Effect of the chronic administration of oxprenolol on the aortic wall of the normotensive and hypertensive rats

4 groups of male Wistar rats were studied: - normotensive control rats (4 animals) treated with s.c. water - normotensive rats (6 animals) treated with s.c. 5 mg/Kg Oxprenolol - hypertensive control rats (renal artery stenosis) (6 animals) treated with s.c. water - hypertensive rats (renal artery stenosis) (9 animals) treated with s.c. 5 mg/Kg Oxprenolol. The animals were treated and/or operated at six weeks of age and sacrificed at 12 weeks of age. Blood Pressure (BP), Heart Rate (HR), Ventricular Mass (VM) and Thickness of the Aortic Media (A Th) were determined. Oxprenolol did reduce HR but not BP in both normotensive and hypertensive rats: these animals showed a reduced A Th but not a reduced VM compared with untreated control rats. These results suggest a direct effect of Oxprenolol on A Th independently from BP values, but not on VM.     

Cardiorespiratory effects of diazepam-ketamine, xylazine-ketamine and thiopentone anesthesia in male Wistar rats--a comparative analysis

Several anesthetics are known to cause respiratory and cardiovascular depression in humans and animals; but, these diverse effects have not been extensively investigated in laboratory rodents. The objective of this study is to choose a suitable anesthetic combination for use in surgical models eg. coronary artery ligation in rats. Male Wistar rats were anesthetized with three different drugs viz. diazepam-ketamine (DK) (2.5 mg/Kg, intraperitoneally (i.p); 50 mg/Kg, i.p), xylazine-ketamine (XK) (5 mg/Kg i.p; 50 mg/Kg i.p) and thiopentone (T) (40 mg/Kg i.p) and the respiratory and cardiovascular functions were assessed after coronary artery ligation. Heart rate (HR), mean arterial pressure (MAP), partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), oxygen saturation percentage (O2 sat (%)), arterial blood pH and rectal body temperature were studied in detail. During the anesthetic regime, HR was lower till 60 min in XK and T ligated group (333 +/- 6; 304 +/- 8 beats/min) and it was near normalcy in the case of DK ligated group (394 +/- 6 beats/min). Significant respiratory depression was particularly reflected in the T ligated group with an increase in PaCO2 at 30 min (40.32 +/- 2.64 mmHg), which decreased to 38.2 +/- 2.23 mmHg at 60 min. Throughout the investigation, DK showed the least overall effects compared to XK and T on respiratory functions. Thus, DK could be considered to be a suitable anesthetic for use in a surgical model such as coronary artery ligation in albino rats.     

Haemodynamic Responses to Selective Vagal Nerve Stimulation under Enalapril Medication in Rats

Selective vagal nerve stimulation (sVNS) has been demonstrated to lower blood pressure (BP) in rats without causing major side effects. This method might be adapted for the treatment of therapy-resistant hypertension in patients. Converting enzyme inhibitors (CEIs) are among the first drugs that are administered for arterial hypertension and prominently reduce BP primarily by interacting with the renin-angiotensin system of the kidneys. Beyond the reduction of BP, CEI have a positive effect on the survival rate after myocardial infarction; they reduce the rates of stroke and improve the neurohormonal status in heart-failure patients. If sVNS might be introduced as a therapy against resistant hypertension, patients will at least partially stay on their CEI medication. It is therefore the aim of this study to investigate the influence of the CEI enalapril on the haemodynamic and respiratory effects of sVNS. In 10 male Wistar rats, a polyimide-based multichannel-cuff-electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibres. Stimulation parameters were adapted to the thresholds of the individual animals and included repetition frequencies between 30 and 50 Hz, amplitudes of 0.5 to 1.5 mA and pulse widths between 0.4 ms and 1.0 ms. BP responses were detected with a microtip transducer in the left carotid artery, and electrocardiography was recorded with subcutaneous electrodes. After intravenous administration of enalapril (2 mg/kg bodyweight), the animals’ mean arterial blood pressures (MAPs) decreased significantly, while the heart rates (HRs) were not significantly influenced. The effects of sVNS on BP and HR were attenuated by enalapril but were still present. We conclude that sVNS can lower the MAP during enalapril treatment without relevant side effects.     

