Search PubMed⌕ Search

Biomedical subjects

R J Koletsky

Publications and source records attributed to R J Koletsky.

30 records · Page 2Linked to original sources
PubMed1994

Refeeding hypertension in obese spontaneously hypertensive rats.

Very-low-calorie diets lower blood pressure acutely in obese humans and rats. However, refeeding after dietary restriction produces mild hypertension in rats. Refeeding hypertension was characterized in genetically obese spontaneously hypertensive rats (obese SHR, Koletsky rat), a model of genetic obesity and hypertension. Obese SHR were fed a restricted diet (Optifast) for 12 days, refed ad libitum for 28 days, dieted again for 12 days, and then refed 4 days and killed. Control obese SHR and lean SHR littermates were fed ad libitum continuously. Dietary restriction led to rapid weight loss followed by prompt regain to baseline weight after return to unrestricted food intake. Heart rate fell with institution of the low-calorie diet and returned to baseline on refeeding. Blood pressure became elevated during refeeding in dieted obese SHR relative to ad libitum fed obese SHR controls. The fall in blood pressure after ganglionic blockade with chlorisondamine was exaggerated in refed obese SHR, and cardiac beta-adrenergic receptors were downregulated. Both of these findings imply increased sympathetic tone. The left ventricular wall was thicker in the refed obese SHR than in the ad libitum fed obese SHR. Shorter cycles of weight loss and regain in lean SHR led to transient increases in blood pressure and heart rate. Cycles of dietary restriction and refeeding in obese SHR elicit sustained blood pressure elevation via sympathetic activation and exacerbate cardiac hypertrophy. Drastic fluctuations in nutrient intake may not be advantageous in hypertension.

Animals↗
PubMed1993

Renal angiotensin receptor mapping in obese spontaneously hypertensive rats.

Obese spontaneously hypertensive rats (SHR) develop nephropathy with severe proteinuria, but lean littermates do not develop renal disease. Intrarenal angiotensin has been suggested to contribute to nephropathy in other experimental models. We examined the regulation of angiotensin receptors as a reflection of target tissue response to possible changes in the renin-angiotensin system. We visualized angiotensin receptors in kidneys of 6-8-month-old obese SHR and their lean littermates. Both obese and lean rats were hypertensive as determined by tail-cuff or by direct measurement. Histologic studies showed early glomerular sclerosis in obese but not lean rats. Autoradiographic visualization of angiotensin receptor binding sites in both obese and lean SHR showed glomeruli and medullary rays having the highest levels of binding with additional diffuse labeling in cortex and outer medulla. In obese rats, binding was reduced relative to lean littermates, particularly in the medulla, while intense binding in glomeruli was preserved. Loss of receptors did not reflect tissue damage, since the medulla showed no pathological changes. Biochemical assays of the binding of subtype-selective antagonists to 125I-angiotensin sites in intact sections showed that both losartan-sensitive and PD 123319-sensitive sites were decreased in nephrotic obese rats. We conclude that specific binding sites for angiotensin are decreased in obese SHR with early glomerular sclerosis, suggesting that angiotensin receptors may be regulated by pathogenic processes in this model of renal disease.

Angiotensin II↗
PubMed1984

Captopril enhances vascular and adrenal responsiveness to angiotensin II in essential hypertension.

The converting-enzyme inhibitor captopril (25-50 mg orally every 6 h for 66 h) was used to dissociate the circulating levels of angiotensin II (ANG II) from changes in sodium balance in 11 patients with normal renin essential hypertension on 10 mmol of sodium/day intake. Pressor, renal vascular and adrenal responses to graded infusions of ANG II (0.3, 1 and 3 pmol kg-1 min-1) were measured before and after captopril administration. Systemic vascular responses were assessed by measuring diastolic blood pressure (DBP), renovascular responses by measuring p-aminohippurate (PAH) clearance and adrenal responses by measuring plasma aldosterone. After receiving captopril for 66 h the hypertensive subjects showed a significantly (P less than 0.004) enhanced blood pressure response to the infused ANG II but not to noradrenaline when compared with the response before captopril. ANG II (3 pmol kg-1 min-1) also produced a significantly (P less than 0.03) greater reduction in PAH clearance after (-194 +/- 40 ml/min) compared with before (-104 +/- 15 ml/min) captopril. These results suggest that the responsiveness to ANG II in these two target tissues is determined by the circulating ANG II level. In the adrenal gland the aldosterone responses to ANG II also were significantly greater after (P less than 0.01) than before captopril (increment at 3 pmol kg-1 min-1: 660 +/- 88 vs 381 +/- 94 pmol/l). These results are in distinct contrast with the responses previously reported for normotensive subjects and support the hypothesis that the regulation of aldosterone secretion is altered in subjects with essential hypertension.

