptors.

GnRH agonist versus GnRH antagonist in poor ovarian responders: A meta-analysis

The aim of this meta-analysis was to compare the efficacy of gonadotrophin antagonist (GnRH-ant) versus GnRH agonist (GnRHa) as coadjuvant therapy for ovarian stimulation in poor ovarian responders in IVF/intracytoplasmic sperm injection cycles. Search strategies included on-line surveys of databases such as MEDLINE, EMBASE and others. A fixed effects model was used for odds ratio (OR) and effect size (weighted mean difference, WMD). Six trials fulfilled the inclusion criteria (randomized controlled trials). There was no difference between GnRH-ant and GnRHa (long and flare-up protocols) with respect to cycle cancellation rate, number of mature oocytes and clinical pregnancy rate per cycle initiated, per oocyte retrieval and per embryo transfer. When the mete-analysis was applied to the two trials that had used GnRH-ant versus long protocols of GnRHa, a significantly higher number of retrieved oocytes was observed in the GnRH-ant protocols [P = 0.018; WMD: 1.12 (0.18, 2.05)]. However, when the meta-analysis was applied to the four trials that had used GnRH-ant versus flare-up protocols, a significantly higher number of retrieved oocytes (P = 0.032; WMD: -0.51, 95% CI -0.99, -0.04) was observed in the GnRHa protocols. Nevertheless, additional randomized controlled trials with better planning are needed to confirm these results.