Influencia de las Endotelinas y el Factor Natriurético Auricular en la respuesta cardiovascular al NaCl hipertónico administrado en la región anteroventral del tercer ventrículo de la rata

La región anteroventral del tercer ventrículo (AV3V) es capaz de detectar la concentración sanguínea de NaCl y ajustar la función cardiovascular y renal en respuesta a la composición hidroelectrolítica del líquido extracelular. La microinyección de NaCl hipertónico en esta área cerebral induce un incremento de la actividad simpática que aumenta de la presión arterial; la frecuencia cardíaca y la función renal. Estos cambios pueden ser modulados por la administración central de antagonistas de receptores 5HT2 de serotonina y bloqueadores de los receptores AT1 de angiotensina o por la administración periférica de antagonistas alfa y beta de los receptores adrenérgicos. El papel de las endotelinas cerebrales y del factor natriurético auricular (FNA) en esta región cerebral no ha sido estudiado. Se evaluó la participación de los receptores para endotelinas cerebrales y del FNA en la respuesta cardiovascular al NaCl hipertónico 1,5 M (2myL) administrado en la región AV3V de ratas anestesiadas. La microinyección de NaCl 1,5 M en la región AV3V de ratas normotensas produjo un incremento de la presión arterial media en un máximo de 17,9 ± 2,2 mm de Hg (p<0,01). La microinyección previa de FNA a una dosis 5myg/2myL no alteró la presión arterial media (PAM) ni el efecto en la PAM inducidos por la microinyección de NaCl 1,5 M en AV3V. La administración previa del antagonista no selectivo de los receptores de endotelinas PD-142893 (3myg/2myL) no alteró la PAM basal pero redujo en 8,52 ± 1,20 mm de Hg (47,6%) el incremento de la presión arterial media inducido por el NaCl 1,5 M (p<0,01). Los resultados indican un papel modulador de las endotelinas en la respuesta cardiovascular al NaCl 1,5 M administrado en la región AV3V y ausencia de la participación del FNA en la respuesta cardiovascular simpática evocada por el NaCl.

Third ventricle anteroventral area (AV3V) is sensitive to changes in NaCl concentration and able to modify blood pressure and renal function in response to NaCl concentration. Hypertonic NaCl microinjections in AV3V induce a sympathetic cardiovascular response which increases blood pressure and heart rate; these changes can be modulated by central administration of 5HT2 and AT1 receptor blockers, and also by peripheral administration of alpha and beta adrenergic receptor antagonists. Influence of endothelin receptors (ETR) and atrial natriuretic factor (ANF) on sensitivity to NaCl has not been explored. Hypertonic 1,5 M NaCl (2 muL volume) microinjections in AV3V of normotensive anesthetized rats increased mean arterial blood pressure by 17,9 ± 2.2 mm Hg (p<0.01). ANF microinjections (5mug/2muL) in AV3V neither changed mean arterial blood pressure nor altered the hypertensive response to NaCl 1,5 M microinjection. Microinjection of PD 142893 into AV3V a non selective endothelin antagonist (3mug/2muL) did not modify basal blood pressure but reduced by 47,6% (p<0,01) the hypertensive response to 1,5 M NaCl injection. These results indicates a possible modulator effect of endothelin receptors in the NaCl centrally- evocated cardiovascular response to hypertonic NaCl injections in AV3V. Acute microinjection of ANF in this brain area seems not to be involved in the NaCl-evoked sympathetic cardiovascular response.

Biological screening of plants of the Venezuelan Amazons.

A total of 21 extracts derived from 17 different plant species collected in Venezuelan Amazons have been tested for the following biological activities: cardiovascular activity, brine shrimp lethality, and inhibitory effects on the hydrolysis of glucose-6-phosphate in intact and disrupted microsomes. Eight extracts diminished rat blood pressure with or without changes in heart rate. The fruit extract of Swartzia leptopetala and the leaf and twig extract of Connarus lambertii resulted in death of experimental animals. The majority of extracts (17 extracts) showed significant toxicity against Artemia salina. Concerning the hydrolysis of glucose-6-phosphate, better inhibitory effects were observed in intact microsomes than in disrupted ones for all the extracts, suggesting that these extracts intervene with variable potency in glucose-6-phosphate transport through the microsomal membrane.

Pharmacological modulation of the cardiovascular response to hypertonic NaCl injection in the anteroventral area of the rat brain third ventricle.