Adrenal Glands↗
PubMed1983

Calmodulin-like activity and calcium-dependent phosphodiesterase in purified cells of the rat zona glomerulosa and zona fasciculata.

We have studied calmodulin (CaM)-like activity and calcium (Ca++)-regulated phosphodiesterase (PDE) activity in cells from the rat adrenal zona glomerulosa (ZG) and zona fasciculata (ZF). Boiled cell sonicates from the ZG and ZF activated CaM-deficient PDE in a dose-dependent fashion by 2.0- to 2.3-fold. The properties of this stimulatory factor were similar to those of authentic CaM in a number of respects: 1) both activated CaM-deficient PDE at micromolar calcium concentrations; 2) both eluted at similar ionic strengths on DEAE-cellulose ion exchange chromatography; 3) the activation of CaM-dependent PDE activity was blocked by the CaM inhibitor trifluoperazine in both cases; and 4) Ca++-dependent activation of PDE was totally inhibited by an excess of EGTA. Boiled sonicates of cells from the ZG and ZF contained 366 +/- 53 and 882 +/- 69 ng/10(6) cells of CaM-like activity (P less than 0.01), respectively, as determined by comparison with activation of CaM-deficient PDE by a known amount of authentic rat CaM. The CaM contents of the ZG and ZF, determined by RIA, were 1050 +/- 35 and 1760 +/- 112 ng/10(6) cells, respectively (P less than 0.01). Under identical conditions, there were 4 times more cAMP and cGMP PDE activities in the ZG than in the ZF. EGTA (1 mM) or trifluoperazine (10(-4) M) inhibited 20% of PDE activity in ZG, and the addition of excess Ca++ (1.1 mM) restored about 50% of the EGTA-inhibited PDE activity. Maximal PDE activity in each cell type eluted at 0.25 M NaCl using DEAE-cellulose ion exchange chromatography. This activity was partially inhibited by EGTA. Moreover, each cell type contained CaM-like activity that migrated at 0.25 M NaCl. The ZF contained a second peak of CaM that migrated at 0.35 M NaCl. Boiled sonicates of the ZF and ZG, on the other hand, each had a single peak of CaM-like activity, which eluted from DEAE-cellulose at 0.28-0.29 M NaCl, similar to that of pure CaM from rat testes. Thus, these experiments demonstrate the presence of a heat-stable activator of CaM-dependent PDE activity in the ZG and ZF that is similar by a number of criteria to purified CaM. The presence of CaM and a Ca++-dependent PDE in the adrenal suggests that the effects of Ca++ on adrenal function might be mediated, in part, by this or other CaM-regulated enzymes.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1982

Abnormal renin short feedback loop in essential hypertension is reversible with converting enzyme inhibition.

The suppression of renin release by angiotensin II (AII) (the so-called short feedback loop) is blunted in essential hypertension. To determine whether this abnormality is reversible, renin release was assessed in sodium-restricted essential hypertensives and normal controls: (a) during the administration of captopril for varying intervals and (b) following the infusion of graded doses of AII (0.3-3 ng/kg per min) before and after plasma levels of AII had been chronically reduced with captopril (25-50 mg every 6 h) for 70 h. In control subjects, the maximal increment above control in plasma renin activity (PRA) after a single dose of captopril (11.9+/-3 ng/ml per h) was significantly (P < 0.02) greater than in hypertensives (8.1+/-1.7 ng/ml per h) despite similar reductions in AII levels and significantly greater decrements in diastolic blood pressure in the hypertensives. When captopril was continued for 70 h, the PRA increments above base line in hypertensive subjects (11.4+/-2.9 ng/ml per h) rose to levels seen in the controls (11+/-2.6 ng/ml per h); there were no significant differences in the AII or diastolic blood pressure decrements between the two groups. Compared with normotensive subjects, AII failed to suppress renin release in hypertensive subjects despite significantly greater diastolic blood increments and comparable AII levels achieved at each AII dose. After captopril treatment, AII now produced significant declines in PRA in the hypertensives; moreover, comparing declines pre- and postcaptopril, greater PRA decrements were seen either at comparable rises in levels of AII or diastolic blood pressure. Finally, the suppression of PRA by AII postcaptopril in hypertensives was now indistinguishable from that seen in normal controls. Thus, the impaired regulation of renin by AII is reversible with prolonged captopril treatment, suggesting that this abnormality is not due to a fixed structural defect but to a reversible lesion.

Angiotensin II↗
PubMed1982

Cortisol suppression test in patients with elevated adrenocorticotropic hormone levels.

