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S Oparil

Publications and source records attributed to S Oparil.

At least 253 records · Page 14Linked to original sources
PubMed1986

Transport and hydrolysis of glucagon in the proximal nephron.

Transport and hydrolysis of glucagon in the rabbit proximal nephron were studied. Iodinated glucagon (0.34 +/- 0.02 pg/nl, mean +/- SE) was microperfused (16.0 +/- 1.1 nl/min) in vitro through proximal straight nephron segments for 30 min. Radiolabeled material, primarily 125I-tyrosine, appeared in the bathing medium in a linear fashion as a function of time (0.406 pg glucagon X mm tubule length-1 X min-1). Hydrolysis of glucagon by proximal tubule homogenates was pH dependent, with a large peak of activity observed at pH 7.0-7.4 and a smaller one at pH 3.0. Analytical cell fractionation studies of proximal tubule cells revealed glucagon-hydrolyzing activity associated with the brush border and cytosol at pH 7.4. Less than 3% of activity was found associated with the contraluminal membrane. Substantial catabolism was observed at lysosomes on lowering the pH to 5.0. Incubation of glucagon directly in the presence of isolated renal cortical microvilli confirmed the presence of a high-capacity glucagon-degrading hydrolase. In addition to glucagon-hydrolyzing activity associated with the proximal nephron, noncortical activity was observed that was not accounted for by proximal tubule hydrolases. The data suggest several mechanisms for renal extraction of glucagon, including hydrolysis by enzymes at the brush border of the proximal tubule, prior to reabsorption of metabolites there. Conversely, enzymes associated with the contraluminal membrane of the proximal nephron probably contribute little to its hydrolysis. Nonproximal extracortical degradation of glucagon may account for its previously observed peritubular hydrolysis.

Aminopeptidases↗
PubMed1986

Impaired pulmonary conversion of angiotensin I to angiotensin II in rats exposed to chronic hypoxia.

The effects of exposing rats to hypoxia at normal atmospheric pressure for periods of 21-24 days on intrapulmonary conversion of angiotensin I (ANG I) to angiotensin II (ANG II) were examined using an isolated rat lung preparation perfused at constant flow. 125I-ANG I (160 fmol) was injected alone and with graded doses (0.1, 1.0, and 100 nmol) of unlabeled ANG I into the pulmonary artery, and the effluent was collected for measurement of ANG I, ANG II, and metabolites. At low doses of injected ANG I (125I-ANG I alone or with 0.1 or 1.0 nmol unlabeled ANG I), the percent conversion of ANG I to ANG II was 67.5 +/- 2.1 (SE), 65.1 +/- 2.0, and 62.5 +/- 1.6 in 21-day hypoxia-exposed animals and 83.8 +/- 2.7, 81.4 +/- 3.9, and 79.6 +/- 2.3 (P less than 0.01) in control rats maintained under normoxic conditions. At the highest dose (100 nmol) of injected ANG I, percent conversion was reduced in both hypoxic and control groups to 46.8 +/- 5.0 and 64.0 +/- 6.0, respectively (P less than 0.05). Mean transit times of labeled material through the pulmonary circulation were not significantly different in hypoxic vs. normoxic lungs at any ANG I load, suggesting that the decreased conversion seen in hypoxic lungs was not related to altered kinetics of substrate exposure. Thus chronic hypoxia is associated with significant inhibition of transpulmonary ANG I conversion that is independent of perfusate flow. We postulate that this phenomenon is due to alterations at the endothelial membrane level.

Angiotensin I↗
PubMed1986

Genetic and salt-related alterations in monoamine neurotransmitters in Dahl salt-sensitive and salt-resistant rats.