Hypotensive effect of naloxone on high blood pressure induced by stress in the rat

A naloxone-reversible enhancement of systolic blood pressure (BP) was induced in rats by application of three different types of stressor, i.e. intense light and sound, cold and foot-shock. In the case of labile high BP provoked by short-term isolation, the opiate antagonist naloxone (1 mg/Kg, i.p.) was also found to reverse hypertension. Naltrexone (2.5 mg/Kg, i.p.) also diminished high BP readings of briefly isolated rats. Conversely, blockade of the opiate receptor with naloxone did not alter elevated BP in cases of established hypertension (spontaneously hypertensive rats, deoxycorticosterone (DOCA)-salt rats and long-term isolated rats). These data can be taken as an evidence of opioid involvement at the onset of high BP readings induced by stress. However, once hypertension becomes established, the opioid system appears to recover its silent features.     

Cardiovascular effects of naloxone,naltrexone and morphine in the squirrel monkey

Heart rate (HR) and mean arterial blood pressure (BP) were recorded from conscious, chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous injections of two opiate antagonists and an agonist. Naloxone (0.3–10.0 mg/kg) or naltrexone (0.3–10.0 mg/kg) had little effect on HR or BP during a 30-minute post-injection period. Morphine (3.0–5.6 mg/kg) produced biphasic effects comprising an initial decrease followed by an increase in HR, and an increase followed by a decrease in BP. Lower morphine doses had lesser effects during a 100-minute post-injection period. Pre-treatment with 0.03 mg/kg naloxone attenuated the depressive effect of morphine on HR and BP, but increases in HR and BP due to morphine were enhanced. Pretreatment with 0.3 mg/kg naloxone prevented morphine-induced decreases in HR and BP, yet increases in HR and BP persisted. In previous behavioral studies, morphine in combination with naloxone similarly increased rates of responding in the squirrel monkey. Together, these data suggest an effect of naloxone that goes beyond mere pharmacological antagonism of the effects of morphine.     

Cardiovascular effects of cocaine in anesthetized and conscious rats

This study examined the cardiovascular and respiratory effects of cocaine and procaine in anesthetized and conscious rats. Intravenous cocaine (0.16-5 mg/Kg) elicited a rapid, dose dependent increase in mean arterial pressure of relatively short duration. In pentobarbital anesthetized (65 mg/Kg, i.p.) animals, the pressor phase was generally followed by a more prolonged depressor phase. These effects on arterial pressure were generally accompanied by a significant tachypnea and at larger doses (2.5 and 5 mg/Kg, i.v.), bradycardia. Procaine (0.31 and 1.25 mg/Kg, i.v.) produced similar cardiovascular and respiratory effects (depressor phase, tachypnea) in pentobarbital anesthetized animals. In conscious-restrained animals, both cocaine and procaine (1.25 mg/kg, i.v.) produced pressor responses. The subsequent depressor response was, however, absent in both cases. The cardiovascular effects of cocaine (0.25-1 mg/Kg, i.v.) in urethane anesthetized (1.25 g/Kg, i.p.) animals were essentially similar to those observed in conscious animals. Procaine (1mg/Kg) did not produce any significant cardiovascular effects in urethane anesthetized animals, but did elicit tachypnea. Reserpine pretreatment (10 mg/Kg, i.p.) did not significantly attenuate the pressor response in urethane anesthetized animals. Phentolamine pretreatment (3 mg/Kg, i.v.) did significantly antagonize the pressor effect in urethane anesthetized animals. These results suggest that: the depressor phase is likely due to a interaction between local anesthetic activity (cocaine and procaine) and barbiturate anesthesia, the cardiovascular effects of cocaine in conscious animals are more similar to those observed in urethane anesthetized rats than in pentobarbital anesthetized rats and the pressor effect in urethane anesthetized rats is apparently due to a reserpine resistant catecholaminergic mechanism.     

