Blood pressure set point.

This paper has two main purposes: A) to emphasize the role of the kidney in setting peripheral resistance, thus arterial blood pressure and flow distribution since birth to full grown; and B) to bring attention to the role that changes in pulse pressure and pulse velocity may have in the genesis of aging hypertension. A) According to the tonus regulation at basal steady conditions, the arterial system may be divided into three areas: I) the skin, in which the vascular tonus is regulated by heat; II) the kidney, whose vessels are regulated by glomerulo-tubular balance; and III) the rest of organs and tissues of the body, whose tonus is regulated according to the oxygen the cell needs to maintain its energetic equilibrium (ATP/ADP relationship). As area III has the higher flow and lowest equivalent resistance, the kidney is--hemodynamically--the organ that sets arterial blood pressure during life. Nevertheless, since birth to full grown, the kidney must progressively adjust the peripheral resistance of area III, in order to allow arterial blood pressure and renal distribution to match glomerular filtration with the increasing body metabolism. The tool that the kidney uses to adjust resistance of area III, thence arterial blood pressure and blood distribution, is the renin-angiotensin system. B) Aging decreases vascular distensibility. Lower distensibility of the arterial tree results in a progressive increase in amplitude and velocity of the pulse wave, then in its potency. Small resistance vessels must increase Bayliss response in order to reduce pulse impact on the precapillarial arteries. Structural changes in the resistance vessels, as well as in preglomerular arteries, should establish a feed-back mechanism responsible for the evolution of arterial blood pressure.

Extracellular ATP and bradykinin increase cGMP in vascular endothelial cells via activation of PKC.

Vasodilation by agents such as bradykinin and ATP is dependent on nitric oxide, the endothelium-dependent relaxing factor (EDRF). The release of EDRF results in elevation of cGMP in endothelial and smooth muscle cells (9). The signaling pathway that leads to increases in cGMP is not completely understood. The role of protein kinase C (PKC) in the elevation of cGMP induced by ATP and bradykinin was studied in cultured porcine aortic endothelial cells, by measuring PKC phosphorylation of a substrate and by measuring cGMP levels by radioimmunoassay. Extracellular ATP and bradykinin simultaneously elevated cGMP levels and PKC activity. The PKC inhibitors staurosporine, calphostin C, and Cremophor EL (T. Tamaoki and H. Nakano. Bio/Technology 8: 732-735, 1990; F. K. Zhao, L. F. Chuang, M. Israel, and R. Y. Chuang. Biochem. Biophys. Res. Commun. 159: 1359-1367, 1989) prevented the elevation of cGMP elicited by ATP and reduced that produced by bradykinin. Cremophor did not affect the elevation of cGMP by nitroprusside, an agent that directly increases guanylate cyclase activity (9). The PKC activator phorbol 12-myristate 13-acetate, but not a phorbol ester analog inactive on PKC, also elevated cGMP levels. These results suggest that EDRF agonists elevate cGMP in endothelial cells via PKC stimulation.

Energética del comportamiento iónico en la contracción muscular cardíaca: aspectos fisiológicos y fisiopatológicos / Energetics of ionic behavior in heart muscle contraction: physiologic and physiopathologic aspects

Es aceptado que los movimientos iónicos a través de diferentes sistemas membranosos (sarcolema, retículo, sarcoplásmico y mitocondria) juegan un papel importante en el metabolismo del músculo cardíaco. Por otra parte, tanto su participación relativa como el gasto de energía asociado a dichos movimientos, no han sido definitivamente establecidos. Mediciones biofísicas y bioquímicas de los diferentes mecanismos de intercambio iónico, han provisto datos que llevaron a postular diferentes modelos funcionales para el metabolismo de reposo y el metabolismo activo del músculo cardíaco. El presente trabalho analisa, desde un punto de vista energético, datos bioquímicos y biofísicos extraídos de la literatura calculando el rango del consumo de energia que sería atribuible a cada mecanismo. Particularmente, son analizados los movimientos de sodio, potasio y calcio durante el estado de reposo y/o el estado activo y se discute la participación fraccional de las distintas organelas (sarcolema, retículo sarcoplásmico y mitocondria). Con este análisis y a partir de la cantidad conocida de energía liberada ( o la cantidad de oxígeno consumido) por el músculo es posible determinar la existencia de suficiente energía para un modelo dado de intercambio iónico durante el proceso de excitación-contracción. Además del análisis mencionado, se presenta una revisión de estudios energéticos realizados en condiciones patológicas. En particular, se analizan patologías con compromiso energético directo tal como la hipertrofia cardíaca, la isquemia y la anoxia en las que la alteración de los mecanismo de transporte iónico parecen jugar un papel crucial