Monoamine and metabolite levels were determined in brain regions and in the kidney, heart and adrenals taken from Dahl salt-sensitive (DS) and salt-resistant (DR) rats on either normal (NS) or high (HS) (8.5% NaCl) salt diets. The HS diet significantly (p less than 0.01) elevated blood pressure only in DS rats. DS-HS rats had a significantly (p less than 0.001) greater increase in renal weight and a significantly (p less than 0.001) greater reductions in renal norepinephrine (NE) content and concentration than the DR-HS rats. Cardiac NE content and concentration were also lower (p less than 0.001) in DS rats when compared to DR rats. Adrenal catecholamines were also altered in DS rats. There were genetic differences in brain regional levels of NE, dopamine (DA) and serotonin (5-HT) between DR and DS rats. NE levels were significantly (p less than 0.03) higher in DS compared to DR rats in the pons and hypothalamus. DA levels were significantly (p less than 0.01) greater in the striatum of DS compared to DR rats as were 5-HT levels in the striatum and cortex. HS diets had no effect on brain monoamine or metabolite levels in either DS or DR rats except to elevate cortical 5-hydroxyindoleacetic acid levels. The cardiovascular implications of these genetic and salt-related changes in peripheral and central nervous system monoamines were discussed.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Mechanism of the pressor action of LY171555, a specific dopamine D2 receptor agonist, in the conscious rat.

Administration of LY171555, a specific dopamine D2 receptor agonist, (10-1000 micrograms/kg i.v.) produced dose-related increases in mean arterial pressure in conscious Sprague-Dawley rats. Pretreatment with metoclopramide (5 mg/kg i.v.) abolished the pressor action of LY171555, whereas pretreatment with domperidone (2.5 mg/kg i.v.) and propranolol (10 mg/kg i.p.) did not affect the pressor action of LY171555. The vasopressor antagonist of arginine vasopressin (AVP), d(CH2)5Tyr(Me)AVP (10 micrograms/kg i.v.) and phenoxybenzamine (1 mg/kg i.v.) partly blocked and hexamethonium (25 mg/kg i.v.) enhanced the pressor action of LY171555. After combined treatment with both d(CH2)5Tyr(Me)AVP and phenoxybenzamine, LY171555 induced a depressor response which was completely blocked by pretreatment with domperidone. LY171555 administration induced a rapid, short-acting depressor response followed by a pressor response in conscious adrenomedullectomized Sprague-Dawley rats which was smaller in magnitude than that seen in intact Sprague-Dawley rats. LY171555 administration increased plasma norepinephrine, epinephrine and AVP in conscious Sprague-Dawley rats. These results suggest that the pressor action of LY171555 in conscious rats is dependent on activation of sympathetic outflow and AVP release through the central D2 dopaminergic system and that the central pressor effects of LY171555 could mask a depressor effect of LY171555 at the peripheral D2 dopamine receptor.

Adrenal Medulla↗
PubMed1986

Effects of locally formed angiotensin II on renal hemodynamics.

The kidney produces angiotensin II (AngII) by conversion of both locally formed and systemically delivered angiotensin I (AngI). The latter may be physiologically significant because the kidney can convert 20-25% of systemically delivered AngI. To determine possible differences between the effects of circulating and locally converted AngII, we compared the renal responses to renal arterial infusions of AngI and AngII in equiconstrictor doses. Both reduced the renal blood flow and increased the filtration fraction; it is important that the AngI infusions consistently reduced glomerular filtration rates (GFR), which indicates effects proximal to or at the glomerulus. Micropuncture experiments revealed that AngI infusions reduced proximal tubular and peritubular capillary pressures and the single-nephron GFR; glomerular capillary pressure was not altered significantly. AngI infusions increased both pre- and postglomerular resistances and reduced the glomerular filtration coefficient. In other studies designed to estimate net intrarenal AngII generation, it was determined that the kidney degrades about 90% of arterially delivered AngII. Thus, most of the AngII in renal venous blood was formed intrarenally. Local production of AngII was enhanced, in association with increased renin release, after reductions in renal arterial pressure. Such increases in intrarenal AngII production may contribute to the AngII-dependent changes in renal vascular resistance that occur in conditions where the renin-angiotensin system is stimulated.

Angiotensin I↗
PubMed1986

Mechanism of the depressor action of LY171555, a selective dopamine D2 receptor agonist, in the anesthetized rat.

