Papers by William McCumbee
Long term potentiation (LTP) in the hippocampus is considered a cellular basis of learning memory... more Long term potentiation (LTP) in the hippocampus is considered a cellular basis of learning memory. Sleep deprivation, especially rapid eye movement (REM) sleep deprivation, impairs learning and memory as well as LTP. Since most of the previous LTP studies were conducted in the in vitro condition, the full consequences of sleep deprivation (SD) in the living animal are yet to be found. Thus, I tested hippocampal LTP in living animals after 5 days of REM sleep deprivation to determine the effect of SD in vivo. SD also disrupts growth hormone (GH) release. Recent evidence indicates that GH regulates cognitive and hippocampal synaptic function. However, the relationship between GH and synaptic function during SD is not well established. Since the N-methyl-D-aspartate receptor (NMDAR) has an important role in inducing LTP, I hypothesized that loss of normal GH signals during SD would impair synaptic NMDAR expression and function, and treating SD animals with GH would restore normal NMDAR...
Abstract. This study assessed the progression of renal damage in obese Zucker rats in response to... more Abstract. This study assessed the progression of renal damage in obese Zucker rats in response to deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Renal damage was evaluated by light microscopy and urine analysis at weekly intervals during the developmental phase of DOCA-salt hypertension and once during the plateau phase 42 days after the onset of treatment. Decreased tubular function was evident by day 8, as indicated by a significant increase in urine N-acetyl-β-D-glucosaminidase activity and glucose excretion. The tubular index, a measure of tubular damage, was significantly elevated by day 15 and continued to increase throughout the experiment. Glomerular damage, which was evident by day 8, was followed by increased urine albumin excretion by day 15. Only a few sclerotic renal glomeruli were apparent before the plateau phase; however, by day 42, approximately 50 % of the glomeruli were sclerotic. Hyperplastic vascular changes were mild at day 8 and slowly increased...
FEBS Letters, 1989
The effects of an immunoaffinity-purified putative endogenous hypertensive factor (HF) on voltage... more The effects of an immunoaffinity-purified putative endogenous hypertensive factor (HF) on voltage-dependent calcium current in frog cardiac myocytes were assessed. In 9 out of 10 cells, HF reversibly increased the peak amplitude of the calcium current. HF increased peak calcium current density at -5 mV from a control level of 1.8 & 1.3 pA/pF (mean & SD) to 4.4 + 2.0 pA/pF. HF shifted the peak of the calcium current-voltage relationship in the hyperpolarizing direction. HF shifted the voltage dependence of the inactivation of the calcium current to more negative potentials with prepulses from 40 to 0 mV, but the inactivation was not affected with prepulses more positive than 0 mV. Modulation of the voltagedependent calcium current by HF may be the mechanism underlying its pressor effects.
General and Comparative Endocrinology, 1977
The effects of a third pancreatic hormone, avian pancreatic polypeptide (APP), on metabolism in i... more The effects of a third pancreatic hormone, avian pancreatic polypeptide (APP), on metabolism in isolated chicken adipocytes and hepatocytes were studied. APP inhibits glucagonstimulated lipolysis within the chicken adipocyte by as much as 45%. Addit~on~ly, APP causes a marked reduction in glucagon-stimulated cyclic AMP accumulation, suggesting that APP in some way interferes with the glucagon-sensitive adenylate cyclase system. APP binds specifically to the chicken adipocyte; two orders of receptor sites were demonstrated: a high affinity (Kd = 5.6 x lo+), low capacity (6.75 x lO+O mot/cell) site and a low affmity (Kd = 8.3 x lo-'), high capacity (3.18 x lo-l8 moYcel1) site. APP does not alter the rate of glycogenolysis or triglyceride synthesis at the chicken hepatocyte; neither does it stimulate glucose utilization by the chicken adipocyte.
