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Biomedical subjects

R H Cox

Publications and source records attributed to R H Cox.

At least 19 recordsLinked to original sources
PubMed1996

Comparison of K+ channel properties in freshly isolated myocytes from thoracic aorta of WKY and SHR.

Altered function of smooth muscle cell K+ channels have been reported in hypertension, but the contribution of various K+ channel types to these changes has not been completely determined. The purpose of this study was to compare the contribution of K+ channel types to whole cell K+ currents recorded from isolated thoracic aorta myocytes of 13 to 15 week old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Cells were isolated by collagenase and elastase digestion, and K+ currents recorded using whole cell voltage clamp methods at room temperature. Cells were superfused with a solution containing (in mmol/ L) 140 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, and 10 glucose. Pipettes were filled with a solution containing (in mmol/L) 120 KCl, 5 NaCl, 5 MgATP, 20 HEPES, and 10 BAPTA. The K+ currents (IK) recorded from a holding potential (HP) of -80 mV were smaller in the SHR compared to those in WKY (for example, at 20 mV: WKY = 6.1 +/- 0.6 pA/pF and SHR = 3.7 +/- 0.2 pA/pF). Values of cell capacitance were not different between the two groups (WKY = 25.2 +/- 3.2 pF and SHR = 26.6 +/- 1.9 pF). A component of IK inhibited by voltage (Kv) over the range from -80 to -20 mV was smaller in SHR. The voltage dependence of Kv availability and activation were not significantly different between the two groups. IK recorded from a HP = -20 mV (KCa) was not different between the two groups. Difference currents calculated from IK measured at HP of -80 and -20 mV (that is, Kv) were smaller in SHR as was the fraction of IK inhibited by 4-aminopyridine. These results suggest that under conditions of low intracellular [Ca2+] there are no differences in KCa currents, but the Kv currents are smaller in SHR. Inhibition of Kv by 4-aminopyridine (0.1 to 10 mmol/L) caused larger increases in basal tone in WKY aorta. These results suggest that Kv channels contribute to resting K+ conductance in both WKY and SHR aorta, but with a relatively larger contribution in the WKY.

4-Aminopyridine↗
PubMed1995

Altered contractile and ion channel function in rabbit portal vein with dietary atherosclerosis.

This study was performed to determine the effects of dietary atherosclerosis on the pharmacology and ion channel properties of rabbit portal vein (PV). New Zealand White rabbits were fed normal rabbit chow +/- 2% cholesterol for 10 wk. Contractions to norepinephrine (NE) and serotonin were studied under isometric conditions with longitudinal strips. Ca2+ and K+ currents (ICa and IK, respectively) were recorded in freshly dispersed myocytes by whole cell voltage clamp methods. Cholesterol feeding increased total plasma cholesterol levels from 28.4 +/- 5.2 to 1,387 +/- 172 mg/dl as well as the cholesterol-to-phospholipid molar ratio of the PV from 0.34 +/- 0.02 to 0.66 +/- 0.08. Only maximum contractile responses to serotonin were larger in atherosclerotic PV when normalized to the maximum KCl response. Concentration-active stress curves of the atherosclerotic PV to NE and serotonin were shifted to the left. Maximum values of ICa were larger in myocytes from atherosclerotic compared with control animals (4.4 +/- 0.4 vs. 3.1 +/- 0.2 pA/pF, P < 0.05). The voltage dependence of activation and availability of ICa was shifted toward more negative potentials by approximately 10 mV. Whole cell K+ currents were smaller in atherosclerotic myocytes. At a test voltage of +20 mV, IK averaged 14.9 +/- 2.8 pA/pF in control compared with 7.7 +/- 0.8 pA/pF in atherosclerotic myocytes from a holding potential of -80 mV with external Ca2+ concentration of 5 mM. The reversal potential for IK tail currents was significantly less negative in atherosclerotic myocytes (-70 +/- 1 vs. -64 +/- 1 mV).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

GTP requirement for isoproterenol activation of calcium channels in vascular myocytes.

