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D F Bohr

Publications and source records attributed to D F Bohr.

At least 19 recordsLinked to original sources
PubMed2001

Central hypotensive action of clonidine requires nitric oxide.

Background- Clonidine has an antihypertensive effect by its action in the brain and, because we observed that the tonic production of nitric oxide (NO) in the brain is required to maintain blood pressure at its low, normotensive level, the current study was designed to determine whether the hypotensive action of clonidine resulted from its stimulation of excess NO in the brain. Methods and Results- Porphyritic microsensors were used to quantify NO concentration in the nucleus tractus solitarius (NTS) in vitro in brain slices and in vivo in the anesthetized rat. In both preparations, the basal production of NO in the NTS was 15+/-3 nmol/L. In vitro stimulation of the NTS with clonidine (50 nmol/L) resulted in an increase in the NO concentration to 84+/-7 nmol/L. In vivo, the intracerebroventricular (ICV) infusion of clonidine (0.03 microgram) caused an increase in NO concentration in the NTS to 128+/-17 nmol/L. This ICV injection of clonidine caused a fall in mean arterial pressure of -22+/-1 mm Hg and a decrease of heart rate of -18+/-2%. The blockade of NO production with N(G)-nitro-L-arginine-methyl ester (2 micromol; delivered ICV, 30 minutes before the clonidine) reduced responses to clonidine for both mean arterial pressure and heart rate (-3+/-1 mm Hg and -2+/-1% change, respectively). Conclusion- The stimulation of the release of NO in the brain by clonidine contributes to its central antihypertensive action.

Animals↗
PubMed2001

Goldmann applanation tonometry in the conscious rat.

PURPOSE: To determine whether the Goldmann applanation tonometer can be modified to measure intraocular pressure (IOP) in the conscious rat. METHODS: In anesthetized rats Goldmann tonometers were tested that had reduced biprism angles in the applanating tips and reduced weights in the tonometer body from those used in humans and species with similar size eyes. Tonometers with tips with biprism angles of 48 degrees and an applied weight of 25 mg per Goldmann scale division (2 g full scale) were calibrated for the rat against manometrically measured IOP. Tonometers, thus modified, were then used in conscious, unsedated rats. RESULTS: In conscious rats the measured mean Goldmann value was 15.5 +/- 0.6 mm Hg (confidence interval = 14.1, 16.6 mm Hg). This was the plateau level reached after the repeated applanations (approximately 10) required to eliminate an artifactual decline in initial Goldmann readings, which was larger than that in humans. CONCLUSIONS: The Goldmann applanation tonometer was modified to measure IOP in the conscious, unsedated rat. This instrument, the standard for measuring this key physiological parameter in the human eye, can now be applied to the laboratory rat. This may advance the use of this important animal as a model in IOP and glaucoma research.

Animals↗
PubMed2001

Measurement of intraocular pressure in awake mice.

PURPOSE: To determine whether the Goldmann applanation tonometer can be modified to measure intraocular pressure (IOP) in the awake mouse. METHODS: Tonometers with reduction of the biprism angles in the applanating tips and in the weight applied by the instrument were tested in anesthetized mice in calibration experiments. Then a tonometer with the appropriate configuration of tip and weight was used in conscious, unsedated mice. RESULTS: Tonometry in mice required a biprism angle of 36 degrees and weight applied of 25 mg per scale division (2 g full scale). This tonometer was calibrated in mice against manometrically measured IOP and showed good agreement across the range of IOP tested (0-50 mm Hg). In conscious mice the measured mean Goldmann value was 13.7 +/- 3.2 mm Hg (mean +/- SD; 95% confidence interval, 13.1, 14.2 mm Hg). CONCLUSIONS: The Goldmann tonometer, the standard for measuring the IOP in the human eye, was modified to measure this fundamental physiologic parameter in the awake mouse. This measurement is required to confirm success in genetically engineering a model in the powerful mouse system, which mimics elevated IOP in humans. The model will open new avenues for studying the causes of the optic neuropathy of glaucoma, the regulation of IOP, and new therapeutic approaches to prevent the irreversible loss of vision from this disease.

Animals↗
PubMed2000

Nitric oxide deficiency contributes to large cerebral infarct size.