General and Comparative Endocrinology, 1978
Isolated chicken and rat adipocytes and hepatocytes were used to compare chicken vs mammalian pan... more Isolated chicken and rat adipocytes and hepatocytes were used to compare chicken vs mammalian pancreatic hormones in regulating glucose and lipid metabolism. Porcine glucagon is twice as potent as chicken glucagon in eliciting lipolysis in both rat and chicken adipocytes. A less marked but significant difference exists between the two glucagon homologs when glucose release by isolated hepatocytes is measured. Chicken adipocytes respond to lower concentrations (1 rig/ml) of glucagon than rat adipocytes (5 r&ml). Hepatocytes from both animal species responded to glucagon at concentrations of 1 @ml. Chicken insulin is slightly more potent than porcine insulin both in inducing glucose utilization and in inhibiting glucagon-stimulated lipolysis in rat adipocytes. Glucose utilization, basal lipolysis, and the rate of glucagon-stimulated lipolysis of the chicken adipocyte are unaltered by insulin concentrations which are 1000 times greater than those required to affect rat adipocytes. The antilipolytic action of avian pancreatic polypeptide (APP) was compared with the bovine homolog of APP, namely bovine pancreatic polypeptide
The American journal of physiology, 1981
Diabetes and malnutrition result in decreased somatomedin production and cartilage growth in rats... more Diabetes and malnutrition result in decreased somatomedin production and cartilage growth in rats. The growth and metabolism of the Swarm rat chondrosarcoma are dramatically affected by somatomedins. Data presented here show that streptozotocin diabetes and diet restriction inhibit in vivo chondrosarcoma growth. Tumors grown in diabetic rats were significantly smaller than tumors grown in diet-restricted rats showing the same changes in body weight. Insulin treatment increased the rate of tumor growth in diabetic rats. Tumors grown in rigidly controlled diabetic rats were as large as tumors grown in nondiabetic controls. Diet restriction and diabetes reduced the capacity of the serum of the rat to stimulate alpha-amino[14C]isobutyrate uptake and [3H]uridine incorporation into RNA in chondrosarcoma pieces grown in nondiabetic rats. This somatomedin activity of the serum was restored by treating diabetic rats with insulin. There was a significant correlation between the in vitro stimu...
The American journal of physiology, 1980
The in vitro effects of cyclic AMP on amino acid transport and synthesis of macromolecules in the... more The in vitro effects of cyclic AMP on amino acid transport and synthesis of macromolecules in the Swarm rat chondrosarcoma were investigated using the cyclic AMP analogue, N6-monobutyryl cyclic AMP (MBcAMP), and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX). Amino acid transport was assessed by measuring alpha-amino-[1-14C]isobutyrate (AIB) uptake. The synthesis of macromolecules was estimated by measuring radiolabeled precursor incorporation into total proteins, proteoglycan, and RNA. MBcAMP stimulated [14C]AIB uptake, [3H]uridine transport, and UTP formation. MBcAMP inhibited 35SO4 and [3H]leucine incorporation into proteoglycan and stimulated [3H]uridine incorporation into RNA. MIX elevated endogenous cyclic AMP levels in the Swarm rat chondrosarcoma and mimicked the effects of MBcAMP on AIB transport and radiolabeled precursor incorporation into macromolecules. For comparative purposes, the effects of MBcAMP on AIB uptake and macromolecule synthesis in rat c...
Clinical and Experimental Hypertension, 1987
A hypertensive factor (HF) has been partially purified from the erythrocytes of spontaneously hyp... more A hypertensive factor (HF) has been partially purified from the erythrocytes of spontaneously hypertensive rats. Injection of the factor produces a sustained elevation of the blood pressure of normotensive rats. The blood pressure response following intravenous injection of the factor is characterized by a prolonged period of onset with maximal elevation obtained several days following the beginning of treatment. Subsequently, the elevation of blood pressure is well maintained and may be observed days or weeks following the cessation of treatment. In addition to its pressor effects, the preparation stimulates an increase in the concentration of "lanthanum-resistant" calcium in aortae excised from normotensive or hypertensive rats. In contrast, the efflux of calcium from aortae in the presence of the factor is enhanced suggesting that the factor involved may induce a change in the lability and exchangeability of calcium stores in aortic tissue. Secondarily, the efflux data indicate that the increase in "lanthanum-resistant" calcium noted in aortae exposed to the erythrocyte extract is due to an increase in calcium uptake by the tissue as opposed to a decrease in the extrusion of the ion.
Clinical and Experimental Hypertension, 1989
ABSTRACT The levels of adenosine 3':5' cyclic monophosphate (cyclic AMP) were mea... more ABSTRACT The levels of adenosine 3':5' cyclic monophosphate (cyclic AMP) were measured in aortae from 2-kidney, 1-clip renovascular hypertensive and DOCA-salt hypertensive rats. Cyclic AMP concentration and content were increased in the arteries from the hypertensive animals compared to their normotensive controls. There was a significant positive linear correlation between aortic cyclic AMP concentration and blood pressure and between aortic cyclic AMP content and blood pressure. Since cyclic AMP has been shown to be involved in cellular proliferation and protein synthesis, a perturbation in the normal functioning of this second messenger system could be related to some of the vascular changes associated with the hypertensive process.