The effects of activating the beta-adrenoceptor pathway on calcium current (ICa) in rabbit portal vein (PV) were studied in myocytes freshly isolated by collagenase and elastase treatment. ICa was measured at room temperature (20 degrees C) using whole cell, voltage-clamp methods from a holding potential of -60 mV in cells dialyzed with a pipette solution containing (mM) 100 CsCl, 20 tetraethylammonium chloride, 5 NaCl, 5 MgATP, 20 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), and 10 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). The cells were superfused with a solution containing (mM) 140 NaCl, 5 KCl, 1 MgCl2, 5 CaCl2, 10 HEPES, and 10 glucose. Only L-type ICa was present in these myocytes, averaging 3.5 +/- 0.3 pA/pF at +10 mV under control conditions. With 0.1 mM guanosine 5'-triphosphate (GTP) added to the pipette solution, 1 microM isoproterenol (Iso) or forskolin (Fsk) uniformly increased ICa: Iso by 45 +/- 5% and Fsk by 88 +/- 11%. This augmentation of ICa was not associated with significant changes in the voltage dependence of activation or inactivation but was associated with a small increase in the rate of inactivation of ICa. Fsk was also associated with an increased rate of ICa activation. The Iso effect was blocked by pretreatment with 1 microM propranolol and reversed by propranolol after Iso exposure. The ICa response to 10 microM Iso or Fsk was smaller than the response to 1 microM, with some cells showing a steady-state reduction in ICa. When the latter occurred, the voltage dependence of availability was shifted to the left by 5 +/- 0.4 mV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Swim training alters sympathoadrenal and endocrine responses to hemorrhage in borderline hypertensive rats.

Swim training alters cardiovascular, sympathoadrenal, and endocrine responses to hemorrhage in borderline hypertensive rats (BHR). The effects of 10, 20, and 30% blood volume hemorrhages on cardiovascular, sympathoadrenal, and endocrine function in swim-trained (T; 2 h/day, 5 day/wk for 10-12 wk) and age-matched, untrained, sedentary, control (UT) borderline hypertensive rats (BHR) were assessed. Heart rate (HR) in UT BHR was significantly greater during the baseline (rest) period than T BHR. HR increased slightly from baseline in both groups after 10% hemorrhage but was significantly decreased in both groups after 20 and 30% hemorrhages. The decrease was eliminated by atropine (1 mg/kg iv). Systolic (SBP) and diastolic (DBP) blood pressures decreased significantly after 20 and 30% hemorrhages in both T and UT BHR but were not different between the groups at these times. Plasma norepinephrine levels were significantly increased above baseline after 20 and 30% hemorrhages in UT BHR and were significantly greater in UT BHR than T BHR after 30% hemorrhage. Plasma glucose levels increased significantly after 30% hemorrhage in both groups but were significantly greater in UT BHR than T BHR. Both plasma norepinephrine and plasma epinephrine levels showed strong positive correlations with plasma glucose. After 20 and 30% hemorrhages, plasma insulin levels were unchanged in T BHR but were significantly decreased in UT BHR. Plasma insulin levels were significantly less in UT than T BHR after 30% hemorrhage. These results suggest that swim training alters the effect that hemorrhage exerts on endocrine and sympathoadrenal function in BHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1995

Augmented calcium currents in mesenteric artery branches of the spontaneously hypertensive rat.

The greater efficacy of organic channel blockers in lowering peripheral resistance and blood pressure in hypertensive subjects has been suggested to be the result of augmented calcium influx through L-type calcium channels in arterial smooth muscle. These studies were performed to determine whether differences exist in voltage-gated calcium channels of mesenteric artery branches from 20-week-old spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Single myocytes were acutely isolated by collagenase and elastase treatment and studied at room temperature (approximately 20 degrees C) with the use of whole-cell, patch-clamp methods. Maximum values of calcium current measured at 0 mV from a holding potential of -90 mV were larger in SHR myocytes (105 +/- 11 versus 149 +/- 15 pA). Values of cell capacitance were smaller in SHR (29.5 +/- 1.3 pF) compared with WKY (35.0 +/- 1.5 pF) myocytes. Cell capacitance measures surface membrane area and, when used to normalize calcium currents, magnified the difference between WKY and SHR to approximately 47%. There was a larger percent reduction of maximum calcium current at holding potentials of -60 and -40 mV in SHR compared with WKY myocytes: for example, at -40 mV calcium current was reduced from values at -90 mV by -73 +/- 2% in SHR compared with -58 +/- 1% in WKY. When divided by the maximum current for each holding potential, the voltage dependence of normalized calcium currents for the two groups was completely superimposed. Difference currents were calculated by subtracting currents measured from holding potentials of -90 and -40 mV. The voltage dependence of difference currents was identical to that of the calcium currents measured from the two values of holding potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1994

