Biomedical subjects

R J Roman

Publications and source records attributed to R J Roman.

At least 37 records · Page 2Linked to original sources

PubMed2000

Impairment of flow-induced dilation of skeletal muscle arterioles with elevated oxygen in normotensive and hypertensive rats.

The effects of elevated PO(2) on flow-induced dilation of in situ skeletal muscle arterioles was assessed in cremaster muscle preparations from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Blood flow increases in selected arterioles were initiated by occlusion of a parallel daughter branch from a parent arteriole. Changes in the diameter of the perfused arteriole were measured with a video micrometer and erythrocyte velocity was measured using optical Doppler velocimetry. Superfusate PO(2) was controlled by changing the O(2) concentration (0% O(2) or 21% O(2)) of the equilibration gas mixture. The increase in arteriolar diameter during occlusion was reduced in SHR compared to WKY rats, resulting in an elevated wall shear rate in SHR. Elevated PO(2) decreased flow-induced dilation in both groups and increased wall shear rate during parallel occlusion. An inhibitor of the formation of 20-HETE via cytochrome P450-4A enzymes (P450), dibromododecenyl methylsulfimide, minimized O(2)-induced constriction of arterioles and prevented the O(2)-induced decrease in flow-induced dilation and the increase in wall shear rate in both SHR and WKY rats. These results suggest that: (1) flow-induced dilation of in situ skeletal muscle arterioles is impaired in SHR compared to WKY, (2) elevated O(2) compromises flow-induced dilation in both groups, (3) 20-HETE contributes to both the O(2)-induced increases in resting tone and the reduced flow-induced dilation of cremasteric arterioles with elevated PO(2).

Amides↗

PubMed2000

Molecular mechanisms controlling nutritive blood flow: role of cytochrome P450 enzymes.

This short review summarizes the potential role of cytochrome P450 (P450) in regulating blood flow in the brain tissue and in the skeletal muscle. We provide data showing that pressure-induced myogenic activity in the brain is largely responsible for autoregulation of CBF. This myogenic response to pressure is maintained, in part, by 20-HETE formation in arterial muscle cells through a P450 omega-hydroxylase coded for by a P450 4A cDNA. Autoregulation of CBF is a hallmark of the cerebral circulation and provides adequate nutritive blood flow despite large fluctuations in arterial pressure. Given the importance of oxidative metabolism in the brain, support of neuronal activity is mediated by functional hyperaemia to active neurones providing adequate delivery of oxidative substrate. We provide data demonstrating that this functional hyperaemia in the brain is regulated by astrocytes which sense neural activity and release dilator metabolites which shunt blood flow to active neurones. One of the metabolites released by astrocytes in this regard are epoxygenated products of arachidonic acid (AA) formed by P450 enzymes. These AA metabolites of P450 enzymes are epoxyeicosatrienoic acid (EETs). One of these P450 enzymes is coded by a 2C11 cDNA present in astrocytes. Furthermore, astrocytes are capable of inducing capillary angiogenesis which appears to be mediated, in part, by P450-derived EETs.

Animals↗

PubMed2000

Renal and cardiovascular actions of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids.

1. Arachidonic acid (AA) is metabolized by cytochrome P450 (CYP)-dependent pathways to epoxyeicosatrienoic acids (EET) and 20-hydroxyeicosatetraenoic acid (20-HETE) in the kidney and the peripheral vasculature. 2. The present short review summarizes the renal and cardiovascular actions of these important mediators. 3. Epoxyeicosatrienoic acids are vasodilators produced by the endothelium that hyperpolarize vascular smooth muscle (VSM) cells by opening Ca2+-activated K+ (KCa) channels. 20-Hydroxyeicosatetraenoic acid is a vasoconstrictor that inhibits the opening of KCa channels in VSM cells. Cytochrome P450 4A inhibitors block the myogenic response of small arterioles to elevations in transmural pressure and autoregulation of renal and cerebral blood flow in vivo. Cytochrome P450 4A blockers also attenuate the vasoconstrictor response to elevations in tissue PO2, suggesting that this system may serve as a vascular oxygen sensor. Nitric oxide and carbon monoxide inhibit the formation of 20-HETE and a fall in 20-HETE levels contributes to the activation of KCa channels in VSM cells and the vasodilator response to these gaseous mediators. 20-Hydroxyeicosatetraenoic acid also mediates the inhibitory actions of peptide hormones on sodium transport in the kidney and the mitogenic effects of growth factors in VSM and mesangial cells. A deficiency in the renal production of 20-HETE is associated with the development of hypertension in Dahl salt-sensitive rats. 4. In summary, the available evidence indicates that CYP metabolites of AA play a central role in the regulation of renal, pulmonary and vascular function and that abnormalities in this system may contribute to the pathogenesis of cardiovascular diseases.