Canadian Journal of Physiology and Pharmacology, 1988
It was recently shown that a peptide (hypertensive factor, HF) isolated from erythrocyte hemolysa... more It was recently shown that a peptide (hypertensive factor, HF) isolated from erythrocyte hemolysates from spontaneously hypertensive rats induced a prolonged elevation of blood pressure in normotensive rats. In addition, the peptide produced a marked stimulation of the in vitro uptake of lanthanum-resistant calcium by the aortae and enhanced the contractile response of aortic rings to constrictor agents. The present report describes findings of calcium stimulatory activity, enhancement of contractile function, or pressor activity in extracts of homogenates from several tissues of the rat and from erythrocyte hemolysates of several mammalian species. Significant stimulation of calcium uptake in aortic rings was obtained with preparations from rat brain, liver, and kidney. The activity per weight of tissue was similar for brain and kidney (approximately 2 units/g), while liver exhibited somewhat higher concentrations (4 units/g). The diffusate of cardiac tissue did not significantly alter in vitro calcium uptake by aortae. The injection of the cardiac and liver diffusates into normotensive Wistar-Kyoto rats produced slight (10 Torr) (1 Torr = 133.3Pa) and moderate (25 Torr) elevations of blood pressure, respectively. Finally, a peptide purified from homogenates of rat brain by the protocol developed for the purification of HF from erythrocytes was shown to significantly enhance the contractile response of aortic rings to K+ and norepinephrine. Diffusates of erythrocytes from the rat, rabbit, dog, and guinea pig each caused a significant stimulation of calcium uptake and contained approximately the same level of activity (500 units/L of whole blood). Diffusates prepared from outdated human erythrocytes had no significant effect on calcium uptake, whereas those of freshly drawn samples exhibited high levels of activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Canadian Journal of Physiology and Pharmacology, 1986
In earlier reports we have described the isolation of a fraction from the erythrocytes of spontan... more In earlier reports we have described the isolation of a fraction from the erythrocytes of spontaneously hypertensive rats that produced hypertension when administered to normotensive rats. In addition, it was found that the fraction stimulated the uptake of "lanthanum-resistant" calcium by aortic rings excised from normotensive rats. In these studies we have found that the fraction causes a greater increase in the in vitro uptake of calcium by aortic tissue than that produced by depolarization of the tissue with high K+ or the receptor-mediated influx of calcium induced with norepinephrine. The hypertensive fraction appeared to be more effective in promoting increased calcium uptake in rabbit than in rat aortic tissue, suggesting that significant differences in tissue sensitivity to the active compound(s) may exist between species. In addition, we obtained evidence indicating that the tissue sensitivity to the action of the hypertensive fraction was greater in aortae from spontaneously hypertensive rats than from those of normotensive animals. Attempts to block the action of the hypertensive fraction with verapamil, nifedipine, and sodium nitroprusside had no significant effect on the elevation in tissue calcium. It was found, however, that the action of the hypertensive fraction was temperature dependent with reduced activity at lower temperatures. The data suggest that a compound(s) is present in the erythrocytes of rats that may have a marked effect on vascular tissue metabolism of calcium.
Canadian Journal of Physiology and Pharmacology, 1991
To assess the effects of cyclic AMP on amino acid transport and incorporation into aortic tissue ... more To assess the effects of cyclic AMP on amino acid transport and incorporation into aortic tissue protein, rat aortic rings were incubated with the cyclic AMP analog, N6-monobutyryl cyclic AMP (MBcAMP), the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX), and radiolabeled amino acids. Subsequently, the aortic rings were homogenized in 5% trichloroacetic acid (TCA) and processed for liquid scintillation counting. Radioactivity present in the TCA supernatant following centrifugation was used to estimate amino acid transport. TCA-precipitable radioactivity was used as a measure of amino acid incorporation into protein. MBcAMP induced an increase in the uptake of [3H]alpha-aminoisobutyric acid into aortic rings and an increase in the incorporation of radiolabeled proline and leucine into TCA-precipitable protein. Similar effects were observed with low concentrations of MIX (0.025-0.25 mM); however, at higher concentrations of MIX, there was an attenuation of the effect or frank inhibition. Maximum stimulation of transport was observed within 90-120 min of the addition of MIX or MBcAMP to the incubation medium, whereas the effect on amino acid incorporation was not detectable until after 12 h of exposure to MIX or MBcAMP. The effects of cyclic AMP on transport were observed in both the tunica media and the tunica adventitia, whereas the effects on amino acid incorporation into protein were observed only in the tunica media. These data are consistent with a possible role for cyclic AMP in promoting changes in the tunica media that could lead to the development of vascular hypertrophy.
