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Biomedical subjects

N Stern

Publications and source records attributed to N Stern.

At least 91 records · Page 5Linked to original sources
PubMed1989

Effects of central and peripheral dopamine antagonism on aldosterone secretion: evidence for adrenal mechanism.

Both domperidone (DOMP) and metoclopramide (MCP) are D2 receptor antagonists, MCP being a central and peripheral dopamine antagonist, whereas DOMP is exclusively a peripheral antagonist. MCP, but not DOMP, has been shown to stimulate aldosterone production. To elucidate whether aldosterone stimulation by dopamine antagonism is centrally mediated, we injected DOMP (28 micrograms/kg body wt) via a cannula into the third ventricle in Sprague-Dawley rats. Plasma aldosterone and renin concentration were measured before and 15 min after the injection. Centrally administered DOMP resulted in an increment in plasma aldosterone (23.8 +/- 7.4 ng/dl) that was not significantly greater than that induced by vehicle alone (15.8 +/- 4.5 ng/dl). This increase was inhibited by pretreatment with dexamethasone (100 micrograms three times daily) and attenuated by captopril (1 mg/kg ip) but not by L-beta-3,4-dihydroxyphenylalanine (30 mg/kg), thus reflecting a stress effect. Similarly, central administration of MCP (21 micrograms/kg) resulted in a significant rise in plasma aldosterone. This increase, however, was eliminated by pretreatment with dexamethasone and attenuated by captopril. Peripherally administered DOMP (280 micrograms/kg) had no effect on plasma aldosterone. The effect of DOMP and MCP on aldosterone secretion by freshly obtained adrenal capsules was also tested. Angiotensin II and MCP, but not DOMP, induced a dose-dependent increase in aldosterone secretion, with a maximal increment (15.7 +/- 5.8 ng.mg capsular protein-1.10 min-1; 50% increase) with MCP at 10(-7) M (P less than 0.01 compared with controls). Dopamine completely inhibited this MCP-induced rise in aldosterone release.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1989

Selective inhibition of angiotensin II-mediated vasoconstriction by lipoxygenase blockade.

We have previously demonstrated that the lipoxygenase (LO) pathway has a specific role in the effect of angiotensin II (ANG II) on aldosterone secretion. To elucidate whether the LO pathway also participates in the vascular effects of ANG II, the nonselective LO inhibitor phenidone (PHE; 30 mg/kg) was administered to rats 1 h before graded dose ANG II infusion. PHE reduced the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) in deendothelialized aortas by an average of 36% as determined by radiometric detection with high-performance liquid chromatography and radioimmunoassay methods. In parallel, the peak systolic pressor response to ANG II was lowered from 36.2 +/- 3.7 to 16.8 +/- 2.0 mmHg. The peak pressor responses to ANG II were also reduced by two other LO inhibitors, baicalein (30 mg/kg) and esculetin (60 mg/kg) (13.9 +/- 2.4 and 22.1 +/- 4.7 mmHg, respectively; P less than 0.01 compared with control rats for both), but not by the cyclooxygenase inhibitor indomethacin. The LO inhibitors baicalein (7.5 X 10(-5) M) and PHE (10(-4) M) markedly attenuated the in vitro contractile response to ANG II of femoral artery rings. In contrast, neither the in vivo nor in vitro constrictor responses to norepinephrine were affected by baicalein. Thus lipoxygenase blockade induces a direct and selective inhibition of ANG II-induced vasoconstriction. The LO pathway may have an important role in mediating the pressor effect of ANG II.

Angiotensin II↗
PubMed1989

Modulation of aortic smooth muscle cell membrane potential by extracellular calcium.

Removal of extracellular calcium may result in depolarization of the resting cell membrane potential. This has been attributed to the stabilizing action of calcium on the ionic permeability of the cell membrane. It is unknown whether this phenomenon is exclusively mediated by extracellular calcium or through associated changes in intracellular calcium. To examine this, we exposed rat aortic smooth muscle cells in culture to different calcium concentrations and studied their effects on the resting membrane potential and intracellular calcium activity. The resting membrane potential was dependent on the extracellular potassium concentration. Exposure to reduced extracellular calcium concentrations (0.25 and 0.5 mM) caused a steep and reversible depolarization of the membrane potential, but intracellular calcium, measured with fura 2-AM, was not reduced below that measured in control conditions (1.8 mM). Atomic absorption spectrophotometric measurements did not indicate a measurable gain in cell sodium after reduction of extracellular calcium levels. We conclude that extracellular calcium controls the resting cell membrane potential of vascular smooth muscle through a mechanism that is independent of cytosolic Ca2+ activity.