Animals↗

PubMed2000

Endotoxin augments cerebral hyperemic response to halothane by inducing nitric oxide synthase and cyclooxygenase.

We examined the cerebral hyperemic response to halothane after treatment with bacterial lipopolysaccharide (LPS). To determine the involvement of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2), we tested whether the effect of LPS on halothane-induced hyperemia was altered by pretreatment with the selective iNOS inhibitor, aminoguanidine (100 mg/kg), COX-2 inhibitor, NS-398 (5 mg/kg), or enzyme expression inhibitor, dexamethasone (4 mg/kg). Further, we examined whether the administration of a nitric oxide donor, diethylamine NONOate, would change the cerebral hyperemic response of halothane. Sprague-Dawley rats were anesthetized with 0.5 minimum alveolar anesthetic concentration of halothane and artificially ventilated. Regional cerebrocortical blood flow (rCBF) was assessed by laser-Doppler flowmetry. LPS (1 mg/kg) was administered intracerebroventricularly; artificial cerebrospinal fluid was used in controls. Four hours after LPS infusion, iNOS and COX-2 messenger ribonucleic acid (mRNA) levels (reverse transcription-polymerase chain reaction) and enzyme activities (arginine-citrulline conversion and prostaglandin E(2) enzyme immunoassay) were significantly increased. LPS enhanced halothane-induced 3.9 and 1.6-fold increases in rCBF at 1.0 and 1.5 minimum alveolar concentration, respectively. Co-treatment with NS-398 attenuated, but aminoguanidine or dexamethasone abolished the effect of LPS on halothane-induced rCBF increase. Diethylamine NONOate mimicked the enhanced rCBF response to halothane. These results suggest that LPS augmented halothane-induced cerebrocortical hyperemia by induction of iNOS and COX-2.

Anesthetics, Inhalation↗

PubMed2000

Role of cGMP versus 20-HETE in the vasodilator response to nitric oxide in rat cerebral arteries.

This study examined the response to nitric oxide (NO) in rat middle cerebral arteries (MCA). NO donors increased the activity of a 205-pS K(+) channel recorded from vascular smooth muscle (VSM) cells isolated from MCA 10-fold. Blockade of guanylyl cyclase activity with 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ, 10(-5) M) did not alter the effect of NO on this channel. In contrast, adding 20-hydroxyeicosatetraenoic acid (20-HETE) to the bath (10(-7) M) abolished the response to NO. NO donors also increased the diameter of serotonin-preconstricted MCA to 85% of control. Blockade of K(+) channels with iberiotoxin or a high-K(+) medium reduced this response by 50%. ODQ (10(-5) M) reduced this response by 47 +/- 3%, whereas preventing the fall of 20-HETE levels reduced the response by 59 +/- 2% (n = 5). Blockade of both pathways eliminated the response to NO donors. These results indicate that activation of K(+) channels contributes 50% to vasodilator response to NO in rat MCA. This is mediated by a fall in 20-HETE levels rather than a rise in cGMP levels or a direct effect of NO.

Animals↗

PubMed2000

Fluorescent HPLC assay for 20-HETE and other P-450 metabolites of arachidonic acid.