The purpose of this study was to examine the role played by a deficit in nitric oxide (NO) in contributing to the large cerebral infarcts seen in hypertension. Cerebral infarction was produced in rats by occlusion of the middle cerebral artery (MCA). Studies were performed in Sprague-Dawley (SD) rats subjected to NO synthase blockade (N(G)-nitro-L-arginine [L-NNA], 20 mg x kg(-1) x d(-1) in drinking water) and in spontaneously hypertensive stroke-prone rats (SHRSP). NO released in the brain in response to MCA occlusion was monitored with a porphyrinic microsensor in Wistar-Kyoto rats. The increment in NO released with MCA occlusion was 1.31+/-0.05 micromol/L in L-NNA-treated rats, 1.25+/-0.04 micromol/L in SHRSP, 2. 24+/-0.07 micromol/L in control SD rats, and 2.25+/-0.06 micromol/L in Wistar-Kyoto rats (P<0.0001 for control versus the other groups). Infarct sizes in the L-NNA-treated and control SD rats were 8.50+/-0. 8% and 5.22+/-0.7% of the brain weights, respectively (P<0.05). The basilar arterial wall was significantly thicker in L-NNA-treated rats compared with their controls. We conclude that both the deficit in NO and the greater wall thickness contribute to the larger infarct size resulting from MCA occlusion in SHRSP and in L-NNA-treated rats compared with their respective controls.

Animals↗
PubMed1999

Intraocular pressure measurement in the conscious rat.

PURPOSE: To develop a method for measurement of intraocular pressure in conscious, unsedated rats. METHODS. The animal was gently held with a thick fabric mitten, topical anesthetic drops were instilled and the Tono-Pen was applied to the cornea. RESULT: Measurements in a total of 51 animals did not differ significantly among four strains studied: the overall mean intraocular pressure+/-standard deviation was 13.0+/-1.2 mm Hg. Several intraocular pressure tolerance limits were calculated from this conscious rat data to provide a baseline estimate for future studies. CONCLUSIONS: This measurement method in conscious rats may contribute to making this widely used laboratory animal available for intraocular pressure research.

Animals↗
PubMed1999

Endothelial function in hypertension: the role of superoxide anion.

Much attention has been focused on the role of nitric oxide in hypertension and cardiovascular disease. More recently, the role of superoxide anion and its interaction with nitric oxide has been investigated in this context. This review will concentrate on the role of superoxide in human and experimental hypertension, paying particular attention to the potential sources of superoxide within the vasculature and discussing some of the molecular mechanisms surrounding its production and dismutation. We discuss what is known about the human superoxide dismutase enzymes. We conclude that the balance between nitric oxide and superoxide is more important than the absolute levels of either alone.

Animals↗
PubMed1996

Central depressor action of nitric oxide is deficient in genetic hypertension.

Inhibition of NO synthase (NOS) in the central nervous system (CNS) causes a pressor response. This observation indicates that NO is normally produced at CNS site(s) where it has a tonic blood pressure lowering effect. The current study tests the hypothesis that a deficient NOS activity in the CNS may contribute to the pressure elevation in genetically hypertensive rats. NO administered intracerebroventricularly (ICV) caused a greater fall in mean arterial pressure (MAP; femoral artery) in hypertensive (SHRSP) than in normotensive (WKY) rats, -66.1 +/- 3.4 mm Hg v -23.7 +/- 3.9 mm Hg, respectively. Yet when endogenous NO was increased by stimulating NOS with ICV calcium, the depressor response was less in SHRSP than in WKY, 13.7 +/- 1.1 mm Hg v 26.7 +/- 1.9 mm Hg. Likewise, when NOS was blocked with N omega- nitro-L-arginine methyl ester (L-NAME), the resultant pressor response was less in SHRSP than in WKY, 13.8 +/- 1.1 mm Hg v 22.2 +/- 1.1 mm Hg. Blockade of the action of cGMP, a mediator of the action of NO, caused a pressor response of 6.0 +/- 2.8 mm Hg and 22.6 +/- 8.7 mm Hg (P < .01) in the hypertensive and normotensive rats, respectively. Electrolytic ablation of the anteroventral third cerebral ventricle (AV3V) did not alter blood pressure responses to NO or to agents that alter NOS activity. We conclude that a deficit in NOS activity in some other central cardiovascular regulatory area may contribute to the elevated arterial pressure of these genetically hypertensive rats.

Animals↗
PubMed1996

Nitric oxide and hypertension in 1995.