Energética del comportamiento iónico en la contracción muscular cardíaca: aspectos fisiológicos y fisiopatológicos / Energetics of ionic behavior in heart muscle contraction: physiologic and physiopathologic aspects

Es aceptado que los movimientos iónicos a través de diferentes sistemas membranosos (sarcolema, retículo, sarcoplásmico y mitocondria) juegan un papel importante en el metabolismo del músculo cardíaco. Por otra parte, tanto su participación relativa como el gasto de energía asociado a dichos movimientos, no han sido definitivamente establecidos. Mediciones biofísicas y bioquímicas de los diferentes mecanismos de intercambio iónico, han provisto datos que llevaron a postular diferentes modelos funcionales para el metabolismo de reposo y el metabolismo activo del músculo cardíaco. El presente trabalho analisa, desde un punto de vista energético, datos bioquímicos y biofísicos extraídos de la literatura calculando el rango del consumo de energia que sería atribuible a cada mecanismo. Particularmente, son analizados los movimientos de sodio, potasio y calcio durante el estado de reposo y/o el estado activo y se discute la participación fraccional de las distintas organelas (sarcolema, retículo sarcoplásmico y mitocondria). Con este análisis y a partir de la cantidad conocida de energía liberada ( o la cantidad de oxígeno consumido) por el músculo es posible determinar la existencia de suficiente energía para un modelo dado de intercambio iónico durante el proceso de excitación-contracción. Además del análisis mencionado, se presenta una revisión de estudios energéticos realizados en condiciones patológicas. En particular, se analizan patologías con compromiso energético directo tal como la hipertrofia cardíaca, la isquemia y la anoxia en las que la alteración de los mecanismo de transporte iónico parecen jugar un papel crucial (AU)

Effect of central norepinephrine depletion on renovascular hypertension and on the renin system.

Some reports have stated that central norepinephrine (NE) depletion inhibited the development of hypertension in the rat. On the other hand, this pharmacological treatment induces changes on the central renin-angiotensin system. The present study was designed to follow the development of 2 kidney-2 clip (2k-2c) renovascular hypertension in rats depleted of central NE and to analyze the central and peripheral renin-angiotensin system. Male Wistar rats (n = 40) were used. Half of the animals was injected, intracisternally, with 6-hydroxydopamine (6-OHDA), the remaining rats only received the vehicle. One week later a silver clip was placed on each renal artery on half of the 6-OHDA treated rats and on half of the vehicle treated animals. A sham operation was performed on the remaining rats. Blood pressure was measured weekly during 7 weeks. Then, blood and cerebrospinal fluid (CSF) samples were obtained. The brain was dissected in several areas. NE and angiotensinogen concentration (AoC) were determined in tissue samples. AoC was evaluated in plasma and CSF; plasma renin activity was also measured. Hypertension development was not prevented by central NE depletion, which was significant in all central areas (p < 0.001). Other significant results showed that renal ischemia and/or NE depletion induced a significant increase in angiotensinogen concentration in the hypothalamus (p < 0.01) and in CSF (p < 0.05). In summary: central NE depletion was not able to modify the development of 2 k - 2 c hypertension. Treatment and renal ischemia induced an increase of central AoC.