This study describes a fluorescent HPLC assay for measuring 20-hydroxyeicosatetraenoic acid (20-HETE) and other cytochrome P-450 metabolites of arachidonic acid in urine, tissue, and interstitial fluid. An internal standard, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, was added to samples, and the lipids were extracted and labeled with 2-(2,3-naphthalimino)ethyl trifluoromethanesulfonate. P-450 metabolites were separated on a C18 reverse-phase HPLC column. Coelution and gas chromatography-mass spectrometry studies confirmed the identity of the 20-HETE peak. The 20-HETE peak can be separated from those for dihydroxyeicosatrienoic acids, other HETEs, and epoxyeicosatrienoic acids. Known amounts of 20-HETE were used to generate a standard curve (range 1-10 ng, r(2) = 0.98). Recovery of 20-HETE from urine averaged 95%, and the intra-assay variation was <5%. Levels of 20-HETE were measured in 100 microliter of urine and renal interstitial fluid or 0.1 mg of renal tissue. The assay was evaluated by studying the effects of 1-aminobenzotriazole (ABT) on the excretion of 20-HETE in rats. ABT reduced excretion of 20-HETE by >65% and inhibited the formation of 20-HETE by renal microsomes. The availability of this assay should facilitate work in this field.

Animals↗

PubMed2000

Hypoxic pulmonary vasoconstriction is modified by P-450 metabolites.

20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 4A (CYP4A) metabolite of arachidonic acid (AA) in human and rabbit lung microsomes and is a dilator of isolated human pulmonary arteries (PA). However, little is known regarding the contribution of P-450 metabolites to pulmonary vascular tone. We examined 1) the effect of two mechanistically distinct omega- and omega1-hydroxylase inhibitors on perfusion pressures in isolated rabbit lungs ventilated with normoxic or hypoxic gases, 2) changes in rabbit PA ring tone elicited by 20-HETE or omega- and omega1-hydroxylase inhibitors, and 3) expression of CYP4A protein in lung tissue. A modest increase in perfusion pressure (55 +/- 11% above normoxic conditions) was observed in isolated perfused lungs during ventilation with hypoxic gas (FI(O(2)) = 0.05). Inhibitors of 20-HETE synthesis, 17-oxydecanoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), increased baseline perfusion pressure above that of vehicle and amplified hypoxia-induced increases in perfusion pressures by 92 +/- 11% and 105 +/- 11% over baseline pressures, respectively. 20-HETE relaxed phenylephrine (PE)-constricted PA rings. Treatment with 17-ODYA enhanced PE-induced contraction of PA rings, consistent with inhibition of a product that promotes arterial relaxation, whereas 6-(20-propargyloxyphenyl)hexanoic acid (PPOH), an epoxygenase inhibitor, blunted contraction to PE. Conversion of AA into 20-HETE was blocked by 17-ODYA, DDMS, and hypoxia. CYP4A immunospecific protein confirms expression of CYP4A in male rabbit lung tissue. Our data suggest that endogenously produced 20-HETE could modify rabbit pulmonary vascular tone, particularly under hypoxic conditions.

Amides↗

PubMed2000

Microvascular flow and tissue PO(2) in skeletal muscle of chronic reduced renal mass hypertensive rats.

This study determined whether arteriolar blood flow, capillary red blood cell (RBC) velocity, capillary hematocrit (Hct(cap)), and tissue PO(2) are altered in cremaster muscles of rats with chronic reduced renal mass hypertension (RRM-HT) relative to normotensive rats on high- or low-salt (NT-HS vs. NT-LS) diet. The blood flow in first- through third-order arterioles was not different between NT and HT rats, either at rest or during maximal relaxation of the vessels with 10(-4) M adenosine. Capillary RBC velocity was similar between the groups at rest but was elevated in RRM-HT and NT-HS rats during adenosine superfusion. Hct(cap) was reduced at rest in RRM-HT and NT-HS rats compared with NT-LS and was reduced in RRM-HT rats during adenosine-induced dilation. Tissue PO(2) was reduced in RRM-HT and NT-HS rats compared with NT-LS rats during control conditions and was lower in RRM-HT than in NT-LS rats during adenosine-induced dilation. These results indicate that both RRM-HT and chronic exposure of normotensive rats to a high-salt diet lead to reduced tissue oxygenation, despite the maintenance of normal arteriolar blood flow.