Action Potentials↗
PubMed1989

Selective inhibition of angiotensin-II-mediated aldosterone secretion by 5-hydroxyeicosatetraenoic acid.

We have previously demonstrated that the 12-lipoxygenase (12-LO) pathway plays a key role in angiotensin-II (AII)-dependent aldosterone production. In the present study we examined the role of the 5LO pathway on AII-induced aldosterone secretion in rat glomerulosa cells in vitro. The 5LO product 5-hydroxyeicosatetraenoic acid (5HETE) and its unstable precursor 5-hydroxyperoxyeicosatetraenoic acid did not significantly alter basal aldosterone secretion in concentrations from 10(-9)-10(-7) M. In contrast, 5HETE reduced peak AII-induced aldosterone production from 59.1 +/- 9.0 to 37.96 +/- 7.2 ng/10(6) cells (P less than 0.01). This was accompanied by inhibition of the AII-stimulated rise in 12HETE production (10(-9)M AII, 160 +/- 4% of control; 10(-9) M AII plus 10(-7) M 5HETE, 90 +/- 1% of control production). However, 5HETE had no effect on the aldosterone response to potassium or ACTH, secretagogues that cause no activation of the 12LO pathway. These results suggest that the 5LO product 5HETE can selectively modulate AII-dependent aldosterone secretion. Further, the selective inhibitory effect of 5HETE on the AII effect in rat glomerulosa cells may be exerted by blockade of arachidonate metabolism via the 12LO pathway. These results suggest that the 5LO pathway may negatively modulate AII action in the adrenal zona glomerulosa.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1989

Evidence for cholinergic modulation of aldosterone secretion in man.

Acetylcholine stimulates aldosterone secretion in bovine glomerulosa cells in vitro via specific cholinergic receptors. In this study we examined the effect of peripheral muscarinic blockade with atropine on metoclopramide-, angiotensin-II-, and ACTH-stimulated aldosterone secretion in man. Atropine (0.6 mg, iv) administered 10 min before MCP delayed the onset of the plasma aldosterone response and attenuated the mean peak response from 502 +/- 103 (+/- SE) to 322 +/- 72 pmol/L (P less than 0.05) without affecting zero time mean plasma aldosterone levels (144 +/- 28 vs. 136 +/- 36 pmol/L for control and atropine, respectively). This inhibitory effect was not mediated by changes in PRA or plasma potassium or ACTH (as reflected by cortisol) concentrations. Atropine also attenuated the plasma aldosterone response to a low dose angiotensin II infusion (2 ng/kg.min; control, 449 +/- 99 pmol/L; atropine, 297 +/- 78 pmol/L; P less than 0.05). In contrast, atropine had no effect on the plasma aldosterone response to a bolus dose (250 micrograms) of ACTH. Neither atropine (0.6 mg, iv) nor the cholinergic muscarinic agonist bethanechol (5 mg, sc) alone elicited a change in plasma aldosterone. Collectively, these data provide evidence for cholinergic modulation of aldosterone secretion in man. We conclude that cholinergic mechanisms may facilitate the aldosterone responses to angiotensin-II and metoclopramide, but not to ACTH.

Adrenocorticotropic Hormone↗
PubMed1988

Diacylglycerol provides arachidonic acid for lipoxygenase products that mediate angiotensin II-induced aldosterone synthesis.