Intermittent hypobaric hypoxia exposure does not cause sustained alterations in autonomic control of blood pressure in young athletes

Intermittent hypoxia (IH), which refers to the discontinuous use of hypoxia to reproduce some key features of altitude acclimatization, is commonly used in athletes to improve their performance. However, variations of IH are also used as a model for sleep apnea, causing sustained sympathoexcitation and hypertension in animals and, thus, raising concerns over the safety of this model. We tested the hypothesis that chronic IH at rest alters autonomic control of arterial pressure in healthy trained individuals. Twenty-two young athletes (11 men and 11 women) were randomly assigned to hypobaric hypoxia (simulated altitude of 4,000-5,500 m) or normoxia (500 m) in a double-blind and placebo-controlled design. Both groups rested in a hypobaric chamber for 3 h/day, 5 days/wk for 4 wk. In the sitting position, resting hemodynamics, including heart rate (HR), blood pressure (BP), cardiac output (Q(c), C(2)H(2) rebreathing), stroke volume (SV = Q(c)/HR), and total peripheral resistance (TPR = mean BP/Q(c)), were measured, dynamic cardiovascular regulation was assessed by spectral and transfer function analysis of cardiovascular variability, and cardiac-vagal baroreflex function was evaluated by a Valsalva maneuver, twice before and 3 days after the last chamber exposure. We found no significant differences in HR, BP, Q(c), SV, TPR, cardiovascular variability, or cardiac-vagal baroreflex function between the groups at any time. These results suggest that exposure to intermittent hypobaric hypoxia for 4 wk does not cause sustained alterations in autonomic control of BP in young athletes. In contrast to animal studies, we found no secondary evidence for sustained physiologically significant sympathoexcitation in this model.     

Chronic estradiol-17β exposure increases superoxide production in the rostral ventrolateral medulla and causes hypertension: reversal by resveratrol

Women are exposed to estrogen in several forms, such as oral contraceptive pills and hormone replacement therapy. Although estrogen was believed to be cardioprotective, lately, its beneficial effects are being questioned. Recent studies indicate that oxidative stress in the rostral ventrolateral medulla (RVLM) may play a role in the development of hypertension. Therefore, we hypothesized that chronic exposure to low levels of estradiol-17β (E(2)) leads to hypertension in adult-cycling female Sprague Dawley (SD) rats potentially through generation of superoxide in the RVLM. To test this hypothesis, young adult (3 or 4 mo old) female SD rats were either sham-implanted or implanted (subcutaneously) with slow-release E(2) pellets (20 ng/day) for 90 days. A group of control and E(2)-treated animals were fed lab chow or chow containing resveratrol (0.84 g/kg of chow), an antioxidant. Rats were implanted with telemeters to continuously monitor blood pressure (BP) and heart rate (HR). At the end of treatment, the RVLM was isolated for measurements of superoxide. E(2) treatment significantly increased mean arterial pressure (mmHg) and HR (beats/min) compared with sham rats (119.6 ± 0.8 vs. 105.1 ± 0.7 mmHg and 371.7 ± 1.5 vs. 354.4 ± 1.3 beats/min, respectively; P < 0.0001). Diastolic and systolic BP were significantly increased in E(2)-treated rats compared with control animals. Superoxide levels in the RVLM increased significantly in the E(2)-treated group (0.833 ± 0.11 nmol/min·mg) compared with control (0.532 ± 0.04 nmol/min·mg; P < 0.05). Treatment with resveratrol reversed the E(2)-induced increases in BP and superoxide levels in the RVLM. In conclusion, these findings support the hypothesis that chronic exposure to low levels of E(2) induces hypertension and increases superoxide levels in the RVLM and that this effect can be reversed by resveratrol treatment.     