Adenosine↗

PubMed2000

Epoxyeicosatrienoic acids constrict isolated pressurized rabbit pulmonary arteries.

Little information is available regarding the vasoactive effects of epoxyeicosatrienoic acids (EETs) in the lung. We demonstrate that 5, 6-, 8,9-, 11,12-, and 14,15-EETs contract pressurized rabbit pulmonary arteries in a concentration-dependent manner. Constriction to 5,6-EET methyl ester or 14,15-EET is blocked by indomethacin or ibuprofen (10(-5) M), SQ-29548, endothelial denuding, or submaximal preconstriction with the thromboxane mimetic U-46619. Constriction of pulmonary artery rings to phenylephrine is blunted by treatment with the epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide. Pulmonary arteries and peripheral lung microsomes metabolize arachidonate to products that comigrate on reverse-phrase HPLC with authentic regioisomers of 5,6-, 8,9-, 11,12-, and 14,15-EETs, but no cyclooxygenase products of EETs could be demonstrated. Proteins of the CYP2B, CYP2E, CYP2J, CYP1A, and CYP2C subfamilies are present in pulmonary artery and peripheral lung microsomes. Constriction of isolated rabbit pulmonary arteries to EETs is nonregioselective and depends on intact endothelium and cyclooxygenase, consistent with the formation of a pressor prostanoid compound. These data raise the possibility that EETs may contribute to regulation of pulmonary vascular tone.

8,11,14-Eicosatrienoic Acid↗

PubMed2000

Glomerular hyperfiltration in hypertensive African Americans.

The incidence of end-stage renal disease attributable to hypertension is 5-fold greater in African Americans than in whites. To determine whether glomerular hyperfiltration is an antecedent to renal failure, we compared responses of renal blood flow and glomerular filtration rate to graded infusions of norepinephrine (0. 01, 0.025, and 0.05 microg. kg(-1). min(-1) for 30 minutes each) in 29 African Americans and 33 age-matched French Canadian whites with essential hypertension. Renal blood flow and glomerular filtration rate were measured by using a constant-infusion technique of PAH and inulin, respectively. Studies were conducted on an inpatient clinical research center, and antihypertensive medications had been discontinued for at least 1 week. Based on 24-hour blood pressure monitoring, nighttime blood pressures decreased (P<0.01) in the French Canadians but not in the African Americans. Baseline renal blood flow was higher (P<0.05) in the African Americans (1310+/-127 mL. min(-1) per 1.73 m(2)) than in the French Canadians (1024+/-42 mL. min(-1) per 1.73 m(2)); baseline glomerular filtration rate was also higher (P<0.01) in the African Americans (140+/-4 versus 121+/-4 mL. min(-1) per 1.73 m(2)). In response to norepinephrine-induced blood pressure increases, renal blood flow was autoregulated and did not change in either patient group. In the African Americans, glomerular filtration rate increased (P<0.01) to 167 mL. min(-1) per 1.73 m(2) during the first norepinephrine infusion, without subsequent change. In contrast, glomerular filtration rate did not change with norepinephrine-induced increases of blood pressure in the French Canadians. In the African Americans, the elevation of baseline glomerular filtration rate, with a further increase in response to norepinephrine, may be indicative of glomerular hyperfiltration. Glomerular hyperfiltration and lack of nocturnal blood pressure decline may contribute to the higher incidence of end-stage renal disease in hypertensive African Americans.

Black People↗

PubMed1999

20-Hydroxyeicosatetraenoic acid and renal function in Lyon hypertensive rats.