Ajuste del nivel basal de la presión arterial / [Adjustment of the basal level of blood pressure]

Basically the circulation must satisfy three requirements: 1) to provide an adequate blood flow to the tissues for maintaining their energetic needs, 2) to sustain renal function (glomerular pressure and renal blood flow) for the precise homeostasis of body fluids, and 3) to grant cutaneous circulation for controlling body temperature. Therefore, the arterial circulation can be separated in oxygen dependent, filtration dependent and thermic dependent sectors. The blood flow distribution through these regions depends on the myogenic tone of the resistance vessels. The oxygen dependent section receives 70

of the cardiac output and settles the equivalent resistance of the arterial tree; so, it is the main one responsible for setting the blood pressure level. The total resistance of this section should be adjusted to maintain the ATP/ADP relationship. The mechanisms involved in the regulation of the myogenic tone are local metabolic products (pO2, pCO2, pH, etc.), vasoactive substances present in the vascular wall (EDRF, AgII, PGs, etc.) and intracellular variations (Na++, Ca++, PKC, IP3, etc.). The vascular resistance of this section, adjusted as an electronic module, settles the minimum blood pressure needed to maintain the energetic equilibrium, independently of the pressure required to achieve a normal renal function. Thus, the kidney to fulfill its function must modulate this previously established myogenic tone by employing the renin angiotensin system. Circulating AgII will increase the vascular tone in the oxygen dependent section overriding its local controls until the blood pressure reaches the necessary level to maintain an adequate renal function.

[Energetics of ionic behavior in heart muscle contraction. Physiologic and physiopathologic aspects]. / Energética del comportamiento iónico en la contracción muscular cardíaca. Aspectos fisiológicos y fisiopatológicos.

It is widely accepted that the ionic movement across the different membrane systems (i.e. sarcolemma, sarcoplasmic reticulum, mitochondria), plays a major role on heart muscle metabolism. On the other hand, neither the relative role nor the associated energy expenditure of those mechanisms have been definitively established. Biochemical and biophysical measurements of the different ion exchange mechanisms, have provided data leading to the postulation of different models for both resting and active metabolism of the heart muscle. The present work analyzes, from an energetic standpoint, available biochemical and biophysical data from the literature calculating the range of energy expenditure that should be attributable to each mechanism. Sodium, potassium and calcium movements during either resting and/or active state are particularly analyzed and the fractional role of various organelles (sarcolemma, sarcoplasmic reticulum and mitochondria) discussed. From this analysis and the known amount of energy released (or the amount of oxygen consumed) by the muscle it is possible to determine whether there is enough energy for a given model of ionic exchange during the excitation contraction process. In addition to this analysis a comparatively short review of energetic studies performed under pathological conditions is also presented. In particular, the pathological conditions analyzed are those with an energetic compromise such as heart hypertrophy, ischemia and anoxia in which the alteration of ionic transport mechanisms seems to be playing a major role.

[Adjustment of the basal level of blood pressure]. / Ajuste del nivel basal de la presión arterial.

Basically the circulation must satisfy three requirements: 1) to provide an adequate blood flow to the tissues for maintaining their energetic needs, 2) to sustain renal function (glomerular pressure and renal blood flow) for the precise homeostasis of body fluids, and 3) to grant cutaneous circulation for controlling body temperature. Therefore, the arterial circulation can be separated in oxygen dependent, filtration dependent and thermic dependent sectors. The blood flow distribution through these regions depends on the myogenic tone of the resistance vessels. The oxygen dependent section receives 70% of the cardiac output and settles the equivalent resistance of the arterial tree; so, it is the main one responsible for setting the blood pressure level. The total resistance of this section should be adjusted to maintain the ATP/ADP relationship. The mechanisms involved in the regulation of the myogenic tone are local metabolic products (pO2, pCO2, pH, etc.), vasoactive substances present in the vascular wall (EDRF, AgII, PGs, etc.) and intracellular variations (Na++, Ca++, PKC, IP3, etc.). The vascular resistance of this section, adjusted as an electronic module, settles the minimum blood pressure needed to maintain the energetic equilibrium, independently of the pressure required to achieve a normal renal function. Thus, the kidney to fulfill its function must modulate this previously established myogenic tone by employing the renin angiotensin system. Circulating AgII will increase the vascular tone in the oxygen dependent section overriding its local controls until the blood pressure reaches the necessary level to maintain an adequate renal function.