Insight is rapidly developing into the physiological production and function of nitric oxide. This small molecule has several physiological actions that oppose the pathogenesis of hypertension. Originating in the endothelium, it causes vascular smooth muscle relaxation, lowering blood pressure. In the central nervous system nitric oxide tonically depresses activity of the sympathetic nervous system, and in the kidney it regulates renin release and causes natriuresis. Nitric oxide may also contribute to the protective action of oestrogen.

Animals↗
PubMed1996

Vascular smooth muscle polyploidy and cardiac hypertrophy in genetic hypertension.

We studied the mechanisms responsible for vascular and cardiac hypertrophy in hypertension (pressure load and humoral and genetic factors) in two experimental approaches: (1) We carried out a cosegregation analysis to correlate cardiac and vascular hypertrophy with subphenotypes of blood pressure in an F2 generation of a cross between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats; (2) we treated 8-week-old SHRSP with perindopril, an angiotensin-converting enzyme inhibitor; losartan, an angiotensin type 1 receptor antagonist; or perindopril combined with a nitric oxide synthase inhibitor to investigate the relative contributions of blood pressure and angiotensin II to the pathogenesis of cardiac hypertrophy and vascular smooth muscle polyploidy. Vascular smooth muscle polyploidy was measured with flow cytometry DNA analysis. Cardiac hypertrophy was assessed by measuring the ratios of heart weight to body weight and left ventricle + septum weight to body weight. Blood pressure was measured with radiotelemetry in the F2 cosegregation experiment and with tail-cuff plethysmography in the pharmacological study. In the F2 rats, the best predictor of smooth muscle polyploidy by ANCOVA was systolic pressure (F=29.28, P < .0001). The ratio of left ventricle + septum weight to body weight had four major predictors: the male progenitor of the cross, sex, pulse pressure, and change in systolic pressure during salt (F=43.67, P < .0001; F=16.37, P < .0001; F=8.41, P=.0022; and F=12.39, P= .0003, respectively). The ratio of heart weight to body weight had similar predictors. In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with N(G)-nitro-L-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy. The prevention of cardiac hypertrophy was most marked in the SHRSP treated with perindopril plus N(G)-nitro-L-arginine methyl ester, despite blood pressure being higher in this group than in the two other treatment groups. We conclude that vascular and cardiac hypertrophy in this form of hypertension are regulated by different variables. However, suppression of the action of angiotensin II lessens hypertrophy of both types of muscle.

Angiotensin II↗
PubMed1995

Role of superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats.

We undertook these studies to determine whether a deficient nitric oxide production in genetically hypertensive rats could result from its being scavenged by an excess production of superoxide. In one study we used a porphyrinic microsensor to measure nitric oxide concentrations released by cultured endothelial cells from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). SHRSP cells released only about one third the concentration of nitric oxide as did WKY cells. Treatment of cells with superoxide dismutase increased nitric oxide release, demonstrating that normally nitric oxide is scavenged by endogenous superoxide. The increase in nitric oxide release in response to superoxide dismutase treatment was more than twice as great from SHRSP as from WKY cells, demonstrating the greater amount of superoxide in the hypertensive rats. A direct measure of superoxide with the use of lucigenin demonstrated the presence of 68.1 +/- 7.1 and 27.4 +/- 3.5 nmol/L of this anion in SHRSP and WKY endothelial cells, respectively. The presence of superoxide in the rat aorta was also estimated by quantification of its effect on carbachol relaxation. This relaxation was diminished when endogenous superoxide dismutase was blocked by diethyldithiocarbamic acid. This blockade reduced the relaxation by 51.2 +/- 5.2% in SHRSP aortas and by only 22.0 +/- 8.2% (P = .015) in WKY aortas. Data from these diverse systems are in agreement that superoxide production is excessive in SHRSP tissues. This excess superoxide, by scavenging endothelial nitric oxide, could contribute to the increased vascular smooth muscle contraction and hence to the elevated total peripheral resistance of these rats.

Animals↗
PubMed1994

Cobalt contraction of vascular smooth muscle is calcium dependent.