To evaluate the contribution of cytochrome P450 (CYP450) metabolites of arachidonic acid in the increased renal vascular resistance and blunted pressure-natriuresis response exhibited by Lyon hypertensive (LH) rats, the effects of an intrarenal infusion of 17-octadecynoic acid (3 microM), an inhibitor of the formation of epoxyeicosatrienoic and 20-hydroxyeicosatetraenoic acids, were compared in 8-week-old LH and low blood pressure (LL) control rats. 17-Octadecynoic acid failed to affect renal function in LL rats. In contrast, it reduced renal vascular resistance and shifted the pressure-natriuresis relationship to lower pressures in LH rats. Blockade of thromboxane-endoperoxide (TP) receptors with GR 32191B prevented the renal vasodilator response to 17-octadecynoic acid but not its natriuretic action. Miconazole (1 microM), an inhibitor of epoxygenase activity, had no effect on renal function in LH rats. These results indicate that CYP450 metabolites of arachidonic acid, likely 20-hydroxyeicosatetraenoic acid, contribute to the resetting of the pressure-natriuresis relation in LH rats and that the renal vasoconstrictor effects of 20-hydroxyeicosatetraenoic acid in LH rats may be related to activation of TP receptors.

Animals↗

PubMed1999

Inflammatory modulation of calcium-activated potassium channels in canine colonic circular smooth muscle cells.

BACKGROUND & AIMS: The characteristics of colonic circular smooth muscle slow waves are altered during inflammation. The aim of this study was to examine whether inflammation modulates the open-state probability of Ca2+-activated K+ (KCa) channels in these cells to contribute to these alterations. METHODS: The experiments were performed on freshly dissociated single smooth muscle cells from the canine colon using standard patch clamp methods. Inflammation was induced by mucosal exposure to ethanol and acetic acid. RESULTS: Inflammation decreased the open-state probability of large-conductance KCa (BK) channels in the cell-attached and excised inside-out configurations. The voltage sensitivity of the channels was also reduced during inflammation. Inflammation had no significant effect on the large, medium, and small conductances or the unitary current levels of channel openings. However, it decreased the maximum number of simultaneous channel openings. The channels were Ca2+-dependent and were blocked by tetraethylammonium and charybdotoxin in normal and inflamed cells. CONCLUSIONS: Inflammation decreases the open-state probability of BK channels. This may partially reverse the decrease in duration and amplitude of slow waves and depolarization of membrane potential seen in inflammation.

Animals↗

PubMed1999

Cytochrome P-450 arachidonate metabolite inhibition improves renal function in Lyon hypertensive rats.

The present study evaluated the effects of miconazole, a selective inhibitor of epoxygenase activity, on renal hemodynamics and the pressure-natriuresis response of saline-drinking, uninephrectomized Lyon hypertensive (LH) and Lyon low blood pressure (LL) rats. Infusion of miconazole (final concentration, 1 micromol/L) into the renal artery had no effect on the renal function of LL rats over a range of renal perfusion pressures (RPP) from 100 to 140 mm Hg. In contrast, miconazole lowered renal vascular resistance (RVR, 17.9 +/- 1.1 v 26.3 +/- 1.5 mm Hg/mL/min/g, P < .01) and increased urinary sodium excretion (6.4 +/- 1.2 v 4.2 +/- 0.8 micromol/min/g, P < .05) in LH rats at a RPP of 140 mm Hg. To determine whether the effects of epoxyeicosatrienoic acids were dependent on activation of the thromboxane A2-prostaglandin H2 (TP) receptor, we studied the effects of a TP receptor antagonist, GR 32191B (0.1 mg/kg/min), on the renal response to an infusion of miconazole into the renal artery in LH rats. GR 32191B decreased basal RVR and prevented the dilation induced by miconazole. It did not, however, alter its natriuretic effect. The renal metabolism of arachidonic acid was also compared in LH and LL rats. The production of epoxygenase metabolites was 25% lower in microsomes prepared from the renal cortex of LH versus LL rats. Miconazole (1 micromol/L) reduced epoxygenase activity similarly, by approximately 60%, in both strains. These results suggest that endogenously formed P450 metabolites of arachidonic acid may serve as a substrate for the formation of vasoconstrictor endoperoxides that interact with TP receptors in LH rats and contribute to the enhanced renal vascular tone but not the blunted pressure-natriuresis response.

Animals↗

PubMed1999

Cytochrome P-450 omega-hydroxylase senses O2 in hamster muscle, but not cheek pouch epithelium, microcirculation.