Cancer Research, Feb 1, 1983
Prostaglandin A1 has a profound inhibitory effect on uridine incorporation into RNA of normal car... more Prostaglandin A1 has a profound inhibitory effect on uridine incorporation into RNA of normal cartilage whereas N6-monobutyryladenosine 3',5'-cyclic monophosphate is either stimulatory or without an effect. Sera from intact and growth hormone-treated hypophysectomized rats stimulate RNA synthesis but serum from untreated hypophysectomized rats does not. The present study investigated the in vitro regulation of [3H]uridine incorporation into RNA of six human chondrosarcomas to determine if malignant human chondrocytes are under similar metabolic and hormonal regulation. Prostaglandin A1 (25/~g/ml) markedly inhibited uridine incorporation in all six tumors (56 to 80%). N6-Monobutyryladenosine 3',5'-cyclic monophosphate (1 raM) inhibited uridine incorporation in five tumors (20 to 50%). Uridine incorporation was stimulated by growth hormone-dependent serum factors in one tumor and by growth hormone-independent serum factors in two tumors. Two tumors were more responsive to serum from growth hormone-treated hypophysectomized rats than to serum from intact rats, and one tumor was unresponsive to serum stimulation. The data indicate that: (a) prostaglandin A~ is a very potent inhibitor of RNA synthesis in human chondrosarcomas; (b) N% monobutyryladenosine 3',5'-cyclic monophosphate affects human chondrosarcomas differently than it does normal cartilage; and (c) responses of human chondrosarcomas to serum growth factors vary among individual tumors.
Nitric oxide (NO) plays an essential role in the regulation of numerous biological processes. Its... more Nitric oxide (NO) plays an essential role in the regulation of numerous biological processes. Its bioavailability is assured by a well regulated balance between NO generation and NO removal.
Canadian Journal of Physiology and Pharmacology, May 1, 1986
The present report describes some aspects of the effects of a recently described antihypertensive... more The present report describes some aspects of the effects of a recently described antihypertensive extract of erythrocytes (AHF) on calcium uptake and efflux in rat aortae. AHF was found to be present in the erythrocytes of both spontaneously hypertensive rats and normotensive rats. Furthermore, AHF obtained from erythrocytes of SH rats was shown to be equally effective in suppressing lanthanum-resistant calcium uptake in aortae from hypertensive and normotensive rats. AHF treatment prior to incubation of aortae with 45Ca caused an apparent increase in the total 45Ca uptake. The analysis of calcium washout curves obtained for tissue in calcium-free or lanthanum-containing media indicated that AHF had no significant effect on the rate of calcium loss from the slow component of efflux, though this compartment tended to be reduced in size. This indicated that the increase in the 45Ca content of AHF-exposed aortae prior to rinsing was confined to the rapid component of efflux. The loss of calcium from the rapidly exchanging compartment was enhanced in either of the efflux media used. The results suggest that a principal action of AHF involves an increase in the lability and exchangeability of calcium stores. In addition to its effects in resting tissue, AHF abolished the increase in lanthanum-resistant calcium uptake induced in rat aortae by the addition of high K+ or norepinephrine to the incubation media. In a second part of the study, the effect of AHF on blood pressure and in vitro calcium uptake were compared with that of phosphatidylethanolamine (PEA), the probable identity of another endogenous antihypertensive (renin preinhibitor) compound earlier shown to share important functional similarities with AHF.(ABSTRACT TRUNCATED AT 250 WORDS)
Clinical and Experimental Hypertension Part a Theory and Practice, Feb 1, 1990
It has been proposed that calcium supplementation in the diet is associated with a reduction in b... more It has been proposed that calcium supplementation in the diet is associated with a reduction in blood pressure. In the present study, we investigated vascular tissue sensitivity to a hypertensive factor (HF) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) fed a high calcium diet, a low calcium diet and a food restricted diet. HF, which has been isolated from erythrocytes, increases blood pressure when injected into normotensive rats and stimulates calcium uptake by aortic rings in vitro. Five-week-old rats were divided into the following groups: SHR and WKY fed a regular diet (1% calcium), SHR and WKY fed a high calcium diet (4% calcium), SHR and WKY fed a low calcium diet (0.02% calcium) and SHR and WKY fed a regular diet (1% calcium) in which food intake was restricted to 65% of ad libitum intake. Food intake, body weight, urine phosphate excretion and blood pressure development were followed for 8 weeks. At sacrifice, plasma levels of calcium and phosphate were determined. Tissue responsiveness to HF was calculated by incubating aortic rings from the rats in the different groups with HF and measuring lanthanum-resistant calcium uptake. A 4-fold increase in dietary calcium reduced blood pressure and tissue responsiveness to HF in SHR. Neither parameter was affected by the high calcium diet in WKY. The low calcium diet had no effect on either blood pressure or tissue responsiveness to HF in SHR or WKY. Restriction of food intake induced a reduction in blood pressure and in tissue responsiveness to HF in SHR. It did not affect the same parameters in WKY. The results suggest that the increased tissue responsiveness to HF in the SHR may be associated with high blood pressure.
