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G Kaley

Publications and source records attributed to G Kaley.

At least 37 records · Page 2Linked to original sources
PubMed1999

Nitric oxide modulates mitochondrial respiration in failing human heart.

Background-Our objective for this study was to investigate whether nitric oxide (NO) modulates tissue respiration in the failing human myocardium. Methods and Results-Left ventricular free wall and right ventricular tissue samples were taken from 14 failing explanted human hearts at the time of transplantation. Tissue oxygen consumption was measured with a Clark-type oxygen electrode in an airtight stirred bath containing Krebs solution buffered with HEPES at 37 degrees C (pH 7.4). Rate of decrease in oxygen concentration was expressed as a percentage of the baseline, and results of the highest dose are indicated. Bradykinin (10(-4) mol/L, -21+/-5%), amlodipine (10(-5) mol/L, -14+/-5%), the ACE inhibitor ramiprilat (10(-4) mol/L, -21+/-2%), and the neutral endopeptidase inhibitor thiorphan (10(-4) mol/L, -16+/-5%) all caused concentration-dependent decreases in tissue oxygen consumption. Responses to bradykinin (-2+/-6%), amlodipine (-2+/-4%), ramiprilat (-5+/-6%), and thiorphan (-4+/-7%) were significantly attenuated after NO synthase blockade with N-nitro-L-arginine methyl ester (10(-4) mol/L; all P<0.05). NO-releasing compounds S-nitroso-N-acetyl-penicillamine (10(-4) mol/L, -34+/-5%) and nitroglycerin (10(-4) mol/L, -21+/-5%), also decreased tissue oxygen consumption in a concentration-dependent manner. However, the reduction in tissue oxygen consumption in response to S-nitroso-N-acetyl-penicillamine (-35+/-7%) or nitroglycerin (-16+/-5%) was not significantly affected by N-nitro-L-arginine methyl ester. Conclusions-These results indicate that the modulation of oxygen consumption by both endogenous and exogenous NO is preserved in the failing human myocardium and that the inhibition of kinin degradation plays an important role in the regulation of mitochondrial respiration.

Amlodipine↗
PubMed1999

Amlodipine promotes kinin-mediated nitric oxide production in coronary microvessels of failing human hearts.

Recently, we found that amlodipine can release nitric oxide (NO) from canine coronary microvessels, which raises the question of whether amlodipine can also promote coronary NO production in failing human hearts. The goal of this study was to define the effect of amlodipine on NO production in failing human hearts and to determine the role of kinins in the control of NO production induced by amlodipine. Six explanted human hearts with end-stage heart failure were obtained immediately at transplant surgery. Coronary microvessels were isolated as previously described, and nitrite, the stable metabolite of NO in aqueous solution, was measured using the Griess Reaction. Amlodipine (10(-10) to 10(-5) mol/L) significantly increased nitrite production in coronary microvessels in a dose-dependent manner. The increase in nitrite in response to the highest dose of amlodipine (79%) was similar in magnitude to either that of the angiotensin-converting enzyme inhibitor ramiprilat (74%) or the neutral endopeptidase inhibitors phosphoramidon (61%) and thiorphan (72%). Interestingly, the increase in nitrite production induced by amlodipine was entirely abolished by N(omega)-nitro-L-arginine methyl ester and also HOE-140 (a bradykinin-2 antagonist) and dichloroisocoumarin (a serine protease inhibitor that blocks kallikrein activity). These results indicate that amlodipine can promote coronary NO production in failing human hearts and that this effect is dependent on a kinin-mediated mechanism.

Amlodipine↗
PubMed1999

Enhanced release of prostaglandins contributes to flow-induced arteriolar dilation in eNOS knockout mice.