The lipoxygenase products of arachidonic acid metabolism have been shown to be important mediators of stimulus secretion coupling in various endocrine tissues. We have recently shown that the 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid plays a key role as a new specific mediator of angiotensin II-induced aldosterone secretion in the adrenal. In view of the several pathways by which cellular arachidonate can be generated and the important role of diacylglycerol in angiotensin II-responses, we studied the role of diacylglycerol as the source of arachidonic acid for 12-hydroxyeicosatetraenoic formation. Treatment of normal human adrenal glomerulosa cells with the selective diacylglycerol-lipase inhibitor, RHC 80267, resulted in a dose-dependent inhibition of angiotensin II-induced aldosterone as well as 12-hydroxyeicosatetraenoic formation. These results suggest that AA derived from diacylglycerol is the precursor of 12-hydroxyeicosatetraenoic involved in angiotensin II-induced aldosterone secretion. These results reveal a new second messenger role for diacylglycerol in addition to activation of protein kinase C.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1988

A graphic comparison of mandibular border movements generated by various articulators. Part I: Methodology.

A method was described by which mandibular border movement of a subject can be compared with the movements generated by various articulators. The fully adjustable articulator, Denar SE, and the semiadjustable instrument, Denar Mark II, were used in this study. The movements were recorded by an electronic pantograph, the Pantronic. The mean values of 12 sets of print-out plots from this device were calculated by using Microsoft Excel software. These mean values were then used by CricatGraph software to generate combined graphs. Both software programs were used with an Apple Macintosh Plus personal computer. The clinical significance of the findings will be discussed in Part II of this study.

Dental Articulators↗
PubMed1988

Hypertension in pseudohypoparathyroidism type I.

PURPOSE: There is increasing evidence of a central role for the calcium ion in blood pressure regulation. By studying blood pressure control in disorders of calcium homeostasis, a better understanding of the role of the calcium ion and certain calcitrophic hormones in modulating arterial pressure in humans may be gained. Our goal was to examine levels of blood pressure in a group of patients with either type Ia or type Ib pseudohypoparathyroidism (PsHP), a disorder characterized by target organ resistance to parathyroid hormone. PATIENTS AND METHODS: Forty-six patients with type I PsHP were recruited for the study (28 with type Ia and 18 with type Ib). Blood pressure was measured and the degree of obesity was assessed in all patients. Detailed measurements of hormones involved in blood pressure regulation were made in nine hypertensive patients with PsHP. RESULTS: Elevated arterial pressure was present in 18 of the 46 patients with PsHP, which comprised 53 percent (18 of 34) of the adult subjects. Prevalence of hypertension was similar in PsHP type Ia (nine of 21) and type Ib (nine of 13; p not significant) and was not related to coexisting hypothyroidism or degree of hypocalcemia. However, hypertension in PsHP was strongly linked to severe obesity. Mean body weights of normotensive and hypertensive patients with PsHP were 64 +/- 2.8 (SEM) kg (125 +/- 6 percent ideal body weight) and 96 +/- 4.7 kg (172 +/- 10 percent ideal body weight), respectively. Compared with obese hypertensive non-PsHP persons, hypertensive subjects with PsHP had reduced basal and posture-stimulated renin activity (basal, 1.68 +/- 0.36 [n = 9] versus 3.97 +/- 0.61 ng/ml/hour [n = 9] [p less than 0.05]; upright posture, 2.11 +/- 0.42 versus 7.13 ng/ml/hour [p less than 0.05]; and lower basal and posture-stimulated plasma norepinephrine levels (basal, 236 +/- 52 versus 426 +/- 37 pg/ml [p less than 0.05]; upright posture, 424 +/- 62 versus 707 +/- 64 pg/ml [p less than 0.05]). CONCLUSION: Our data suggest that hypertension is common in PsHP types Ia and Ib. This newly identified form of endocrine hypertension is strongly linked to excessive body weight but is associated with alterations in the renin-aldosterone and sympathetic nervous systems that are distinct from those encountered in obesity-related hypertension in the general population. The pathophysiologic basis for hypertension in these two distinctly different forms of PsHP remains to be determined.

Adolescent↗
PubMed1988

Role of the lipoxygenase pathway in angiotensin II-mediated aldosterone biosynthesis in human adrenal glomerulosa cells.