The goal of this study was to investigate the role of cytochrome P-450 omega-hydroxylase in mediating O2-induced constriction of arterioles in the microcirculation of the hamster. Male Golden hamsters were anesthetized with pentobarbital sodium, and the cremaster muscle or cheek pouch was prepared for observation by intravital microscopy. Arteriolar diameters were measured during elevations of superfusate PO2 from approximately 5 to 150 mmHg. Arteriolar responses to elevated PO2 were determined in the cremaster muscle, in the retractor muscle where it inserts on the cheek pouch, and in the epithelial portion of the cheek pouch. Elevation of superfusion solution PO2 caused a vigorous constriction of arterioles in the cremaster and retractor muscles and in the epithelial portion of the cheek pouch. Superfusion with 10 microM 17-octadecynoic acid, a suicide substrate inhibitor of cytochrome P-450 omega-hydroxylase, and intravenous infusion of N-methylsulfonyl-12,12-dibromododec-11-enamide, a mechanistically different and highly selective inhibitor of cytochrome P-450 omega-hydroxylase, caused a significant reduction in the magnitude of O2-induced constriction of arterioles in the cremaster and retractor muscles. However, arteriolar constriction in response to elevated PO2 was unaffected by 17-octadecynoic acid or N-methylsulfonyl-12,12-dibromododec-11-enamide in the epithelial portion of the cheek pouch. These data confirm that there are regional differences in the mechanism of action of O2 on the microcirculation and indicate that cytochrome P-450 omega-hydroxylase senses O2 in the microcirculation of hamster skeletal muscle, but not in the cheek pouch epithelium.

Amides↗

PubMed1999

Electrical and mechanical responses of rat middle cerebral arteries to reduced PO2 and prostacyclin.

Isolated rat middle cerebral arteries were perfused and superfused with physiological salt solution equilibrated with a control (approximately 140 mmHg) or reduced (approximately 35-40 mmHg) PO2. In other experiments, cerebral arteries were isolated and prostacyclin release was determined by radioimmunoassay for 6-ketoprostaglandin F1alpha. Equilibration of the vessels with reduced PO2 (35 mmHg) solution caused a significant increase in prostacyclin release relative to control PO2 (140 mmHg) conditions. Exposure of middle cerebral arteries to reduced PO2 caused vascular smooth muscle (VSM) hyperpolarization and vessel relaxation, which could be blocked by 1 microM glibenclamide, an inhibitor of the ATP-sensitive K+ channel, but not by 1 mM tetraethylammonium (TEA), an inhibitor of the Ca2+-activated K+ channel. Glibenclamide also inhibited VSM hyperpolarization and vasodilation in response to the stable prostacyclin analog iloprost, but TEA did not affect iloprost-induced dilation of the vessel. Endothelial removal eliminated the electrical and mechanical responses of the arteries to reduced PO2, but vessel responses to iloprost were similar to those of intact vessels. The results of this study are consistent with the hypothesis that hypoxic dilation of rat middle cerebral arteries is due to VSM hyperpolarization mediated by prostacyclin-induced activation of glibenclamide-sensitive K+ channels.

Animals↗

PubMed1999

Impaired autoregulation of renal blood flow in the fawn-hooded rat.