Nitric oxide and prostaglandins were shown to contribute to the endothelial mediation of flow-induced dilation of skeletal muscle arterioles of rats. Thus, we hypothesized that flow-induced dilation and its mediation are altered in gracilis muscle arterioles of mice deficient in the gene for endothelial nitric oxide synthase (eNOS-KO) compared with control wild-type (WT) mice. Gracilis muscle arterioles ( approximately 80 micrometer) of male mice were isolated, then cannulated and pressurized in a vessel chamber. The increases in diameter elicited by increases in perfusate flow from 0 to 10 microq/min were similar in arterioles from eNOS-KO (n=28) and WT (n=22) mice ( approximately 20 micrometer at 10 microL/min flow). Removal of the endothelium eliminated flow-induced dilations in vessels of both strains of mice. N(omega)-nitro-L-arginine (L-NNA, 10(-4) mol/L) significantly inhibited flow-induced dilation in arterioles of WT mice by approximately 51% but had no effect on responses of arterioles from eNOS-KO mice. Indomethacin (INDO, 10(-5) mol/L) inhibited flow-induced dilation of WT mice by approximately 49%, whereas it completely abolished this response in arterioles of eNOS-KO mice. Simultaneous administration of INDO and L-NNA eliminated flow-induced responses in arterioles of WT mice. Dilations to carbaprostacyclin were similar at concentrations of 10(-8) and 3x10(-8) mol/L but decreased significantly at 10(-7) mol/L in arterioles of eNOS-KO compared with those of WT mice. These findings demonstrate that, despite the lack of nitric oxide mediation, flow-induced dilation is close to normal in arterioles of eNOS-KO mice because of an enhanced release of endothelial dilator prostaglandins and suggest that this vascular adaptation may contribute to the regulation of peripheral resistance in eNOS-KO mice.

Animals↗
PubMed1999

Endogenous endothelial nitric oxide synthase-derived nitric oxide is a physiological regulator of myocardial oxygen consumption.

Our objective was to determine the precise role of endothelial nitric oxide synthase (eNOS) as a modulator of cardiac O2 consumption and to further examine the role of nitric oxide (NO) in the control of mitochondrial respiration. Left ventricle O2 consumption in mice with defects in the expression of eNOS [eNOS (-/-)] and inducible NOS [iNOS (-/-)] was measured with a Clark-type O2 electrode. The rate of decreases in O2 concentration was expressed as a percentage of the baseline. Baseline O2 consumption was not significantly different between groups of mice. Bradykinin (10(-4) mol/L) induced significant decreases in O2 consumption in tissues taken from iNOS (-/-) (-28+/-4%), wild-type eNOS (+/+) (-22+/-4%), and heterozygous eNOS(+/-) (-22+/-5%) but not homozygous eNOS (-/-) (-3+/-4%) mice. Responses to bradykinin in iNOS (-/-) and both wild-type and heterozygous eNOS mice were attenuated after NOS blockade with N-nitro-L-arginine methyl ester (L-NAME) (-2+/-5%, -3+/-2%, and -6+/-5%, respectively, P<0.05). In contrast, S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4) mol/L), which releases NO spontaneously, induced decreases in myocardial O2 consumption in all groups of mice, and such responses were not affected by L-NAME. In addition, pretreatment with bacterial endotoxin elicited a reduction in basal O2 consumption in tissues taken from normal but not iNOS (-/-)-deficient mice. Our results indicate that the pivotal role of eNOS in the control of myocardial O2 consumption and modulation of mitochondrial respiration by NO may have an important role in pathological conditions such as endotoxemia in which the production of NO is altered.

Animals↗
PubMed1999

Role of nitric oxide in the control of mitochondrial function.

In summary, NO is capable of decreasing mitochondrial respiration in a variety of mammalian tissues. This effect is mediated primarily via binding of NO to the O2 binding site of cytochrome oxidase. This highly sensitive interaction presumably reflects a remnant homology between cytochrome oxidase and bacterial nitrate reductase. This effect has been demonstrated at physiologic levels of NO, highlighting the role for NO in the tonic control of cellular respiration. As this inhibition is dependent upon the levels figure: see text[ of NO and O2 in the tissue, various states of NO production and oxygen supply dictate the ultimate respiratory rate of the mitochondria. Furthermore, deviation from a physiologic NO: O2 may lead to an exacerbation of pathologic states, such as congestive heart failure and septic shock. Thus, NO may play a crucial role in the control of cellular respiration, providing an additional mechanism of action for this biologically diverse molecule that is distinct yet inseparable from its dilator effect on blood vessels.

Animals↗
PubMed1999

Flow reduces the amplitude and increases the frequency of lymphatic vasomotion: role of endothelial prostanoids.