Evidence that muscimol acts in the forced swimming test by activating the rat dopaminergic system

Muscimol as well as catecholaminergic drugs reduce immobility time in the forced swimming test. In view of the fact that GABAergic drugs may facilitate some brain catecholaminergic functions, we investigated as to whether or not muscimol would reduce immobility time through activation of catecholaminergic mechanisms. The effect of muscimol (2 mg/Kg i.p.) on reduction of immobility time was prevented by intraperitoneal alpha-methyl-para-tyrosine (250 mg/Kg i.p.), which reduces brain catecholamine content, haloperidol (0.5 mg/Kg) and sulpiride (100 and 50 mg/Kg), antidopaminergic drugs, and meta-chlorphenyl-piperazine (0.6 and 1.25 mg/Kg), a serotonergic agonist, but not by clonidine (0.1 mg/Kg), an alpha2-adrenoceptor agonist, d, 1-propranolol (5 mg/Kg), an antagonist of beta-adrenergic receptors, or subcutaneous prazosin (3 mg/Kg), an alpha1-adrenolytic drug. Our findings indicate that a) muscimol reduces immobility time by stimulating dopaminergic neurons and b) activation of the serotonergic system antagonizes muscimol effect.     

Effect of preventive and regressive isosorbide 5-mononitrate treatment on catecholamine levels in plasma, platelets, adrenals, left ventricle and aorta in cyclosporin A-induced hypertensive rats

Increased vascular reactivity associated with cyclosporin A (CsA)-induced arterial hypertension might result from increased vasoconstriction and/or decreased vasodilatation. The administration of organic NO donors could have beneficial effects by the NO-cGMP reposition, but there is the risk of sympathetic nervous system worsening by neuro-hormonal counter-regulation. We evaluate the effect of preventive and regressive (curative) isosorbide 5-mononitrate (Is-5-Mn) treatment on blood pressures and on plasma, platelets, adrenals, left ventricle and aorta norepinephrine (NE) and epinephrine (E) contents, assessed by HPLC, in CsA-induced hypertensive rats. Five rat groups were tested: control (orange juice), CsA (5 mg/kg/day) and Is-5-Mn (150 mg/kg/day, bid) groups were treated for 7 weeks; preventive group (Is-5-Mn+CsA): Is-5-Mn during 2 weeks plus 7 weeks of Is-5-Mn+CsA; regressive group (CsA+Is-5-Mn): CsA during 7 weeks plus 5 weeks of CsA+Is-5-Mn. The increased BP in the CsA group was prevented, but was not reverted, by concomitant Is-5-Mn treatment. In the CsA-treated rats, there was a noticeable decrease in left ventricle NE and E contents and aorta NE levels and a moderate increase in circulating catecholamines, without significant effect in the adrenals values. When Is-5-Mn was preventively used, the CsA-induced effect on left ventricle and aorta was prevented. Concomitantly, however, the plasma-platelet catecholamine balance was disrupted, accumulating NE in plasma, whereas E increased in aorta, mimic the single Is-5-Mn-treated group. In opposition, in the group used as regressive Is-5-Mn therapy, the adrenals contents were higher compared with the CsA-group and, simultaneously, the CsA-evoked effects on circulating, left ventricle and aorta catecholamines were not reverted. In conclusion, regressive Is-5-Mn therapy was unable to attenuate CsA-induced catecholamine changes and BP values even worsened. On the contrary, preventive Is-5-Mn treatment prevented the catecholamine changes on left ventricle and aorta, but increased plasma NE and aorta E accumulation. Even though with those effects, hypertension development was totally prevented, suggesting that peripheral SNS per se cannot fully explain CsA-induced hypertension. Furthermore, Is-5-Mn might produce beneficial effects only if preventively employed but, considering the changes on peripheral catecholamine contents, a judicious evaluation of the nitrate therapy impact is recommended in order to avoid further deleterious effects.     