We examined the mechanism by which cobalt causes contraction of vascular smooth muscle (VSM), determining whether contractile response of VSM from normotensive and hypertensive rats differed. Contraction of rings of rat thoracic aorta from normotensive Wistar-Kyoto rats (WKY) and hypertensive spontaneously hypertensive stroke-prone rats (SHRSP) in response to addition of cobalt chloride to the muscle bath was recorded. Threshold contraction occurred at 3 microM; maximum contraction occurred at 100 microM. There was no difference between rings from WKY and SHRSP in sensitivity or maximum response to cobalt. No contractile response occurred when cobalt was added to a calcium-free physiologic salt solution (PSS) to which 1.0 mM EGTA had been added. When no EGTA was added to the PSS, cobalt caused a contraction 20% as great as that observed in calcium-containing physiologic salt solution, but this small contraction was eliminated after intracellular sequestration of calcium had been prevented by treatment of the rings with cyclopiazonic acid (3 x 10(-4) M). A concentration-dependent contraction occurred when calcium was added back to the bath in the presence of cobalt. The contraction in response to this addition of calcium did not differ between rings from WKY and SHRSP. Threshold concentrations of cobalt produced marked potentiations of contractile responses to either norepinephrine (NE) or KCl. We conclude that cobalt causes contraction by activating both voltage-sensitive and receptor-operated calcium channels in the plasma membrane. Cobalt also caused release of intracellularly sequestered calcium. There was no difference between the responses to cobalt of VSM from WKY and SHRSP.

Animals↗
PubMed1993

Lateral diffusion and fatty acid composition in vascular smooth muscle membrane from stroke-prone spontaneously hypertensive rats.

We measured membrane fluidity and fatty acid composition in cultured vascular smooth muscle cells from stroke-prone spontaneously hypertensive and Wistar-Kyoto normotensive rats. Membrane fluidity was measured as a lateral diffusion of 5 N (octadecanoyl) aminofluorescein using fluorescence microscopy and fluorescence recovery after photobleaching. Fatty acid composition of membrane fractions was measured using high performance liquid chromatography. Lateral diffusion was significantly lower (the membrane had lower fluidity) in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats as compared to those cells isolated from Wistar-Kyoto reference strain. The ratio of arachidonic acid to total fatty acids was 0.058 +/- 0.007 in the plasma membrane from stroke-prone spontaneously hypertensive rats and 0.036 +/- 0.005 in that from Wistar-Kyoto rats, P = .005. Similarly, the ratios of arachidonic to oleic acid and arachidonic to palmitic acid were significantly greater in cells from stroke-prone spontaneously hypertensive rats (P = .002 for difference in each ratio). These results show decreased lateral diffusion (decreased membrane fluidity) in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. This is associated with increased content of arachidonic acid, the major precursor of prostaglandins and other eicosanoids. We postulate that local changes in the unsaturated fatty acid composition related to arachidonic acid storage and release contribute to reduced membrane fluidity in stroke-prone spontaneously hypertensive rats.

Animals↗
PubMed1993

Membrane microviscosity does not correlate with blood pressure: a cosegregation study.

OBJECTIVE: To determine whether elevated microviscosity is associated with elevated arterial pressure in segregating (F2) hybrids produced by crossing stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. METHODS: SHRSP and WKY rats were obtained from the colony at the University of Heidelberg. F2 progeny were obtained by brother-sister mating of the F1 progeny of the cross between SHRSP and WKY rats. Membrane microviscosity (the inverse of fluidity) was measured as a fluorescence anisotropy of trimethylammonium diphenylhexatriene incubated with the erythrocyte membranes. The measurements were made using a luminescence spectrometer with computer-controlled excitation and emission polarizers. RESULTS: Membrane microviscosity was significantly greater (fluidity was lower) in erythrocyte membranes obtained from SHRSP than in those obtained from WKY rats. In the F2 cohort there were no significant correlations between membrane microviscosity and systolic blood pressure, diastolic blood pressure, salt-loaded systolic blood pressure or salt-loaded diastolic blood pressure. A similar lack of relationship between these parameters was shown in a subgroup analysis, in which males or females with a male WKY rat progenitor and males or females with a male SHRSP progenitor were analysed separately. CONCLUSIONS: Erythrocyte membrane microviscosity is elevated in SHRSP compared with WKY rats. In segregating F2 hybrid rats the membrane microviscosity trait does not correlate with blood pressure. These results eliminate the microviscosity trait as being directly related to the cause of genetic differences in blood pressure between WKY rats and SHRSP.