Ajuste del nivel basal de la presión arterial. / [Adjustment of the basal level of blood pressure]

Basically the circulation must satisfy three requirements: 1) to provide an adequate blood flow to the tissues for maintaining their energetic needs, 2) to sustain renal function (glomerular pressure and renal blood flow) for the precise homeostasis of body fluids, and 3) to grant cutaneous circulation for controlling body temperature. Therefore, the arterial circulation can be separated in oxygen dependent, filtration dependent and thermic dependent sectors. The blood flow distribution through these regions depends on the myogenic tone of the resistance vessels. The oxygen dependent section receives 70

of the cardiac output and settles the equivalent resistance of the arterial tree; so, it is the main one responsible for setting the blood pressure level. The total resistance of this section should be adjusted to maintain the ATP/ADP relationship. The mechanisms involved in the regulation of the myogenic tone are local metabolic products (pO2, pCO2, pH, etc.), vasoactive substances present in the vascular wall (EDRF, AgII, PGs, etc.) and intracellular variations (Na++, Ca++, PKC, IP3, etc.). The vascular resistance of this section, adjusted as an electronic module, settles the minimum blood pressure needed to maintain the energetic equilibrium, independently of the pressure required to achieve a normal renal function. Thus, the kidney to fulfill its function must modulate this previously established myogenic tone by employing the renin angiotensin system. Circulating AgII will increase the vascular tone in the oxygen dependent section overriding its local controls until the blood pressure reaches the necessary level to maintain an adequate renal function.

Energética del comportamiento iónico en la contracción muscular cardíaca. Aspectos fisiológicos y fisiopatológicos. / [Energetics of ionic behavior in heart muscle contraction. Physiologic and physiopathologic aspects]

It is widely accepted that the ionic movement across the different membrane systems (i.e. sarcolemma, sarcoplasmic reticulum, mitochondria), plays a major role on heart muscle metabolism. On the other hand, neither the relative role nor the associated energy expenditure of those mechanisms have been definitively established. Biochemical and biophysical measurements of the different ion exchange mechanisms, have provided data leading to the postulation of different models for both resting and active metabolism of the heart muscle. The present work analyzes, from an energetic standpoint, available biochemical and biophysical data from the literature calculating the range of energy expenditure that should be attributable to each mechanism. Sodium, potassium and calcium movements during either resting and/or active state are particularly analyzed and the fractional role of various organelles (sarcolemma, sarcoplasmic reticulum and mitochondria) discussed. From this analysis and the known amount of energy released (or the amount of oxygen consumed) by the muscle it is possible to determine whether there is enough energy for a given model of ionic exchange during the excitation contraction process. In addition to this analysis a comparatively short review of energetic studies performed under pathological conditions is also presented. In particular, the pathological conditions analyzed are those with an energetic compromise such as heart hypertrophy, ischemia and anoxia in which the alteration of ionic transport mechanisms seems to be playing a major role.

Haemodynamics and arterial wall metabolism: their possible combined role in atherogenesis.

An integrated model for the genesis of atherosclerosis is proposed on the basis of the evidence reported in the literature from the fields of haemodynamics and arterial wall metabolism. The model is based on the hypothesis of 'localized nutrient shortage' in the arterial wall at critical regions of the vascular tree, such as branchings, bendings, stenosis etc. In particular, it is proposed that a tissue deficit of glucose and oxygen, more pronounced at those regions, may be the main cause of endothelial dysfunction and lesion initiation. LDL-cholesterol level and hypertension are included as strongly interacting risk factors, and new explanations are provided for the effects of smoking and diabetes. For the latter factors, transport limitations in the lumen and/or in the tissue are likely to interact with wall metabolism; in the case of smoking, additional competition of CO and O2 within the tissue is suggested, and for diabetes, the impaired uptake of glucose by the tissue is proposed as the main causal factor. Also, the incorporation of secondary risk factors to the model is shown to be feasible on the basis of their suggested action mechanism. It is concluded that the study of nutrients and LDL transport at regions of complex arterial geometry in connection with wall metabolic requirements can provide a better understanding of the atherogenic process.