Administration of LY171555 (1 mg/kg i.v.) decreased mean arterial pressure (MAP) and heart rate in both pentobarbital- and urethane-anesthesized Sprague-Dawley rats. The depressor response to LY171555 in pentobarbital-anesthetized rats was sustained for at least 30 min, but in urethane-anesthetized rats lasted only approximately 3 min after LY171555 injection. In pentobarbital-anesthetized rats, pretreatment with domperidone (0.5 mg/kg) or metoclopramide (5 mg/kg) attenuated the depressor action of LY171555, whereas pretreatment with d(CH2)5Tyr(Me)arginine vasopressin (AVP) (10 micrograms/kg) only delayed the recovery phase of the depressor response to LY171555. In contrast, LY171555 administered to urethane-anesthetized rats after domperidone pretreatment induced a pressor response which was blocked completely by d(CH2)5Tyr(Me)AVP. Metoclopramide pretreatment in urethane-anesthetized rats prevented the decreases in MAP and heart rate induced by LY171555, whereas pretreatment with d(CH2)5Tyr(Me)AVP delayed the recovery phase of the depressor response. Pretreatment with d(CH2)5Tyr(Me)AVP per se decreased basal MAP in the urethane-anesthetized group, but not in pentobarbital-anesthetized rats. Basal plasma norepinephrine, epinephrine and AVP levels were higher in urethane-anesthetized rats than in the pentobarbital-anesthetized group. LY171555 administration decreased plasma norepinephrine without altering plasma epinephrine in both groups and induced a significant increase in plasma AVP which was greater in the urethane-anesthetized rats than in pentobarbital-anesthetized animals. These results suggest that LY171555 decreases MAP and heart rate in anesthetized rats by inhibiting norepinephrine release from nerve endings through the peripheral dopamine D2 receptor and that the time course of the depressor response may be altered by LY171555-induced AVP release, the magnitude of which appears to be dependent on the anesthetic agent.

Anesthesia↗
PubMed1985

Pathogenesis of ventricular hypertrophy.

Growth of the vertebrate heart during embryonic and fetal life is characterized by hyperplasia of myocardial cells. Shortly after birth, myocardial cells lose the capability of dividing, and further growth of the heart is due to myocardial cell hypertrophy and nonmuscle cell hyperplasia. This process results in a 30- to 40-fold increase in volume of individual myocardial cells during normal postnatal growth and maturation. The transition from hyperplastic to hypertrophic growth is related to formation of binucleated myocardial cells as a result of karyokinesis without cytokinesis. The molecular mechanism of this transition is uncertain. The response of the heart to increased metabolic demands or an increased work load depends on the age of the animal at the time when the stress is imposed. Increased myocardial work loads in fetal or early neonatal life lead to cardiac enlargement by causing an increased rate of hyperplasia of myocardial cells or continuation of hyperplasia beyond the normal period of hyperplastic growth. In contrast, imposition of increased loads on the hearts of older animals results in cardiac hypertrophy due to enlargement of myocardial cells and hyperplasia of nonmuscular components. In addition to cellular enlargement, structural remodeling of the myocardial cells and of the chambers of the heart occurs during the development of hypertrophy. Important stimuli of cardiac hypertrophy include increased systolic force or tension generated by the myocardial fibers (pressure overload), increased end-diastolic wall stress (volume overload) and neurohumoral factors such as increased circulating catecholamines or discharge of cardiac sympathetic nerves, or both, activation of the renin-angiotensin system and increased levels of thyroxine and growth hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Enhanced depressor effect of bromocriptine in the DOCA/NaCl hypertensive rat.

To elucidate the role of the dopaminergic system in the maintenance of hypertension in the deoxycorticosterone acetate (DOCA)/NaCl hypertensive rat, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), epinephrine (E), and prolactin (PRL) to intravenous (iv) administration of bromocriptine, a dopamine agonist, and hexamethonium bromide, a ganglion blocker, were examined in conscious, unrestrained 4-wk DOCA/NaCl hypertensive rats. Bromocriptine was administered to adrenomedullectomized (ADMX) rats to assess the role of the adrenal medulla in its depressor effect. Bromocriptine (50, 250, and 500 micrograms/kg) and hexamethonium (3 and 30 mg/kg) caused dose-dependent decreases in MAP that were greater in DOCA/NaCl rats than in uninephrectomized controls. Basal plasma NE, E, and PRL were significantly higher in DOCA/NaCl rats than in controls. Bromocriptine (500 micrograms/kg iv) decreased plasma PRL to undetectable levels and increased plasma E significantly without changing NE levels in DOCA/NaCl and uninephrectomized control rats. In ADMX rats bromocriptine (500 micrograms/kg iv) decreased MAP, PRL, and NE without affecting E levels. These results suggest that the depressor response to bromocriptine could be related to inhibition of sympathetic outflow without participation of the adrenal medulla. The hyperprolactinemia and enhanced depressor response to bromocriptine observed in DOCA/NaCl animals suggest that the dopaminergic system might be altered in this model of hypertension.