Sex differences in the development of angiotensin II-induced hypertension in conscious mice

Sex has an important influence on blood pressure (BP) regulation. There is increasing evidence that sex hormones interfere with the renin-angiotensin system. Thus the purpose of this study was to determine whether there are sex differences in the development of ANG II-induced hypertension in conscious male and female mice. We used telemetry implants to measure aortic BP and heart rate (HR) in conscious, freely moving animals. ANG II (800 ng.kg(-1).min(-1)) was delivered via an osmotic pump implanted subcutaneously. Our results showed baseline BP in male and female mice to be similar. Chronic systemic infusion of ANG II induced a greater increase in BP in male (35.1 +/- 5.7 mmHg) than in female mice (7.2 +/- 2.0 mmHg). Gonadectomy attenuated ANG II-induced hypertension in male mice (15.2 +/- 2.4 mmHg) and augmented it in female mice (23.1 +/- 1.0 mmHg). Baseline HR was significantly higher in females relative to males (630.1 +/- 7.9 vs. 544.8 +/- 16.2 beats/min). In females, ANG II infusion significantly decreased HR. However, the increase in BP with ANG II did not result in the expected decrease in HR in either intact male or gonadectomized mice. Moreover, the slope of the baroreflex bradycardia to phenylephrine was blunted in males (-5.6 +/- 0.3 to -2.9 +/- 0.5) but not in females (-6.5 +/- 0.5 to -5.6 +/- 0.3) during infusion of ANG II, suggesting that, in male mice, infusion of ANG II results in a resetting of the baroreflex control of HR. Ganglionic blockade resulted in greater reduction in BP on day 7 after ANG II infusion in males compared with females (-61.0 +/- 8.9 vs. -36.6 +/- 6.6 mmHg), suggesting an increased contribution of sympathetic nerve activity in arterial BP maintenance in male mice. Together, these data indicate that there are sex differences in the development of chronic ANG II-induced hypertension in conscious mice and that females may be protected from the increases in BP induced by ANG II.     

Arg16/Gly beta2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise.

Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic-receptor polymorphism have 1) greater forearm beta2-receptor mediated vasodilation and 2) a higher heart rate (HR) response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the higher HR response in Gly16 subjects serves to maintain the pressor response [increased cardiac output (CO)] in the setting of augmented peripheral vasodilation to endogenous catecholamines, we measured continuous HR (ECG), arterial pressure (Finapres), and CO (transthoracic echocardiography) during isometric, 40% submaximal handgrip to fatigue in healthy subjects homozygous for Gly (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg (n = 17, age 30 +/- 1.6, 11 women). Resting data were similar between groups. Handgrip produced similar increases in arterial pressure and venous norepinephrine and epinephrine concentrations; however, HR increased more in the Gly group (60.1 +/- 4.3% increase from baseline vs. 45.5 +/- 3.9%, P = 0.03), and this caused CO to be higher (Gly: 7.6 +/- 0.3 l/m vs. Arg: 6.5 +/- 0.3 l/m, P = 0.03), whereas the decrease in systemic vascular resistance in the Gly group did not reach significance (P = 0.09). We conclude that Gly16 homozygotes generate a higher CO to maintain the pressor response to handgrip. The influence of polymorphic variants in the beta2-adrenergic receptor gene on the cardiovascular response to sympathoexcitation may have important implications in the development of hypertension and heart failure.     

Longitudinal studies on the effect of hypertension on circadian hemodynamic and autonomic rhythms in telemetered rats

This study dealt with the long-term effects of hypertension on circadian rhythms of hemodynamic and cardiovascular autonomic functions in radiotelemetered rats. Blood pressure (BP), heart rate (HR), spontaneous locomotor activity, and respiration.were monitored in spontaneously hypertensive rats (SHRs), a model of human hypertension, from 14 to 27 weeks of age and in Wistar-Kyoto rats (WKY) as controls. Cardiovascular autonomic changes were determined by time-domain analysis of the variability of BP (standard deviation of mean arterial pressure, SDMAP) and HR (standard deviation of R-R intervals, SDRR, and the root mean square of successive differences in R-R intervals, rMSSD). Compared with WKY rats, the 24-hr MAP and SDMAP were higher at week 14 in SHRs and showed stepwise increases over the study duration, suggesting progressive increases in vasomotor sympathetic activity in hypertensive rats. Also, higher SDRR, rMSSD, and activity and lower HR and respiration were demonstrated in SHRs. Normal circadian rhythms (higher dark-time values) of MAP, HR, SDMAP, and SDRR were evident in WKY rats at week 20 and continued thereafter. Compared with WKY rats, the circadian BP and HR patterns were abolished and inverted, respectively, in SHRs. Lower dark-time, compared with light-time, SDMAP values were observed in SHRs that were associated with temporal increases in HR variability indices. These findings demonstrate that hypertension elicits significant alterations in circadian autonomic and hemodynamic profiles. Further, the steady increases in BP, average level and oscillations, in SHRs may explain the reported progressive age-related vascular and cardiac hypertrophy in these rats.     