Natriuretic response to saline load in one-kidney/one-clip hypertensive rats.

Parameters of renal function were studied in conscious and anesthetized one-kidney (1K) and one-kidney/one-clip (1K-1C) rats. Effective renal blood flow (ERBF) was significantly lower in anesthetized 1K-1C rats than in conscious ones (12.1 +/- 1.6 vs. 16.4 +/- 1.2 ml/min). Renal function was evaluated in two-kidney (2K), 1K and 1K-1C unanesthetized rats. ERBF was lower in 1K and 1K-1C animals than in 2K rats. Glomerular filtration rate (GFR) and urinary sodium excretion (UNa.V) were not affected by uninephrectomy with or without clipping the renal artery. In 1K-1C rats, mean arterial pressure (MAP) increased from 100 +/- 2 to 140 +/- 1 mm Hg. Subsequently, the renal ability of unanesthetized rats to handle Na was studied by a sustained extracellular fluid volume expansion (EFVE) in all groups. During EFVE, MAP remained unchanged in the 2K and 1K groups and decreased significantly in the 1K-1C group, ERBF did not change and GFR increased to the same extent in all groups. The increase in UNa.V was 40% higher in 2K than in 1K or 1K-1C rats. These findings indicate that the relatively smaller natriuretic response to a saline load of 1K rats with or without a clip in the renal artery, as compared with 2K rats, could be ascribed to renal mass reduction. Finally, the study shows the advantage of performing studies of renal function in hypertension in conscious rather than anesthetized rats.

Development of renovascular hypertension after central serotonin depletion.

The participation of the central serotonergic system in the development of two-kidney, two clip (2K2C) Goldblatt renovascular hypertension in the rat has been examined. Half of the rats were treated with desmethylimipramine intraperitoneally and 5,7-dihydroxytryptamine intracisternally; the other half received only desmethylimipramine and the 5,7-dihydroxytryptamine vehicle. Two days later, a silver clip was placed in both renal arteries in half of the rats of each group. A sham operation was performed in the remaining rats. Blood pressure was recorded during the 5 weeks after treatment. At the end of the experiment, blood and cerebrospinal fluid samples were obtained. The brain was dissected into several areas and kept frozen. Norepinephrine, serotonin, angiotensinogen, and renin-like concentration were evaluated in the brain areas. Plasma renin activity and angiotensinogen concentration in the plasma and cerebrospinal fluid were estimated. In the sham-operated groups, blood pressure was lower in the treated than in the control rats. The curve of blood pressure increase, as well as the final blood pressure, was similar in the treated and control 2K2C rats. Serotonin was significantly depleted by the 5,7-dihydroxytryptamine treatment in all brain areas. Treatment did not induce any changes in central norepinephrine concentration. Plasma renin activity was diminished in the treated sham-operated rats. These data indicate that the central serotonin depletion does not prevent the development of hypertension and confirm the role of the amine in normal blood pressure regulation. On the other hand, the peripheral renin-angiotensin system might participate in the development of high blood pressure in serotonin-depleted animals.

Sodium intake modulates the development of cardiac hypertrophy in two-kidney, one clip rats.

Sodium homeostasis exerts a powerful influence on the cardiovascular system in normotensive and hypertensive animals. Previous studies indicate that factors other than blood pressure can influence cardiac hypertrophy. In the present experiments, we evaluated the effects of different sodium diets in the two-kidney, one clip hypertension model in the rat. After the renal artery had been clipped, the rats received a normal sodium (177 meq/kg), high sodium (517 meq/kg), and low sodium (7 meq/kg) diet during 4 weeks. The final blood pressure was almost the same in the three groups (normal sodium 170 +/- 12 mm Hg; low sodium 168 +/- 4 mm Hg; and high sodium 162 +/- 7 mm Hg). Sodium restriction significantly reduced the development of cardiac hypertrophy as compared with rats on normal or high sodium diets. Thus, ventricular weight and ventricular weight/body weight ratio were significantly higher in rats subjected to a normal or high sodium diet (p less than 0.01). The hypertrophied hearts of rats on normal and high sodium diets showed a larger increase in the number of cardiac beta-adrenergic receptors than those observed in hearts from low sodium diet, clipped rats. These results show that sodium modulates the development of cardiac hypertrophy in two-kidney, one clip hypertensive rats. Similarly, the cardiac beta-adrenergic receptors appear to be influenced by dietary sodium intake. A possible role of the sympathetic nervous system is suggested.