The anteroventral area of the rat brain third ventricle (AV3V) was stimulated by stereotaxically placed microinjections (1 microliter) of hypertonic 1.5 mol/l NaCl and the responses of mean arterial pressure (MAP) and heart rate (HR) were recorded. Previous injection of terazosin or propranolol (5.0 micrograms) into AV3V, 15 min before 1.5 mol/l NaCl microinjection, did not alter the cardiovascular response pattern induced by 1.5 mol/l NaCl. Prior AV3V treatment with ketanserin (1.0 microgram) significantly reduced (p < 0.01) the MAP and HR increase induced by 1.0 microliter of 1.5 mol/l NaCl without changing basal cardiovascular parameters. Prior AV3V treatment with losartan (10.0 micrograms) significantly reduced (p < 0.01) the hypertension and tachycardia induced by hypertonic NaCl administration. Thus, AV3V serotonin and angiotensin II-sensitive neurons may exert an excitatory role on blood pressure and HR involved with the sympathetic discharge produced by hypertonic NaCl stimulation.

Decreased cardiovascular responses to cisterna magna NaCl injection in hypertensive rats.

Albino rats were made hypertensive by 1% NaCl in the drinking water for 4-5 months, systolic (SBP) and distolic blood pressure (DBP) were 164.0 +/- 10.1 mm Hg and 118.7 +/- 4.6 mm Hg respectively, vs. control rats whose SBP and DBP were 119.0 +/- 4.4 mm Hg and 86.8 +/- 4.3 mm Hg respectively. Psychosocial stress (1 hour daily for 4-5 months) only raised SBP to 140.0 +/- 5.2 mm Hg; DBP remained unaltered. One percent NaCl intake combined with psychosocial stress, increased SBP and DBP but not significantly beyond the level observed with single 1% NaCl administration. Formerly described control and hypertensive rats were anesthetized with sodium pentobarbital (40 mg/kg) and stereotaxically injected into de cisterna magna (i.c.) with 20 microliters of 1.5 M NaCl solution. During i.c. injection, intraarterial SBP, DBP and heart rate (HR) were continuously recorded. After i.c., 1.5 M NaCl injection, mean arterial pressure (MAP) increased 21.0 +/- 4.0 mm Hg and HR 51.0 +/- 5.0 beats/min in control rats. Rats made hypertensive by 1% NaCl intake showed a significantly lower increase of MAP, 11.0 +/- 1.8 mm Hg; HR increased 37.0 +/- 4.3 beats/min. Rats submitted only to psychosocial stress displayed a response similar to the one described in control rats. Hypertensive rats submitted to both 1% NaCl intake and psychosocial stress had a more intense reduction of the hypertensive and tachycardic response, 8.0 +/- 2.2 mm Hg and 20.0 +/- 3.2 beats/min respectively. Control i.c. injection with the same volume of saline (0.15 M NaCl) did not change significantly SBP, DBP or HR in a separate group of rats. Left ventricle weight (0.754 +/- 0.0333 g) was augmented in the 1% NaCl treated group (0.795 +/- 0.038 g), and increased its protein content by 13.1% (changes not statistically significant). The highest increase of the left ventricle weight (23.7% above control) with no change in its protein content was observed in rats submitted to 1% NaCl intake plus psychosocial stress. In conclusion, chronic high NaCl intake increased blood pressure; psychosocial stress acted as a weak stimulus for SBP and DBP increase, and central nervous system sodium chloride sensitivity for delivering a peripheral sympathetic discharge was found decreased in rats made hypertensive by a high salt intake.

[Direct negative inotropic effect of cocaine in rat ventricle strip]. / Efecto inotrópico negativo directo de la cocaína en ventrículo de rata.