Adrenal Medulla↗
PubMed1985

Hyperresponsiveness of monoaminergic mechanisms in DOCA/NaCl hypertensive rats.

To examine the role of the sympathetic nervous system in the development of deoxycorticosterone acetate (DOCA)/NaCl hypertension and to test the hypothesis that the responsiveness of the sympathetic nervous system to stress is enhanced during the developmental phase of hypertension in this model before resting sympathetic activity becomes increased, DOCA/NaCl-treated rats and uninephrectomized control animals were studied after 3, 7, 14, and 28 days of treatment. Basal plasma norepinephrine and epinephrine in conscious, unrestrained resting DOCA/NaCl-treated rats were the same as in controls at 3, 7, and 14 days but were significantly elevated at 28 days of treatment. Ganglionic blockade resulted in a significantly greater decrease in mean arterial pressure in DOCA/NaCl rats than in controls at 14 and 28 days of treatment. At 14 days, DOCA/NaCl rats exhibited significantly greater increments in plasma norepinephrine and epinephrine following cold stress than did H2O controls. Basal plasma prolactin levels were elevated and release of dopamine from isolated superfused mediobasal hypothalami reduced in 28-day DOCA/NaCl hypertensive rats. These results indicate that sympathetic nervous system activity increases progressively during the development of DOCA/NaCl hypertension and that the sympathoadrenal system is hyperresponsive to environmental stress even early in the course of DOCA/NaCl treatment and suggest that hypothalamo-hypophyseal function is altered in this model of hypertension.

Animals↗
PubMed1985

Enhanced depressor effect of muscimol in the DOCA/NaCl hypertensive rat: evidence for altered GABAergic activity in brain.

To elucidate the role of the central gamma-aminobutyric acid (GABA) system in the maintenance of deoxycorticosterone (DOCA)NaCl hypertension, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), and epinephrine (EP) to intracerebroventricular (ICV) administration of muscimol, a GABA agonist, and the responses of MAP to bicuculline, a GABA antagonist, and to clonidine, an alpha 2-adrenoceptor agonist known to lower blood pressure by inhibiting sympathetic tone, were examined in conscious, unrestrained 4 week DOCA/NaCl hypertensive rats and age-matched uninephrectomized control rats. Muscimol (50-1000 ng/300 g, ICV) caused dose-dependent decreases in MAP which were greater in DOCA/NaCl rats than in controls. Basal plasma NE and EP were significantly higher in DOCA/NaCl rats than in controls. Muscimol (1000 ng/300 g, ICV) induced decreases in plasma EP which were greater in DOCA/NaCl rats than in controls without changing NE levels in either group. Bicuculline (3 micrograms/300 g, ICV) caused increases in MAP which were the same in both groups. The depressor response to clonidine (5 micrograms/300 g) was greater in DOCA/NaCl rats than in controls. These results suggest that the activity of the central GABAergic system is altered in the rat with established DOCA/NaCl hypertension and that the alteration in central GABAergic function may be related to the increased sympathoadrenal activity and the maintenance of hypertension in this model.

Animals↗
PubMed1984

The role of the posterior hypothalamic area in the pathogenesis of hypertension in the spontaneously hypertensive rat.