Prevention of fluvastatin-induced toxicity, mortality, and cardiac myopathy in pregnant rats by mevalonic acid supplementation.

Mevalonic acid is a product of the enzyme HMG-CoA reductase which is essential for cholesterol biosynthesis. Fluvastatin (Sandoz compound XU 62-320) is a potent inhibitor of this enzyme and, hence, mevalonic acid production. In three separate studies, oral administration of fluvastatin at 12 and 24 mg/kg/day to mated rats from day 15 of gestation through weaning resulted in unanticipated maternal mortality at the time of parturition and during lactation. Microscopic evaluations performed in two studies revealed significant cardiac myopathy in the dying animals. Drug-related clinical signs, significant maternal body weight loss, and an increase in stillborn pups and neonatal mortality were also noted at one or both dose levels. Supplementation of fluvastatin administration with 500 mg/kg b.i.d. of mevalonic acid completely blocked and/or ameliorated the mortality, cardiac myopathy, and other adverse effects. These studies indicate that the adverse maternal effects observed with fluvastatin before or following parturition resulted from exaggerated pharmacologic activity at the dose levels administered, i.e., inhibition of the enzyme HMG-CoA reductase, its immediate product mevalonic acid, and cholesterol biosynthesis.

Analysis of Variance↗
PubMed1994

Carcinogenicity and mutagenicity studies with fluvastatin, a new, entirely synthetic HMG-CoA reductase inhibitor.

The HMG-CoA reductase inhibitors are a new and novel class of cholesterol-lowering agents which are widely used worldwide. Fluvastatin is the first entirely synthetic compound in this class and is structurally distinct from fungal metabolite derivatives which are already marketed. As the liver is the site of some toxic effects for these compounds, it was not entirely unexpected that liver cancer was found in rats and/or mice with the first three marketed compounds, lovastatin, pravastatin, and simvastatin. Four lifetime carcinogenicity studies (two rat and two mouse) did not give any evidence that fluvastatin induced liver tumors in rodents. Fluvastatin induced thyroid neoplasms in rats and forestomach papillomas in rodents, as other compounds in this pharmacologic class have also done. The genotoxic potential of fluvastatin has been assessed in vitro using Salmonella typhimurium, Escherichia coli (gene mutations), V79 Chinese hamster cells (HGPRT gene mutations, chromosomal aberrations), rat hepatocyte primary cultures (DNA repair), and BALB/3T3 cells (malignant transformations). Fluvastatin was also tested in vivo for clastogenicity using the mouse bone marrow micronucleus test and by performing a cytogenetic analysis in the rat bone marrow after acute and subacute treatment. In all seven assays fluvastatin was found to be free of any genotoxic potential.

3T3 Cells↗
PubMed1994

Physiological and psychological responses to eccentric exercise.

In order to compare the physiological and psychological responses to various levels of eccentric exercise, 7 active men (25 +/- 5 yrs) exercised for 60 min on separate days at 60% of apparatus specific VO2 max using downhill jogging (-5% 60DH), level jogging (60J), and cycling (60C). Virtually all of the responses to 60DH fell between 60J and 60C. Heart rate, O2 pulse, and respiratory exchange ratio were significantly different among modes, with the responses during 60DH falling between those during 60J and 60C. Fat energy expenditure during the 60-min exercise bout was significantly higher during 60J, followed by 60DH and then 60C. Ratings of perceived exertion followed the order of 60C > 60DH > 60J. Vigor and fatigue scores on the Profile of Mood States also followed a hierarchy that paralleled the physiological responses. These results suggest that downhill jogging elicits physiological and psychological responses that are between those elicited by level jogging and cycling.