Cocaine, when used as a recreative drug, can induce cardiovascular toxic effects such as acute reduction of left ventricle ejection fraction, which indicates a negative inotropic effect of the drug. The purpose of this study was to clarify the direct negative inotropic effect of cocaine in in vitro conditions. Rat right ventricle strips were incubated in Krebs solution gassed with 95% O2 and 5% CO2 at 37 degrees, and electrically driven with 2 ms square pulses, 17 mA, at 110 systoles/min. Separate experiments were conducted to study cocaine effect at 210 and 310 systoles/min. The contractile force was recorded through a strain-gauge isometric transducer. Cocaine increased contractile force at doses of 0.3-10.0 micrograms/ml, up to 53% over basal contraction. In the presence of 4 x 10(-8) M atenolol, low doses of cocaine did not increase contractile force and at doses between 3.0-10.0 micrograms/ml revealed a depressant activity on heart muscle contractions. Doxazosin (1.0 microM) and yohimbine (0.1 microM) did not modify the positive inotropic effect of cocaine, showing that alpha 1 and alpha 2 adrenergic receptors were not involved in this cocaine ventricle action. Increasing ventricle strip stimulation rate to 210 and 310 systoles/min for 30 seconds, the contractile force was risen by 55% and 95%, respectively. Cocaine at doses 1.0-3.0 micrograms/ml did not modify the physiological increase of contractile force seen upon ventricle rate increase. The mechanism involved in the contractile force increment after ventricle rate increase is a transient rise of cytosolic Ca2+, mainly derived from the sarcoplasmic reticulum and from extracellular fluid. Atenolol (4 x 10(-8) M) exposure of the right ventricle strip intensified the negative inotropic effect of cocaine (3.0-10 micrograms/ml) seen by ventricle stimulation at 210 and 310 systoles/min. The myocardial direct depressant effect of cocaine, in the presence of atenolol, was gradually reversed by extracelular Ca2+ increase at 3.2 and 5.0 mM, respectively. In conclusion, the mechanism of myocardial direct depressant effect of cocaine is related to the beating frequency of the ventricle, which may be associated to interference with the Ca2+ release process from the myocite sarcoplasmic reticulum, and not to calcium entry blockade from extracellular fluid. However, a dpressant effect of cocaine on phase "0" of depolarization, related to its local anesthetic properties can not be ruled out.

[Increase of renal dopamine production induced by nifedipine in hypertensive patients. Double blind vs placebo study]. / Aumento de la producción de dopamina renal por nifedipina en pacientes hipertensos. Estudio a doble ciego vs. placebo.

Dopamine is synthetized and excreted by kidneys, this amine exerts its natriuretic and diuretic effects by inhibition of sodium reabsorption on kidney convoluted tubules. The objective of this study was to verify the changes of dopamine urinary excretion induced by nifedipine-LP treatment in hypertensive patients. Twenty four patients with essential hypertension (stages 1, 2) were included in this double-blind, placebo controlled study. Twelve patients received nifedipine (average daily dose, 21.5 mg/day) for 4 weeks, and 12 patients received placebo for the same time period. No significant changes were detected upon nifedipine treatment neither in plasma biochemical nor hematological parameters. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was significantly reduced from pretreatment values 168.0 +/- 8.7 mmHg and 102.0 +/- 5.2 mmHg respectively, to end-treatment values 140.0 +/- 6.6 mmHg and 88.0 +/- 5.6 mmHg (p < 0.05). Placebo treatment did not modify SBP and DBP. Urinary dopamine excretion increased by 53% from 679.5 +/- 80.1 micrograms/24 h prior to treatment to 1040.0 +/- 110.1 micrograms/24 h after treatment (p < 0.009. 95% Confidence Interval of the Difference: -538.9 to -183.6). Urinary volume of nifedipine treated patients increased from 1613 +/- 85 mL/24 h to 1920 +/- 160 mL/24 h post-treatment (p < 0.05). No significant changes were observed in urinary noradrenaline and adrenaline excretion in nifedipine or placebo treated patients. Analysis of fluorescent light excitation and emission spectra (200 nm to 800 nm) of dopamine extracted from patient's urine submitted to nifedipine treatment did not reveal any interference when compared to chemically pure dopamine. If is concluded that nifedipine treatment of hypertensive patients increases kidney dopamine production which in turn can exert a natriuretic and diuretic effect besides its well known vasodilator properties.

Low urinary dopamine excretion associated to low sodium excretion in normotensive Piaroa Amazonian ethnia compared to urban subjects.