Animals↗
PubMed1991

Many membrane abnormalities in hypertension result from one primary defect.

Evidence has been presented that: 1.) Changes in lipid bilayer alter the function of integral membrane proteins. 2.) There is less calcium bound to the plasma membrane in hypertension. 3.) Structural and functional abnormalities of the lipid bilayer have been reported in genetic hypertension. We hypothesize that multiple abnormalities of membrane transport systems in hypertension are secondary to an inherent abnormality of the lipid bilayer in which these transport proteins reside.

Animals↗
PubMed1991

The primacy of membrane microviscosity in genetic hypertension.

Because of the known influence of the lipid bilayer on membrane transport systems, the characteristics of the bilayer from vascular smooth muscle and from platelets were studied in genetically hypertensive and in normotensive rats. Membrane microviscosity was measured by the degree of polarization of embedded fluorophores. Both the core of the bilayer in which diphenylhexatriene (DPH) was embedded and the surface in which the trimethyl-ammonium derivative of DPH (TMA-DPH) was embedded evidence a greater microviscosity (less fluid) in the hypertensive than in the normotensive rat. We had previously observed that monovalent cation fluxes were elevated in hypertension. We now observe that an increase in calcium concentration reverses both the elevated microviscosity and the increased cation fluxes. Conversely an increased incorporation of cholesterol in the membrane increases both the microviscosity and the cation fluxes. We hypothesize that the greater microviscosity of the lipid bilayer in hypertension constitutes a generalized defect of the matrix in which the transport proteins function. We further hypothesize that this defect is responsible for the multiple abnormalities of membrane transport systems and the increase in vascular reactivity that have been described in genetic hypertension.

Animals↗
PubMed1991

Endothelium in functional aortic changes of coarctation hypertension.

Eleven coarctation hypertensive (CH), twelve sham control (C), and seven one-kidney, one-clip (1K,1C) rats were used to examine the role of pressure and the endothelium in vascular sensitivity changes to acetylcholine (ACh), serotonin (5-HT), and norepinephrine (NE) in chronic arterial hypertension. Terminal mean carotid artery pressures were CH = 156 +/- 5 mmHg, C = 99 +/- 3 mmHg, and 1K,1C = 159 +/- 5 mmHg. Femoral artery pressures were CH = 100 +/- 3 mmHg, C = 98 +/- 4 mmHg, and 1K,1C = 154 +/- 4 mmHg, respectively. Isometric tension recordings were made from helically cut strips of thoracic and abdominal aortas, with and without functional endothelium, from the three groups of rats. Sensitivity to relaxation by acetylcholine, expressed as -log of 50% effective dose, was significantly depressed in thoracic aortas from CH and 1K,1C rats and abdominal aortas from 1K,1C rats but not from abdominal aortas of CH rats. A similar relationship between the groups was seen for 5-HT contractions. Sensitivity to NE was enhanced in thoracic and abdominal aortas of hypertensive rats. Inactivation of aortic endothelia abolished ACh responses, did not alter 5-HT relationships between the three groups, and abolished the differences in sensitivity to NE in thoracic aortas. The data suggest that pressure and the endothelium may play a role in vascular sensitivity changes in hypertension.

Acetylcholine↗
PubMed1991

Contraction and relaxation of rat aorta in response to ATP.

Vascular responses to ATP were studied in aortic rings isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Low concentrations of ATP (10 nM to 10 microM) caused relaxation and high concentrations (0.1 mM to 10 mM) caused contraction. Both of these responses were accentuated by factors released from the endothelium. The endothelium-derived relaxing factor (EDRF) was blocked by NG-monomethyl-L-arginine (L-NMMA). This is the first time that it has been reported that ATP causes the release of an endothelium-derived contracting factor (EDCF). Its release was diminished but not completely blocked by cyclooxygenase inhibitors. Assays of muscle bath prostanoid composition indicated that ATP stimulation caused the release of prostaglandins I2 and E2 and thromboxane A2 from intact aortic rings. Evidence is presented that neither endothelin nor superoxide anion contributed to the EDCF. No difference was observed between WKY and SHRSP with regard to either the endothelial contributions to the response, or the direct action on vascular smooth muscle of ATP. High concentrations of ATP achieved intravascularly in hypoxia may cause vasospasm by release of endothelial prostanoids.

Adenosine Triphosphate↗