To examine the hypothesis that abnormalities of noradrenergic innervation of hypothalamic pressor areas influence the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR), the norepinephrine content of individual hypothalamic and brainstem nuclei was determined in SHR and control Wistar-Kyoto (WKY) rats at 5, 7, and 11 weeks of age. At 5 and 7 weeks of age, the norepinephrine content of the posterior hypothalamic area (PHA) of SHR was significantly greater than that of WKY controls. These changes occurred at a time when blood pressure was not significantly different between the two groups. The increase in the norepinephrine content of the PHA was accompanied by increases in the norepinephrine content of the A1 region and locus coeruleus in 5-week SHR. In seven week old animals, studies of norepinephrine turnover using alpha-methyl-p-tyrosine revealed no differences between SHR and WKY in turnover in the PHA. The increase in norepinephrine content of the PHA in the absence of changes in turnover is interpreted to indicate increased noradrenergic input to the PHA of SHR and supports the hypothesis that noradrenergic pathways to the PHA are important in the development of hypertension in this model.

Animals↗
PubMed1984

Elevated catecholamines during cardiac surgery: consequences of reperfusion of the postarrested heart.

This study determines whether reperfusion of the heart with elevated blood levels of epinephrine (E) and norepinephrine (NE) during cardiac surgery produces deleterious effects. The study was conducted in 60 patients undergoing coronary artery bypass surgery. Arterial catecholamine values increased significantly (p less than 0.05), from prebypass control levels of 152 +/- 29 and 327 +/- 30 pg/ml of E and NE, respectively, to 415 +/- 78 and 554 +/- 49 pg/ml, at initiation of perfusion of the heart after the aortic cross-clamp was removed. Serial measurement of arterial (A) and coronary sinus (CS) E, NE, potassium, lactate, PO2 and CK-MB revealed that during 10 minutes of reperfusion the heart extracted E (positive A-CS difference, p less than 0.05), but that the NE A-CS difference was 0. The CS effluent contained significantly (p less than 0.05) higher concentrations of potassium, lactate and CK-MB during reperfusion than before aortic occlusion. There was no significant correlation of arterial E and NE, CS E and NE or A-CS differences in E and NE with myocardial release of lactate, potassium or CK-MB. There was a weak association (r = 0.4, p less than 0.01) between coronary sinus CK-MB and aortic occlusion time. Maximal arterial E and NE values did not correlate with 10-hour postoperative (maximal) CK-MB values. These results indicate that reperfusion of the postarrested ischemic heart with high levels of endogenously released catecholamines does not worsen ischemia or contribute significantly to myocardial damage.

Cardiopulmonary Bypass↗
PubMed1984

Hormonal and haemodynamic responses to upper abdominal surgery during isoflurane and balanced anaesthesia.

The purpose of the study was to compare the protective role of different anaesthetic techniques against surgical stress. Sixty patients undergoing elective laparotomy were randomly divided into six groups of ten patients each: Group I was given 0.65 MAC nitrous oxide (66 per cent inspired) and 0.65 MAC isoflurane (0.75 per cent end-expired); Group II was given 0.65 MAC nitrous oxide and 1-1.2 MAC isoflurane (1.2-1.4 per cent end-expired); Group III was given the same anaesthetic management as patients in Group I but with the addition of fentanyl (2 micrograms X kg-1) before the skin incision and 1/8 of the initial dose every 15 minutes during surgery; Group IV was treated as patients in Group I with an additional infusion of lidocaine (30 micrograms X kg-1 X min-1); Groups V and VI were given 0.65 MAC of nitrous oxide and fentanyl, 7.5 and 15 micrograms X kg-1, respectively, before skin incision with 1/8 of the initial dose every 15 minutes during the operation; diazepam, 5 mg IV each hour of surgery, was given to prevent intraoperative awareness. Cortisol concentration was determined by radioimmunoassay method and catecholamines were measured by high performance liquid gas chromatography in blood samples taken at different stages perioperatively. All patients had satisfactory haemodynamic courses of anaesthesia. Statistically significant increases in both epinephrine and norepinephrine concentrations were observed during the immediate postoperative period in Group I patients only. Haemodynamic stability was maintained despite a two- to three-fold increase in cortisol which occurred during the operation and immediate postoperative period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

Subcellular sites of insulin hydrolysis in renal proximal tubules.