Effects of phencyclidine and ketamine on cardiovascular activity and temperature in the squirrel monkey

Heart rate (HR), mean arterial blood pressure (BP) and core temperature (TEMP) were recorded from chair-restrained squirrel monkeys surgically prepared with chronically indwelling arterial and venous catheters to determine the effects of acute intravenous (i.v.) injections of phencyclidine and ketamine and intramuscular (i.m.) injections of ketamine. Phencyclidine (0.03-3.0 mg/kg) and ketamine (0.3-30.0 mg/kg) i.v. increased BP and decreased TEMP, and the changes in BP and in TEMP were greater in magnitude and duration after phencyclidine. Heart rate also increased monotonically after 0.03-0.3 mg/kg phencyclidine or 0.3-10.0 mg/kg ketamine, but the effects of higher doses of either drug were biphasic with decreases followed by increases in HR. When either of two doses of ketamine (10.0 and 30.0 mg/kg) was injected i.m., the effects were qualitatively similar to those observed after i.v. administration although of much less magnitude, and there was no evidence of a biphasic change in HR. The data show that these two dissociative anesthetics differ in duration of action and in magnitude of effect on cardiovascular activity and core temperature in the squirrel monkey, and that phencyclidine is approximately ten times as potent as ketamine.     

Arterial hypertension assessed “out-of-office” in a contemporary cohort of rheumatoid arthritis patients free of cardiovascular disease is characterized by high prevalence,low awareness,poor control and increased vascular damage-associated “white coat” phenomenon

Introduction

Rheumatoid arthritis (RA) is associated with a high cardiovascular disease (CVD) risk, whereas arterial hypertension is a major modifiable CVD risk factor with still unclear prevalence in RA disease. We conducted a comprehensive study on hypertension characteristics evaluating for the first time out-of-office blood pressure (BP) in a typical contemporary RA cohort.

Methods

Assessment of office and out-of-office BP (when office systolic/diastolic BP was >129/79) and vascular studies including evaluation of aortic stiffness, carotid hypertrophy/plaques and ankle-brachial index, were performed in 214 consecutive, consenting RA patients free of CVD (aged 58.4 ± 12.3 years, 82% women). As comparators regarding office hypertension measurements, data from 214 subjects (1:1 matched for age and gender with the RA patients) derived from a cohort designed to assess the prevalence of hypertension in the general population were used.

Results

The prevalence of declared known hypertension in the RA population was 44%. Of the remaining RA patients, 2 in every 5 individuals had abnormal office BP (systolic/diastolic >139/89 mmHg), contributing to almost double the prevalence of declared/office hypertension compared to the general matched population (67% vs. 34%). Out-of-office (home or ambulatory 24 hour) BP measurements revealed that: (i) a 54% prevalence of actual hypertension in RA, in other words almost 10% of the patients were unaware of having hypertension and (ii) 29% of the RA patients with known hypertension were not well controlled. Actual hypertension was positively associated with age and body mass index, and inversely with the use of biologic drugs. Overall, almost 1 out of 5 presented the ''white coat’ phenomenon. An intermediately compromised vascular phenotype was evident in this “white coat” subgroup (lying between patients with sustained normotension and sustained hypertension) in terms of aortic stiffness, carotid hypertrophy and ankle-brachial index, even after adjustment for confounders.

Conclusion

Beyond any doubt on the basis of out-of-office evaluation, arterial hypertension in RA has a high prevalence, low awareness and poor control, as well as substantial and vascular damage-associated “white coat” phenomenon. Thus, correct diagnosis and effective treatment of hypertension is of key importance in RA for CVD risk reduction.     