We studied the role of the lipoxygenase pathway of arachidonic acid metabolism in angiotensin II (AII)-stimulated aldosterone secretion in normal and adenomatous human adrenal glomerulosa tissue. In freshly isolated normal adrenal glomerulosa cells, the AII-mediated stimulation of aldosterone secretion was not altered by cyclooxygenase blockade with ibuprofen. In contrast, BW755c (10(-5) mol/L), a nonselective lipoxygenase inhibitor, and baicalein (10(-6) mol/L), a more selective 12-lipoxygenase blocker, inhibited AII-mediated aldosterone secretion, but did not alter basal aldosterone secretion. The glomerulosa cells produced the lipoxygenase products 12- and 15-hydroxyeicosatetraenoic acid (HETE) in the basal state, as measured by high pressure liquid chromatography and RIA. However, AII selectively stimulated only 12-HETE production [basal, 1329 +/- 207 (+/- SE) pg (3.99 +/- 0.62 pmol)/10(5) cells.h; AII, 2365 +/- 333 (7.09 +/- 1.0); n = 9; P less than 0.02], suggesting that 12-lipoxygenase activation may be involved in AII-mediated aldosterone secretion by normal cells. In addition, the lipoxygenase inhibitors that blocked AII-mediated aldosterone secretion also prevented AII-mediated 12-HETE formation. In contrast, neither ACTH nor K+ stimulated 12-HETE formation, suggesting that 12-lipoxygenase activation is primarily involved in AII action in normal glomerulosa cells. BW755c caused a marked dose-dependent inhibition of basal aldosterone secretion in freshly isolated cells from aldosterone-producing adenomas [APA; basal, 66 +/- 3 ng (182 +/- 8 pmol)/10(6) cells.h; 10(-5) mol/L BW755c, 49 +/- 2 (136 +/- 6); 10(-4) mol/L BW755c, 30 +/- 2 (83 +/- 6)]. In contrast, the cyclooxygenase inhibitor indomethacin and the selective 5-lipoxygenase inhibitor U60257 did not alter basal aldosterone secretion by these cells. The APA cells produced 12- and 15-HETE, and BW755c at the same dose that inhibited aldosterone secretion also inhibited the production of both 12- and 15-HETE. In the cultured APA cells, AII-stimulated aldosterone secretion was inhibited by BW755c [basal, 26 +/- 8 pg/mL (72.0 +/- 22.1 pmol/L); AII, 336 +/- 79 (930 +/- 218); AII plus BW755c, 92 +/- 38 (255 +/- 105) n = 13; P less than 0.01]. The lipoxygenase products 12- and 15-HETE restored the stimulatory effect of AII during inhibition by BW755c, indicating a role for these lipoxygenase pathways in AII-mediated aldosterone secretion in APA cells. These results suggest that the stimulatory effects of AII on aldosterone secretion are mediated by stimulation of the lipoxygenase pathway in human zona glomerulosa cells.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1988

Nocturnal hypotension in older men with sleep-related breathing disorders.

Sleeping and awake blood pressures were related to sleep oxygenation and awake control of breathing in hypertensive and normotensive older men. During sleep, episodes of both hypertension and hypotension were observed, but hypotension was prominent. Five of 26 subjects exhibited episodes with a minimum mean arterial pressure of 60 mm Hg or less. These hypotensive episodes were associated with hemoglobin desaturation below 80 percent, secondary to sleep-related breathing disorders, and elevated supine nasopharyngeal airway resistance. Hypotensive subjects were habitual snorers. Waking hypertension was not associated with sleep-related breathing disorders in this older sample. In some older persons with sleep-related breathing disorders, sympathetic reflexes may be impaired, permitting hypotension and risk of circulatory failure. Epidemiologic evidence supports the hypothesis that this mechanism can explain the elevated incidence of cerebral infarction during sleep.

Aged↗
PubMed1987

Effect of high calcium intake on pressor responsivity in hypertensive rats.