Effect of enalaprilic acid on cardiac contractile response to beta-adrenergic stimulation.

Studies in two-kidney--one clip hypertensive rats have demonstrated that long-term treatment with enalapril induced regression of cardiac hypertrophy, but the cardiac contractile response to beta-adrenergic stimulation remained depressed. In the present study, we evaluate the contractile response to beta-adrenergic stimulation of isolated papillary muscle in normal rats with isoproterenol (10(-11) M to 10(-4) M) in the presence of enalaprilic acid (10(-6) M or 10(-4) M) or enalaprilic acid (10(-4) M) and angiotensin II (10(-6) M). Myocardial contractility was characterized by maximal developed tension and maximal rate of rise of tension (+T), and the relaxant effect of isoproterenol by the ratio of (+T), and the maximal velocity of relaxation (-T)(+T/-T ratio). The rest tension (g/mm2) and the cross-sectional area (mm2) were similar in all the muscles studied. Enalaprilic acid (either 10(-6) M or 10(-4) M) in the bath did not induce any change in contractile and relaxation parameters. The increment in +T and -T (expressed as percentage) in response to cumulative doses of isoproterenol (10(-11) M to 10(-4) M) was significantly depressed in the presence of enalaprilic acid (10(-4) M) when compared with control hearts in which only vehicle was added before isoproterenol (p less than 0.05). The addition of angiotensin II after enalaprilic acid (10(-4) M) did not normalize the response in +T and -T. Enalaprilic acid diminishes the contractile response of the papillary muscle to beta-adrenergic stimulation. The inhibition of the local angiotensin II does not seem to be involved in this result.

The renin-angiotensin system in different stages of spontaneous hypertension in the rat (S H R).

The present study analyzed the concentration of renin-like activity and angiotensinogen concentration (AoC) in different brain areas related to cardiovascular control in SHR and Wistar Kyoto (WKY) animals. Male rats of both strains were studied at 8, 16 and 30 weeks of age. The following brain areas were isolated: anterior, medial and posterior hypothalamus, septal area, periaqueductal gray (PG) and the remaining brain stem; nucleus tractus solitarius (NTS) and the remaining medulla oblongata. Plasma renin activity (PRA) and plasma and cerebrospinal fluid (CSF) AoC were determined. Renin-like concentration was higher in SHR than in WKY in the anterior hypothalamus, PG and NTS at different stages of hypertension development. AoC was also higher in some areas of the SHR brain during different periods. PRA, plasma and CSF angiotensinogen concentration showed significant differences between both strain of rats during the development of high blood pressure. Present data support the possibility that the central and peripheral renin-angiotensin system may participate in the maintenance of high blood pressure in the SHR animals.

Amiloride prevents the metabolic acidosis of a KCl load in nephrectomized rats.

1. Counter movements of K+ and H+ across cell membranes were studied in nephrectomized KCl-loaded rats. In one group of animals, the movements of K+ and H+ were determined during and after a KCl load, and in another group, amiloride was used in order to evaluate Na+ participation in K+/H+ exchange. 2. After a KCl load at constant PCO2, 79% of infused K+ left the inulin space, half of which was in exchange for H+. As a result, blood pH fell from 7.40 +/- 0.01 to 7.30 +/- 0.01 (mean +/- SEM; P less than 0.001). 3. During KCl infusion, the K+/H+ exchange ratio varied between 1.3 and 6.8, showing that the coupling ratio is not fixed. 4. Amiloride did not change blood pH and plasma [K+], but prevented the metabolic acidosis produced by the KCl load without affecting K+ entry into the non-inulin space. Therefore, K+ and H+ movements became completely dissociated. 5. The results indicate that KCl activates an amiloride-sensitive H+ extrusion from the cells. This finding is compatible with the view that Na+/H+ exchange participates in the metabolic acidosis produced by a KCl load.