Effect of Anapsos in a murine model of experimental trichomoniasis

Immunomodulator effect of Anapsos (Polypodium leukotomas extract) in NMRI (US Naval Medical Research Institute) outbred mice infected by the intraperitoneal route with 10(7) Trichomonas vaginalis has been tested. Gross histopathologic changes in abdominal organs and mortality rate, as a consequence of the pathogenicity of the protozoa and the immune response of the host, were evaluated. Among the different treatment regimes assayed, Anapsos at doses of 20 mg/Kg/day administered for 10 days before infection decreases the parasite pathogenicity index (PI) in the treated animals when compared to those of the untreated control group. The immunosuppressor treatments with azathioprine (100 mg/Kg/day x 1), cyclophosphamide (100 mg/Kg/day x 1), and FK-506 (10 mg/Kg/day x 10) significantly decreased the PI, while an immunostimulant treatment with glycophosphopeptical (13 mg/Kg/day x 10) increased it. These assays have shown the usefulness of the murine model of experimental trichomoniasis for the study of immunomodulator activity of natural or synthetic drugs.     

Regional differences of cardiovascular effects of diltiazem in the rat

The dose-response relations of the central and peripheral effects of diltiazem were studied in 26 anaesthetized rats. Measured were the heart rate (HR), atrioventricular conduction time (PR), mean arterial blood pressure (BP), carotid and renal blood flow (Fc, Fr) and the corresponding relative regional resistance (RRc, RRr). The effects were evaluated by their maxima regularly reached 15-20 s after the i.v. bolus administration. The minimum dose which produced a significant HR decrease and PR prolongation were 0.4 and 2.0 mg/kg, respectively. In the mg/kg dose range a transient second degree AV block was regularly recorded. The lethal dose (cardiac arrest) was 20 mg/kg. BP significantly already decreased after 4 micrograms/kg. The dose-dependent decrease of Fr matched the hypotensive effect in the whole range due to unchanged RRr. In contrast Fc invariably increased at lower doses reflecting the RRc decay. Only in the mg/kg dose range Fc decreased in accord with BP since RRc dropped to a constant value (50% of control) with each administration. The peripheral reactions were significantly augmented in rats with renovascular hypertension. It is concluded that, in this model, the peripheral effects of diltiazem evidently surpass the central ones. The regional difference between the inert renal and responsive carotid vasculature might be due to a different mode of regulation of the respective vascular tone, hypothetically reflecting different density of membrane, potential-dependent Ca2+ channels.     

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.     