The subcellular sites of insulin degradation as measured by trichloroacetic acid precipitation were defined for rabbit renal proximal tubule cells. Fractionation in linear sucrose gradients of the postnuclear supernates prepared from isolated proximal tubule segments revealed three pools of insulin hydrolytic activity. Insulin hydrolytic activity assayed at pH 3.5 distributed in the gradients in a manner nearly identical to the activity of the lysosomal enzymes, N-acetyl-beta-glucosaminidase and alpha-mannosidase. At pH 7.4 the insulin-degrading activity distributed in a bimodal fashion with the major component following the cytosolic enzyme, phosphoglucomutase, and the minor component nearly identically overlapping with the activity of the inner mitochondrial enzyme, cytochrome oxidase. Upon microperfusion of 125I-insulin through proximal straight nephron segments, metabolites of the hormone were not observed in the collected perfusates for six of eight experiments. Average values for percent intact insulin in the original and collected perfusates showed no significant difference. These data suggest that three potential sites for insulin hydrolysis are present in proximal tubule cells, including lysosomes, the cytosol, and mitochondria. The results do not support the concept of degradation occurring at the brush border or contraluminal membranes.

Animals↗
PubMed1984

A randomized comparison of crystalloid and blood-containing cardioplegic solutions in 60 patients.

To determine whether adding blood to a cardioplegic solution affects myocardial preservation, a randomized prospective study was carried out in 60 patients undergoing coronary revascularization to compare the effects of crystalloid potassium cardioplegics (group C) and potassium cardioplegic solutions to which blood has been added (group B) on markers of myocardial metabolism (lactate, inorganic phosphate, base deficit release, glucose and lactate uptake, oxygen extraction), myocardial damage (creatine kinase [CK]-MB levels), and cardiac performance (cardiac index and left atrial pressure). The solution with added blood had a significantly (p less than .05) greater oxygen content, a lower pH, and higher concentrations of potassium, calcium, sodium, and glucose. In group B patients there was a suggestion (p less than .06) of greater uptake of oxygen during the beginning of the initial cardioplegic infusion. During reperfusion there was no evidence of differential release of the metabolites of anaerobiosis and myocardial oxygen extraction and glucose and lactate uptake were similarly depressed in both groups. Likewise, CK-MB release after bypass was the same in both groups. Prompt, adequate functional recovery of cardiac index and left atrial pressure was observed in both groups. It was concluded that although there may be more oxygen available from the blood-containing solution during early infusion, there is no evidence that under the conditions of this investigation adding blood to cardioplegic solution improves myocardial preservation.

Blood↗
PubMed1984

Effect of central administration of MK-422 (the diacid form of enalapril) on the development of hypertension in the spontaneously hypertensive rat.

Intracerebroventricular (i.c.v.) administration of captopril attenuates the development of hypertension in spontaneously hypertensive rats (SHR). To determine whether these effects are related to inhibition of angiotensin-converting enzyme we assessed the effects of chronic i.c.v. administration of MK-422 (a converting enzyme inhibitor chemically unrelated to captopril) on arterial pressure and vascular reactivity in young (seven-week-old) male SHR. MK-422 (0.2 or 1.0 microgram/h, osmotic mini pump) was infused into the lateral ventrical for 4 weeks. Control SHR received artificial CSF i.c.v., or 0.2 microgram/h MK-422 i.v. Vascular reactivity to phenylephrine, vasopressin and direct sympathetic nerve stimulation was assessed in renal and mesenteric vascular beds using miniaturized pulsed Doppler flow probes. MK-422 attenuated the development of hypertension. Arterial pressure at 4 weeks of treatment was: SHR-i.c.v. MK-422 (0.1 microgram/h): 137 +/- 3.4; (1.0 microgram/h): 138 +/- 2.9; SHR i.v. MK-422 176 +/- 4.5 and SHR control: 168 +/- 4.9 mmHg (P less than 0.01). SHR-i.c.v. MK-422 showed significantly attenuated increases in mesenteric vascular reactivity in response to vasoconstrictors, nerves and sympathetic nervous stimulation. Dose and frequency response curves were characterized by a shift to the right and a significant decrease in the slopes. In conclusion, both captopril and MK-422 prevent the development of hypertension in SHR, presumably by blocking angiotensin-converting enzyme, suggesting that the brain renin-angiotensin system contributes to the pathogenesis of hypertension in that model.

Animals↗