The central and peripheral renin-angiotensin and noradrenergic systems in the spontaneous hypertensive rats (SHR).

The aim of this study was to evaluate the components of the renin-angiotensin system in the periphery and in the central nervous system (CNS) of the spontaneous hypertensive rats (SHR). On the other hand, the norepinephrine (NE) content of the different areas and of the mesenteric artery were also measured. Sixteen SHR and 9 Wistar Kyoto (WKY) control animals were used at about 6 months of age. Blood and cerebrospinal fluid (CSF) samples were collected. The brain was dissected into several areas and the mesenteric artery was excised. Plasma renin activity (PRA), plasma angiotensinogen concentration (P1AoC), brain renin (RC) and angiotensinogen concentrations (AoC) were evaluated by radioimmunoassay. NE was determined in all the tissues by a fluorimetric technique. PRA, P1AoC and NE concentration in the mesenteric artery were similar in both groups. An increase in the NE content of the cerebellum was detected in the SHR without changes in the other areas of the CNS. AoC was decreased in the CSF and in the brain stem of the SHR animals. RC was evaluated in the hypothalamus, brain stem, cerebral cortex and cerebellum of the same strain of rats. These results seem to indicate the some alteration of the peptidergic system in the CNS is present in the hypertensive animals.

Effect of ketanserin and prazosin on blood pressure and cardiovascular reactivity to vasopressor agents during the development of two kidney-two clip renal hypertension in the conscious rat.

The present experiment was performed in order to evaluate some of the actions of ketanserin, a blocking agent active at the serotonin 2 (S2) receptors. Male rats were divided into: 1. Two kidney-two clip (2K-2C) renal hypertensive: a silver clip (0.25 mm width) was placed in both renal arteries. 2. Sham-operated: a similar operation without placing the clip was performed. Blood pressure (BP), heart rate and pressor responses to tyramine, angiotensin II and norepinephrine (NE), and the hypotensive effect of prazosin (Pz) and ketanserin (Kt) were recorded in the conscious animals 8 weeks later. Results showed that Pz produced a similar decrease in BP in hypertensive and sham animals while Kt lowered BP much more in hypertensive than in normotensive rats. Prazosin abolished the pressor response to tyramine while ketanserin only diminished tyramine effect. Both hypotensive agents shifted the dose-response curve to NE to the right. Present data have shown that ketanserin and prazosin are effective hypotensive agents in 2K - 2C renovascular hypertension in the rat. They also suggest that both hypotensive compounds have an alpha 1-blocking effect, somehow they seem to have some differences in their pattern of pharmacological action.

Liver and heart mitochondria in rats submitted to chronic hypobaric hypoxia.

Mitochondrial mass was determined in the heart and liver of rats submitted to 4,400 m (simulated altitude) for 9 mo and their controls at sea level. This was done 1) by evaluation of isolated mitochondrial protein per gram of tissue, 2) by evaluation of the ratio between cytochrome oxidase activity in tissue homogenate and in isolated mitochondria, and 3) by evaluation of mitochondrial numerical and volume density in fixed tissues analyzed by electron microscopy. An increase in mitochondrial mass and a more homogeneous distribution of mitochondria were found in liver. In cardiac tissue an increase in numerical density of mitochondria accompanied by a slight decrease in their mean volume was observed. Maximal physiological rate of mitochondrial respiration (state 3, active respiration), resting respiration, ADP/O, and acceptor control ratio were determined in the isolated mitochondria. No differences were found in the intrinsic properties of mitochondria. The results suggest that chronic mild hypoxia promotes tissue adaptation by increasing the mitochondrial mass or number in liver and heart, respectively, and improves intracellular O2 diffusion by adopting a more homogeneous intracellular distribution of mitochondria in the liver.