Annals of clinical and laboratory science, 2005
This study assessed the progression of renal damage in obese Zucker rats in response to deoxycort... more This study assessed the progression of renal damage in obese Zucker rats in response to deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Renal damage was evaluated by light microscopy and urine analysis at weekly intervals during the developmental phase of DOCA-salt hypertension and once during the plateau phase 42 days after the onset of treatment. Decreased tubular function was evident by day 8, as indicated by a significant increase in urine N-acetyl-beta-D-glucosaminidase activity and glucose excretion. The tubular index, a measure of tubular damage, was significantly elevated by day 15 and continued to increase throughout the experiment. Glomerular damage, which was evident by day 8, was followed by increased urine albumin excretion by day 15. Only a few sclerotic renal glomeruli were apparent before the plateau phase; however, by day 42, approximately 50% of the glomeruli were sclerotic. Hyperplastic vascular changes were mild at day 8 and slowly increased in seve...
Cancer research, 1983
Prostaglandin A1 has a profound inhibitory effect on uridine incorporation into RNA of normal car... more Prostaglandin A1 has a profound inhibitory effect on uridine incorporation into RNA of normal cartilage whereas N6-monobutyryladenosine 3',5'-cyclic monophosphate is either stimulatory or without an effect. Sera from intact and growth hormone-treated hypophysectomized rats stimulate RNA synthesis but serum from untreated hypophysectomized rats does not. The present study investigated the in vitro regulation of [3H]uridine incorporation into RNA of six human chondrosarcomas to determine if malignant human chondrocytes are under similar metabolic and hormonal regulation. Prostaglandin A1 (25 micrograms/ml) markedly inhibited uridine incorporation in all six tumors (56 to 80%). N6-Monobutyryladenosine 3',5'-cyclic monophosphate (1 mM) inhibited uridine incorporation in five tumors (20 to 50%). Uridine incorporation was stimulated by growth hormone-dependent serum factors in one tumor and by growth hormone-independent serum factors in two tumors. Two tumors were more res...
The American journal of physiology, 1985
An extract was prepared from hemolyzed erythrocytes of spontaneously hypertensive rats (SHR) whic... more An extract was prepared from hemolyzed erythrocytes of spontaneously hypertensive rats (SHR) which inhibits lanthanum-resistant calcium uptake by aortic segments and lowers blood pressure in several models of hypertension. Erythrocyte hemolysates were extracted with Triton X-100 and partially purified by boiling and Sephadex G-150 column chromatography. The effects of the extract on calcium uptake by aortic segments in vitro were reversible and dose dependent. The extract was administered by intraperitoneal injection to male and female SHR, deoxycorticosterone-NaCl hypertensive rats (DOCA-NaCl), one-kidney one-clip (1K,1C) and two-kidney, one-clip (2K,1C) renovascular hypertensive rats, and their appropriate control groups. At 24 h postinjection, the antihypertensive factor (AHF) lowered the systolic blood pressure (SBP) in the conscious SHR male (200 +/- 7 to 132 +/- 11 Torr), SHR female (172 +/- 4 to 117 +/- 11), DOCA-NaCl (187 +/- 6 to 121 +/- 8), 2K,1C (165 +/- 8 to 127 +/- 7), ...
Journal of hypertension. Supplement : official journal of the International Society of Hypertension, 1986
We have previously demonstrated the existence of an active component(s) of extracts prepared from... more We have previously demonstrated the existence of an active component(s) of extracts prepared from rat erythrocytes that stimulates the in vitro uptake of calcium in aortic rings and induces a sustained elevation in the blood pressure of normotensive rats. The apparent concentration of the calcium stimulatory component and the responsiveness of aortic rings to stimulation of calcium uptake by the compound is exaggerated in adult spontaneously hypertensive rats (SHR) compared with normotensive controls. Although no effect was observed on tissue responsiveness to the compound, a decrease in the concentration of the compound was observed in the blood of adult SHR subjected to dietary manipulation designed to blunt the elevation of blood pressure. These data suggest that blood concentration of the active compound may be influenced by external stimuli such as dietary manipulation.
Uploads
Papers by William McCumbee