Chronotherapy With Low-Dose Aspirin for Prevention of Complications in Pregnancy

Preeclampsia and gestational hypertension are major contributors to perinatal morbidity and mortality. Several studies aimed to test the effects of low-dose aspirin (ASA) in the prevention of preeclampsia concluded that the beneficial effects of such treatment outweigh adverse ones. Such benefits have not been fully corroborated by larger randomized trials usually carried out in low-risk women, testing a dose of 60?mg/d ASA presumably ingested in the morning, and including women randomized as late as at 26–32 wks of gestation. The authors conducted a prospective, randomized, double-blind, placebo-controlled, chronotherapy trial on 350 high-risk pregnant women (183 nulliparous), 30.7?±?5.3 (mean?±?SD) yrs of age, and 13.5?±?1.4 wks of gestation at the time of recruitment. Women were randomly assigned to one of six groups, defined according to treatment (placebo or ASA, 100?mg/d) and time of treatment: upon awakening, 8?h after awakening, or at bedtime. Intervention started at 12–16 wks of gestation and continued until delivery. Blood pressure (BP) was measured by ambulatory monitoring (ABPM) for 48-h at baseline, every 4 wks until the 7th month of gestation, every 2 wks thereafter until delivery, and at puerperium. The effects of ASA on ambulatory BP were markedly dependent on administration time: there was no effect on BP, compared with placebo, when ASA was ingested upon awakening, but the BP reduction was highly statistically significant when low-dose ASA was ingested 8?h after awakening and, to a greater extent, at bedtime (p?<?.001). At puerperium, 6–8 wks after discontinuation of treatment, there was no statistically significant difference in 24-h BP means between the groups of women who ingested ASA at different circadian times. Women ingesting low-dose ASA, compared with placebo, evidenced a significantly lower hazard ratio (HR) of serious adverse outcomes, a composite of preeclampsia, preterm delivery, intrauterine growth retardation (IUGR), and stillbirth (.35, 95% confidence interval [CI]: .22–.56; p?<?.001). The HR of individual outcome variables, i.e., preeclampsia, preterm delivery, IUGR, and gestational hypertension, were also significantly lower with ASA versus placebo (p always?<?.041). There were small and nonsignificant differences in outcomes between placebo and low-dose ASA ingested upon awakening. These four groups combined showed highly significant greater event rate of serious adverse outcomes than women ingesting ASA either in the evening or at bedtime (HR: .19, 95% CI: .10–.39; p?<?.001). There was no increased risk of hemorrhage, either before or after delivery, with low-dose ASA relative to placebo (HR: .57, 95% CI: .25–1.33; p =?.194). Results indicate that (i) 100?mg/d ASA should be the recommended minimum dose for prevention of complications in pregnancy; (ii) ingestion of low-dose ASA should start at ≤16 wks of gestation; and (iii) low-dose ASA ingested at bedtime, but not upon awakening, significantly regulates ambulatory BP and reduces the incidence of preeclampsia, gestational hypertension, preterm delivery, and IUGR. ABPM evaluation at the first trimester of pregnancy provides sensitive endpoints for identification of women at high risk for preeclampsia who might benefit most from the cost-effective preventive intervention with timed low-dose ASA. (Author correspondence: rhermida@uvigo.es)     

Impaired glucose metabolism in hypertensive patients

We have studied glucose tolerance under carefully controlled conditions in 79 patients with arterial hypertension. The results show that, in patients with arterial hypertension but without clinical diabetes mellitus, the glucose tolerance was abnormal in 77.3% and normal in 22.3%. The corresponding figure in the control group of normotensive subjects was 0%. In each test the responses to glucose administration were analyzed by plotting the logarithm of the blood glucose concentration against time. For the points between 60 and 120 min, corresponding to the periods following glucose administration, a linear relationship was obtained and showed a decline at an exponential rate, as noted by other observers. An estimate of the volume of distribution of glucose was obtained as follows. Values observed in hypertensives with a pathological percent fall in blood glucose per minute (Kg) were 29.8 +/- 12.0 (mean +/- SD) liters and those in normal subjects with normal Kg values had a mean of 14.35 +/- 2.98, the difference being highly significant (p less than 0.0001). The results of the theoretical glucose concentration are also presented. Those obtained from subjects with normal Kg values (359.0 +/- 58.4 mg/dl) are significantly higher than in subjects with pathological Kg values (257.6 +/- 51.3 mg/dl; p less than 0.0001). All patients with either pathological or normal Kg values had normal glucose concentration levels, fasting blood sugar and no glucose in the urine specimen. The difference between pathological Kg values (107.0 +/- 25.8 mg/dl) and normal Kg values (90.6 +/- 13.0 mg/dl) was not found to be statistically different (p greater than 0.05). The distribution and means of glucose half time in controls with normal Kg values and hypertensives with pathological Kg values were: 63.5 +/- 11.5 and 137.8 +/- 48.1 min, respectively. The difference between normal and pathological Kg values being statistically significant at a confidence level above 99.5%. We also studied the free glucose pool at zero time. A significantly higher level was found in hypertensives with pathological Kg values, again indicating an impairment in glucose metabolism in this group: 90.6 +/- 26.5 vs. 65.0 +/- 5.4 g (p less than 0.0001). Another study showed an estimate of the mean cellular glucose uptake (MCUg) per minute and per kilogram body weight. The MCUg following glucose loading decreased considerably in hypertensives with pathological Kg values. The percentage reduction ranged between 50 and 55% hypertensives with pathological Kg values 4.1 +/- 0.8, and normotensives with normal Kg values, 8.0 +/- 0.6 (p less than 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)