The responses to changes in renal perfusion pressure (RPP) were compared in 12-wk-old fawn-hooded hypertensive (FHH), fawn-hooded low blood pressure (FHL), and August Copenhagen Irish (ACI) rats to determine whether autoregulation of renal blood flow (RBF) is altered in the FHH rat. Mean arterial pressure was significantly higher in conscious, chronically instrumented FHH rats than in FHL rats (121 +/- 4 vs. 109 +/- 6 mmHg). Baseline arterial pressures measured in ketamine-Inactin-anesthetized rats averaged 147 +/- 2 mmHg (n = 9) in FHH, 132 +/- 2 mmHg (n = 10) in FHL, and 123 +/- 4 mmHg (n = 9) in ACI rats. Baseline RBF was significantly higher in FHH than in FHL and ACI rats and averaged 9.6 +/- 0.7, 7.4 +/- 0.5, and 7.8 +/- 0.9 ml. min-1. g kidney wt-1, respectively. RBF was autoregulated in ACI and FHL but not in FHH rats. Autoregulatory indexes in the range of RPPs from 100 to 150 mmHg averaged 0.96 +/- 0.12 in FHH vs. 0.42 +/- 0.04 in FHL and 0.30 +/- 0.02 in ACI rats. Glomerular filtration rate was 20-30% higher in FHH than in FHL and ACI rats. Elevations in RPP from 100 to 150 mmHg increased urinary protein excretion in FHH rats from 27 +/- 2 to 87 +/- 3 microg/min, whereas it was not significantly altered in FHL or ACI rats. The percentage of glomeruli exhibiting histological evidence of injury was not significantly different in the three strains of rats. These results indicate that autoregulation of RBF is impaired in FHH rats before the development of glomerulosclerosis and suggest that an abnormality in the control of renal vascular resistance may contribute to the development of proteinuria and renal failure in this strain of rats.

Animals↗

PubMed1999

Altered renal hemodynamics and impaired myogenic responses in the fawn-hooded rat.

The present study examined whether an abnormality in the myogenic response of renal arterioles that impairs autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) contributes to the development of renal damage in fawn-hooded hypertensive (FHH) rats. Autoregulation of whole kidney, cortical, and medullary blood flow and PGC were compared in young (12 wk old) FHH and fawn-hooded low blood pressure (FHL) rats in volume-replete and volume-expanded conditions. Baseline RBF, cortical and medullary blood flow, and PGC were significantly greater in FHH than in FHL rats. Autoregulation of renal and cortical blood flow was significantly impaired in FHH rats compared with results obtained in FHL rats. Myogenically mediated autoregulation of PGC was significantly greater in FHL than in FHH rats. PGC rose from 46 +/- 1 to 71 +/- 2 mmHg in response to an increase in renal perfusion pressure from 100 to 150 mmHg in FHH rats, whereas it only increased from 39 +/- 2 to 53 +/- 1 mmHg in FHL rats. Isolated perfused renal interlobular arteries from FHL rats constricted by 10% in response to elevations in transmural pressure from 70 to 120 mmHg. In contrast, the diameter of vessels from FHH rats increased by 15%. These results indicate that the myogenic response of small renal arteries is altered in FHH rats, and this contributes to an impaired autoregulation of renal blood flow and elevations in PGC in this strain.

Animals↗

PubMed1999

Regulation of P-450 4A activity in the glomerulus of the rat.

We recently reported that an enzyme of the cytochrome P-450 4A family is expressed in the glomerulus, but there is no evidence that 20-hydroxyeicosatetraenoic acid (20-HETE) can be produced by this tissue. The purpose of present study was to determine whether glomeruli isolated from the kidney of rats can produce 20-HETE and whether the production of this metabolite is regulated by nitric oxide (NO) and dietary salt intake. Isolated glomeruli produced 20-HETE, dihydroxyeicosatrienoic acids, and 12-hydroxyeicosatetraenoic acid (4.13 +/- 0.38, 4.20 +/- 0.38, and 2. 10 +/- 0.20 pmol. min-1. mg protein-1, respectively) when incubated with arachidonic acid (10 microM). The formation of 20-HETE was dependent on the availability of NADPH and the PO2 of the incubation medium. The formation of 20-HETE was inhibited by NO donors in a concentration-dependent manner. The production of 20-HETE was greater in glomeruli isolated from the kidneys of rats fed a low-salt diet than in kidneys of rats fed a high-salt diet (5.67 +/- 0.32 vs. 2.83 +/- 0.32 pmol. min-1. mg protein-1). Immunoblot experiments indicated that the expression of P-450 4A protein in glomeruli from the kidneys of rats fed a low-salt diet was sixfold higher than in kidneys of rats fed a high-salt diet. These results indicate that arachidonic acid is primarily metabolized to 20-HETE and dihydroxyeicosatrienoic acids in glomeruli and that glomerular P-450 activity is modulated by NO and dietary salt intake.

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