The objective of this work was to compare urinary dopamine, noradrenaline, adrenaline, sodium and potassium excretion in a group of normotensive Piaroa Amazonic ethnia who do not use salt in their regular food intake, against a group of urban normotensive citizens known to have a high salt intake in their regular meals. Twenty adult normotensive Piaroa subjects living in the Amazonas forest, 11 men and 9 women, 23-72 years old, and 33 normotensive urban citizens, 25-70 years old, 17 men and 17 women, were included in the study. After a 10 min. rest, an average of three supine systolic (SBP) and diastolic (DBP) blood pressure recordings was obtained. Piaroas subjects SBP and DBP were 111.3 +/- 2.9 mmHg and 62.7 +/- 1.9 mmHg respectively; urban subjects SBP and DBP were 111.8 +/- 2.2 mmHg and 70.3 +/- 1.6 mmHg respectively. Supine heart rate was lower in Piaroas (58.0 +/- 1.8 beats/min) than in urban subjects (76.5 +/- 1.9 beats/min), p < 0.05. Sodium urinary excretion was much lower in Piaroas (12.6 +/- 5.2 mmol/24 h) when compared to urban subjects (210.7 +/- 24.5 mmol/24 h), p < 0.01. No difference was found in daily urinary potassium excretion between Piaroas and urban subjects (50.4 +/- 7.2 mmol/24 h vs 45.1 +/- 7.4 mmol/24 h). Urinary dopamine excretion was lower in Piaroas (314.7 +/- 40.1 micrograms/24 h) in comparison to urban subjects (800.4 +/- 59.2 micrograms/24 h), p < 0.05. Daily urinary noradrenaline and adrenaline excretion were 67.9% and 85.4% respectively lower in Piaroas than in urban subjects. In conclusion, lower amounts of sodium daily intake are associated to lower kidney dopamine production in Piaroas as compared to urban subjects. Apparently indigenous tribes might require less kidney dopamine synthesis to excrete the very small amounts of salt they consume in their regular food intake. The opposite was found in urban subjects; more kidney dopamine synthesis would be required for larger amounts of urinary sodium excretion. In this population, essential hypertension has been associated to a failure of the natriuretic mechanism triggered by dopamine onkidney tubules.

[Changes produced by age in cardiovascular reflex responses]. / Cambios producidos por la edad en las respuestas cardiovasculares reflejas.

The influence of age on reflex cardiovascular responses, elicited by orthostatic change and Valsalva's maneuver was studied in 105 healthy volunteers, and the response to cold pressor test in 87 healthy adults. The age range of the subjects was 12 to 79 years old; they were stratified by decades for statistical analysis. Included in this study were only subjects without diseases, as evidenced by anamnesis, physical examination, blood pressure recording, ECG tracings, chest X-Ray and routine laboratory tests. None of subjects showed obesity, the body mass index was between 19.6 +/- 0.9 Kg/m2 in the 10-19 year old group and 25.2 +/- 1.2 Kg/m2 in the 50-59 year old group (mean +/- SE). Systolic and diastolic blood pressure (SBP, DBP) were between 113.6 +/- 4.2 and 64.2 +/- 2.9 mmHg respectively in the 10-19 years old group and 139.8 +/- 5.0 mmHg and 79.5 +/- 3.2 mmHg respectively in the 70-79 years old group (mean +/- SE). Heart rate in supine position varied between 71.2 +/- 3.2 beats/min in the 10-19 years group and 75.8 +/- 3.0 beats/min in the 70-79 years old group (mean +/- SE). Orthostatic response. Change from supine to standing position increased mean arterial pressure (MAP) by 10.0 +/- 1.25 mmHg in the 10-19 years old group; a similar increase occurred up to 40-49 years old group; from that age on, the response became bimodal, the percentage of subjects showing a MAP decrease upon standing, increased from 20% in the 50-59 years old group to 48% in the 70-79 years old group; MAP descents ranged between -5.3 +/- 0.63 and -12.6 +/- 1.37 mmHg (mean +/- SE) and were non symptomatic. The same bimodal pattern of responses was observed in the heart rate. Cold pressor test. In the 10-19 years old group the cold pressor test induced an increase of SBP and DBP of 17.6 +/- 5.0 mmHg and 11.5 +/- 3.5 mmHg (mean +/- SE) respectively, this response remained unchanged up to 40-49 years old age. After 50-59 years old this SBP and DBP increase was reduced by 50% and 63% in the 60-69 and 70-79 years old groups respectively. Return of SBP and DBP to cold prestimulation levels was normal in all studied groups.(ABSTRACT TRUNCATED AT 400 WORDS)

[Effect of cerebral noradrenaline and dopamine depletion on spontaneous and amphetamine-stimulated motor activity in rats]. / Efecto del agotamiento de la noradrenalina y dopamina cerebrales de la rata sobre la actividad locomotriz espontanea y la estimulada por anfetamina.

Selective depletion of rat brain noradrenaline and dopamine by 6-hydroxidopamine, 30-60 days after cisterna magna microinjection, reduced nocturnal spontaneous locomotor activity by 40%. This treatment also reduced by 90% the excitatory effect of amphetamine on locomotion. Disulfiram and FLA-63, selective inhibitors of dopamine-B-hydroxilase, depleted by 70% the noradrenaline content of striatum and brain cortex, without changes of dopamine concentration in the same areas. These rats showed a reduced spontaneous locomotor activity and a blockade of amphetamine stimulating activity. In conclusion, our results give support to the hypothesis of brain noradrenaline having a major role on the control of locomotor activity of rodents.