Some proposed mechanisms for the hypotensive effect of high calcium intake involve reduction in vascular responsivity. To assess the effect of dietary calcium on vascular responsivity, spontaneously hypertensive rats (SHR) were placed on normal (N-Ca; 0.4%) or high (H-Ca; 2.8%) casein-based synthetic diet for 4 wk. Intraarterial pressure, pressor response to graded intravenous infusion of norepinephrine (NE) and angiotensin II (ANG II), and in vitro vascular reactivity of tail artery segments to NE and transmural nerve stimulation (TNS) were studied. Urinary electrolyte excretion, plasma renin activity (PRA), aldosterone, NE, and epinephrine (EPI) were also determined. H-Ca SHR had a lower intraarterial systolic and diastolic pressure. However, H-Ca SHR had greater in vivo pressor response to both ANG II and NE. Maximal contractile force developed by tail artery segments in vitro in response to NE and TNS was slightly, but not significantly, higher in H-Ca SHR. In vitro dose-response curves to NE and TNS were not significantly different. Although H-Ca SHR had increased urinary excretion of sodium throughout the study period, PRA and aldosterone levels were similar in both groups. Plasma NE and EPI levels in the two groups were also not different. Despite lowered intra-arterial blood pressure, H-Ca SHR exhibited enhanced pressor response to ANG II and NE in vivo and a similar in vitro vascular reactivity to NE and TNS when compared with N-Ca SHR. Our results do not support a role for alterations in vascular reactivity to NE or ANG II in the hypotensive effect of high calcium intake in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1987

Effect of cyclosporin on blood pressure and renin-aldosterone axis in rats.

Although hypertension is a frequent complication of cyclosporin A (CSA) therapy in clinical practice, little experimental information is available on the nature and the mechanism of this form of hypertension. We studied the effect of currently recommended therapeutic dosages of CSA, i.e., 5 (CSA5) and 20 (CSA20) mg.kg-1.day-1, on blood pressure and the renin-aldosterone system (RAS) in spontaneously hypertensive rats (SHR). Influence of in vivo CSA treatment on in vitro angiotensin II (ANG II)-stimulated aldosterone secretion by isolated adrenal glomerulosa cells (AGC) was also measured. CSA treatment in SHR resulted in a consistent increase in systolic blood pressure. This increase in blood pressure occurred in the absence of significant changes in creatinine clearance in CSA5 rats, whereas in CSA20 rats a significant reduction in creatinine clearance was observed. Sodium balance and serum calcium and magnesium concentrations were not different between the control group and either of the two CSA-treated groups of rats. Plasma renin concentration (PRC) and inactive renin (IR) were markedly elevated, but plasma renin substrate remained unchanged with CSA administration. Despite the presence of hyperreninemia, plasma aldosterone was not elevated, suggesting that CSA may induce relative adrenal resistance to ANG II. This possibility was tested using AGC isolated from CSA-treated rats. ANG II-stimulated aldosterone secretion in AGC was diminished by low dose and aborted by high dose CSA-treatment. Thus CSA administration in SHR induces a predictable increase in blood pressure in association with "hyperreninemic hypoaldosteronism."

Adrenal Cortex↗
PubMed1987

Kinetic analysis of erythrocyte Na+-K+ pump and cotransport in essential hypertension.

Alterations in red blood cell (RBC) Na+-K+ pump and Na+-K+ cotransport have been described in essential hypertension. We evaluated Na+-K+ pump and cotransport in 30 hypertensive and 26 normotensive subjects subdivided by race and family history of hypertension using an improved method to examine the kinetics of Na and K effluxes. RBCs were Na-loaded by the nystatin method to five different levels of internal Na with pump determined as ouabain-sensitive Na efflux and cotransport as furosemide-sensitive Na and K efflux. Two kinetic parameters were determined for both transport systems: the apparent affinity for Na (K0.5) and the velocity of efflux at saturating internal Na concentration (Vmax). Mean intracellular Na content in fresh RBCs (mmol/L cells) was higher in black hypertensive (12.6 +/- 1.8 mmol/L cells) and normotensive subjects (10.9 +/- 1.2 mmol/L cells) than in white hypertensive (8.7 +/- 1.0 mmol/L cells) or normotensive subjects (8.5 +/- 0.8 mmol/L cells). The Vmax and K0.5 for pump were not significantly different between study groups. The Vmax for cotransport was elevated in white hypertensive compared with normotensive subjects, but the K0.5 values were similar. Black normotensive and hypertensive subjects displayed a lower Vmax and increased K0.5 for cotransport compared with the white groups. A family history of hypertension had no influence on cotransport kinetics in blacks but did predict white normotensive and hypertensive subjects with low cotransport. The reduction in intracellular Na affinity for cotransport in black subjects may explain their higher intracellular Na in fresh RBCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