Adult↗
PubMed1993

Swim training alters renal and cardiovascular responses to stress in borderline hypertensive rats.

The present study assessed the effects of 40 min of tail shock stress (1-s shock, 0.2 mA every 30 s) on renal and cardiovascular function in swim-trained (T), water-immersed (IM), and untrained (UT) borderline hypertensive rats (BHR). T BHR swam for 2 h/day 5 days/wk for 10-12 wk, whereas IM BHR on the same schedule were placed in water at neck level and were not permitted to swim. Age-matched sedentary controls were paired one each with the exercise group (group 1) and the immersion group (group 2). Heart rate was significantly greater in UT than in T BHR (P = 0.09) during baseline (rest). Heart rate responses during stress were not different between UT and IM BHR (group 2). Systolic and diastolic blood pressures during stress and recovery were not different between UT BHR and T or IM BHR. Urine flow rate was significantly increased from baseline during the first 20 min of stress in UT and IM BHR only. Changes in glomerular filtration rate were not consistent across studies. Renal blood flow decreased significantly from baseline during tail shock stress in UT but not T BHR. Plasma glucose levels were significantly increased above baseline during the second 20 min of stress in UT BHR only and were significantly greater than those in the T BHR. Plasma insulin levels in UT BHR were significantly decreased from baseline during tail shock stress and recovery but were unchanged from baseline in T BHR. These observations suggest that swim training independent of water immersion alters the effect that stress exerts on renal and cardiovascular function in BHR, which results in better fluid and electrolyte conservation in T BHR.

Animals↗
PubMed1993

Characteristics of arterial myosin in experimental renal hypertension in the dog.

We compared myosin samples isolated from iliac-femoral arteries of control and renal (stenosis) hypertensive dogs to determine the effects of increased blood pressure on the characteristics of the myosin. The ratio of 204-kd (SM-1) to 200-kd (SM-2) myosin heavy chains was approximately 1:0.75 for myosin from the iliac-femoral artery of normotensive dogs. This was not altered significantly in response to hypertension. Both SM-1 and SM-2 myosin heavy chains cross-reacted with antibody against smooth muscle myosin on Western blot analysis. In addition to these heavy chains, purified myosin from both groups showed a very faint protein band slightly below the 200-kd myosin heavy chain on electrophoresis on a highly porous sodium dodecyl sulfate-polyacrylamide gel. This protein band cross-reacted with antibody against nonmuscle myosin but not with smooth muscle myosin antibody. The 20- and 17-kd light chains of myosin isolated from normotensive and hypertensive dogs gave similar results on isoelectric focusing. Peptide maps of tryptic digests of heavy chains revealed both quantitative and qualitative differences. The Ca(2+)-activated myosin ATPase activity measured in high salt (0.5 mol/L KCl) was similar for myosin from both groups, whereas the potassium (ethylenedinitrilo)tetraacetic acid-stimulated ATPase of myosin from hypertensive animals was higher than that from normotensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Development of the concept of middleness in children: response time and complexity.

24 boys and 16 girls ages 4 through 7 years were tested on an apparatus that required children to select the middle of 3, 5, 7, or 9 stimulus lights when arranged adjacent to one another and when spaced symmetrically or asymmetrically. Analysis indicated response time decreased with age and increased as a function of the number of stimulus lights in the task. Time to respond to asymmetrical arrangements was greater than for problems whose stimuli were arranged symmetrically.

Attention↗
PubMed1992

Age-related changes in thoracic aorta of obese Zucker rats.