Increased adrenocorticotropic hormone (ACTH) levels after bilateral adrenalectomy could be secondary to a pituitary tumor, under replacement with cortisol, or an abnormality in the hypothalamic-pituitary-adrenal feedback loop. To distinguish between these possibilities, ACTH levels were measured before and after cortisol infusion (20 mg/h for 4 hours) in five groups: normal volunteers; patients with idiopathic adrenal insufficiency; and with bilateral adrenalectomy for Cushing's syndrome with no roentgenographic evidence of pituitary tumor, with pituitary tumors, and with equivocal roentgenographic studies (suspect pituitary tumors). Control ACTH levels in all groups of patients were higher than in normal volunteers but there was overlapping. Cortisol infusion suppressed ACTH in all subjects but the reductions in the last two groups were less than in the first three. The cortisol suppression test appears to be useful in determining whether increased ACTH level after adrenalectomy is due to a pituitary tumor.

Adrenalectomy↗
PubMed1981

Dietary chloride modifies renin release in normal humans.

The effect of high and low chloride diets on the responses of plasma renin activity (PRA), angiotensin II (ANG II), and aldosterone (Aldo) to upright posture was studied in the same normal subjects in balance on constant sodium intake. Diet 1 consisted of 10 meq Na/day (low Na) and either 50 or 150 meq Cl/day. Diet 2 consisted of 200 meq Na/day (high Na) and either 20 or 200 meq Cl/day. The mean recumbent PRA level on the high Na-high Cl diet tended to be lower than on the high Na-low Cl diet but was not significantly different. However, the absolute peak upright PRA levels, 8.8 +/- 1.0 vs. 4.4 +/- 0.8 ng . ml-1 . h-1, and the incremental difference (delta PRA) between recumbent and peak upright PRA levels, 5.5 +/- 0.8 vs. 2.2 +/- 0.5 ng . ml-1 . h-1, were significantly less on the high Na-high Cl diet compared with the high Na-low Cl diet. Similar significant changes were seen in ANG II and Aldo levels. However, there were no significant changes in PRA, ANG II, and Aldo responses to upright posture on the low Na diet when the dietary Cl was varied. It is concluded that dietary Cl is another factor modifying renin release. However, Cl is probably less important than Na because Cl-induced changes in PRA were not seen in the low salt state.

Adult↗
PubMed1980

Fulminant Mycoplasma pneumoniae infection. Report of a fatal case, and a review of the literature.

Fatal Mycoplasma pneumoniae infection in a 30-yr-old woman is described. After 9 days of symptoms, the patient developed severe respiratory distress, rapidly progressive pneumonia, cardiovascular collapse, and acute renal failure. Death occurred 24 h after hospital admission. Postmortem examination demonstrated a diffuse membranous laryngotracheobronchitis, massive bilateral pneumonia, disseminated intravascular coagulation with widespread renal involvement, and hemorrhagic necrosis of the adrenal glands. Mycoplasma pneumoniae was isolated from the trachea, lungs, kidney, and brain, indicating hematogenous dissemination of the organism from its portal of entry in the respiratory tract.

Adult↗
PubMed1976

Simultaneous determination of plasma aldosterone, corticosterone, 11-deoxycorticosterone, 18-hydroxydeoxycorticosterone, cortisol, and 11-deoxycortisol. Methods and applications.

A method for the simultaneous determination of aldosterone, corticosterone (B), 11-deoxycorticosterone (DOC), 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), cortisol, and 11-deoxycortisol in a single 1-ml sample of plasma is described. The method is applicable to both man and experimental animal. After extraction and purification by thin-layer chromatography (TLC), aldosterone was determined by radioimmunoassay (RIA) employing antibodies to aldosterone: B, DOC, cortisol and 11-deoxycortisol were determined by RIA employing antibodies to corticosterone; 18-OH-DOC was obtained colorimetrically using the Porter-Silber reagent. Recoveries after extraction and chromatography were: aldosterone 71% +/- 9.4 SD; B 81% +/- 10.2; DOC 73% +/- 8.4; cortisol 65% +/- 7.2; 11-deoxycortisol 74% +/- 6.3 using labeled steroids; 18-OH-DOC 82% +/- 8.7 using inert steroid. The method has a high specificity and is reproducible and accurate.

18-Hydroxydesoxycorticosterone↗
PubMedDate not supplied

Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension.

To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandin levels by radioimmunoassy before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captopril's antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained unmeasurable and that of thromboxane A2 did not change, while the metabolite of PGE2 (PGE-M) increased by 53% (34 +/- 4pg/ml pre-captopril, 52 +/- 5 pg/ml after; p less than 0.001). As expected, blood pressure (BP) and angiotension II (AII levels fell, and kinin levels rose (all changes p less than 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (-20 +/- 3mm Hg pre-synthetase inhibition vs - 13 +/- 2 mm Hg post; p less than 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 +/- 4mm Hg pre, -18 +/- 5mm Hg post). Neither indomethacin nor aspirin changed the AII or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captopril's antihypertensive effect in the sodium-restricted state.

Adult↗