Studies were performed on the ontogeny of arterial blood pressure and functional properties of the thoracic aorta in lean (L) and obese (O) male Zucker rats at ages of 6-36 wk. Body weight was larger in the O than the L at all ages, with differences reaching values of 200-250 g at ages over 24 wk (at 33-36 wk: L = 510 +/- 9 and O = 730 +/- 15 g). Systolic blood pressure was lower in young O compared with L (6-15 wk) but increased with age at a rate seven times greater in O than in L. For ages of 33-36 wk, systolic pressure was significantly higher in O compared with L (O = 132 +/- 2 vs. L = 122 +/- 2 mmHg). Total serum cholesterol (at 36 wk: L = 278 +/- 31 and O = 354 +/- 12 mg/dl) and triglycerides (at 36 wk: L = 493 +/- 71 and O = 1,618 +/- 220 mg/dl), as well as glucose levels, increased with age in both groups and were significantly higher in O at all ages. Serum levels of thyroxine but not triiodothyronine were significantly lower in O at all ages. No differences were found in passive mechanics at any age. Values of maximum active stress with smooth muscle activation by 75 mM K+ plus 10 microM norepinephrine were significantly higher at 24 and 36 wk in O (at 36 wk: L = 573 +/- 42 and O = 821 +/- 89 x 10(3) dyn/m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Characteristics of calcium currents in rabbit portal vein myocytes.

The properties of voltage-dependent Ca2+ channels were studied in isolated portal vein myocytes using the whole cell voltage-clamp method. Ca2+ currents (ICa) were identified based on their activation and inactivation potential, their dependence on external Ca2+ ([Ca2+]o), their suppression by organic or inorganic Ca2+ channel blockers, their augmentation by BAY K 8644, and their insensitivity to tetrodotoxin or alterations in external Na+ ([Na+]o). Changing the holding potential from -90 to -40 mV decreased ICa from 4.6 +/- 0.6 to 2.0 +/- 0.3 pA/pF at 0 mV but did not shift its voltage dependence significantly. The voltage dependence of steady-state inactivation and activation was represented by Boltzmann distributions with the following parameters: inactivation, half-maximal voltage (V0.5) = -32 +/- 7 mV and slope factor (k) = 6.1 +/- 0.2 mV; activation, V0.5 = -15 +/- 4 mV and k = 5.6 +/- 0.6 mV. Doubling the [Ca2+]o increased ICa and shifted the voltage dependence of its activation and inactivation by approximately 10 mV toward more positive potentials without altering the window currents. Substituting Na+, Ba2+, or Sr2+ for Ca2+ as the charge carrier through the Ca2+ channel slowed the rate of its inactivation and shifted its voltage dependence toward more negative potentials. Divalent selectivity of the Ca2+ channel showed an apparent concentration dependence: at 2 mMISr less than IBa = ICa, while at 10 mM ICa less than ISr = IBa. Because 50-100 microM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid abolished the apparent concentration dependence of the divalent ion selectivity, this phenomenon was attributed to a high Ca2+ selectivity of the channel. Our data support the presence of only one type of Ca2+ channel in rabbit portal vein myocytes with characteristics similar to the L-type Ca2+ channel described in other cells, but with somewhat different divalent selectivity, holding potential, and [Na+]o dependence.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

Isometric exercise training lowers resting blood pressure.

Both rhythmic and "resistive" (weight lifting) exercise training can produce modest decreases in resting blood pressure. The next logical point along an exercise continuum consisting of different proportions of rhythmic and isometric efforts is a strictly isometric effort. The purpose of these studies was to assess the effects of isometric, handgrip exercise training on resting blood pressure. To avoid the extreme pressor responses elicited by fatiguing isometric efforts, the isometric exercise training used in this study consisted of brief handgrip contractions separated by rest periods. Modest repeated rises in systolic and diastolic pressures therefore served as the putative stimuli for training adaptations in resting blood pressures. Human subjects in study 1 trained with four, 2-min isometric handgrip contractions with 3-min rests between contractions. The intensity of the contractions was equal to 30% of their maximal effort for each day. The bouts of isometric exercise were performed three times per week for 8 wk. Study 2 training consisted of four contractions of 50% of maximum effort held for a duration of 45 s with 1-min rests. These were performed 5 d.wk-1 for 5 wk. In Study 1, all eight trained subjects had a significant decline in both systolic and diastolic resting blood pressures, with group averages of 12.5 and 14.9 mm Hg, respectively. Seven matched control subjects who did not train had no change in resting pressures. In study 2, subjects were trained in their home or workplace and experienced significant mean declines in resting systolic and diastolic pressures of 9.5 and 8.9 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