Fluid dynamic forces have substantial effects on the movement of lymph and activity of lymph vessels. The effect of increases in intraluminal flow on spontaneous pumping activity of isolated collecting lymphatics has not yet been characterized in a condition in which the intraluminal pressure is constant. Thus, in afferent lymph microvessels isolated from rat iliac lymph nodes, changes in maximum (Dmax) and minimum (Dmin) diameter to increases in perfusate flow were investigated in the presence of a constant perfusion pressure of 6 cmH2O. Intraluminal flow was elicited by increases in the difference between outflow and inflow pressures (Pdiff, from 0 to 6 cmH2O). Diameters were measured by videomicroscopy. In response to increases in perfusate flow, Dmax and Dmin of lymphatics decreased from 157.5 +/- 6.1 to 90.9 +/- 5.6 micron and from 91.9 +/- 5.3 to 66.3 +/- 3.6 micron, respectively, whereas vasomotion frequency increased from 18.0 +/- 0.7 min(-1) to 23.4 +/- 1.1 min(-1) (at Pdiff of 4 cmH2O). Removal of extracellular Ca2+ abolished spontaneous diameter oscillations; under these conditions the passive diameter of lymphatics was 216.0 +/- 7.1 micron and did not change in response to increases in perfusion. In the absence of endothelium, flow-induced changes in Dmax, Dmin, and oscillation frequency were eliminated. Nomega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, did not affect flow-induced changes in diameter of lymphatics. In contrast, indomethacin, an inhibitor of prostaglandin synthesis, or SQ-29,548, a PGH2/thromboxane A2 (PGH2/TxA2) receptor blocker, inhibited the perfusion-induced reduction of Dmax and Dmin of lymphatics and also the increase in the frequency of vasomotion. These findings suggest that the sensitivity of lymphatic endothelium to increases in intraluminal flow could provide an important local intrinsic mechanism for the control of lymphatic resistance by release of constrictor prostanoids PGH2/TxA2.

Animals↗
PubMed1998

Superoxide released to high intra-arteriolar pressure reduces nitric oxide-mediated shear stress- and agonist-induced dilations.

It is thought that elevated levels of reactive oxygen metabolites contribute to the dysfunction of vascular endothelium in hypertension. We hypothesized that high intravascular pressure itself elicits production of superoxide, which then interferes with nitric oxide (NO)-mediated responses of arterioles. Thus, isolated arterioles (approximately 80 microm in diameter) from gracilis muscle of normotensive Wistar rats were cannulated and exposed to 140 mm Hg perfusion pressure for 30 minutes (in the absence of perfusate flow). After high intravascular pressure treatment, dilations to increases in perfusate flow (0 to 30 microL/min) were significantly reduced (from 39+/-2.2 to 19+/-2.1 microm at 30 microL/min), eliciting an increase in wall shear stress from approximately 20 to approximately 60 dyne/cm2. Nomega-nitro-L-arginine (10(-4) mol/L) did not affect, whereas indomethacin eliminated, flow-induced dilations after pressure treatment. In control, substance P (SP, 10(-9) to 5x10(-8) mol/L), sodium nitroprusside (SNP, 10(-8) to 10(-6) mol/L), and adenosine (ADO, 10(-6) to 5x10(-5) mol/L) elicited dilations (SP: 31.5+/-1.9 microm, SNP: 45.6+/-4 microm, and ADO: 37.2+/-4.1 microm, at maximum concentrations, respectively). After pressure treatment, maximum dilations to SP and SNP were significantly reduced (by 49% and 39%, respectively), whereas responses to ADO were not affected. Presence of superoxide dismutase (120 U/mL) and catalase (80 U/mL), but not catalase alone, in the perfusate solution prevented the reduction in dilation of arterioles to flow and agonists after pressure treatment by restoring NO mediation. We conclude that high intravascular pressure per se elicits the release of superoxide, which then interferes with NO, a mechanism that contributes to the elevation of wall shear stress and peripheral resistance in hypertension.

Adenosine↗
PubMed1998

Adaptation of flow-induced dilation of arterioles to daily exercise.

We aimed to test the hypothesis that daily exercise elicits an adaptation of blood flow/shear stress-induced dilation of arterioles. To this end we investigated the responses of isolated, pressurized arterioles of mesentery (MES) and plantaris (PL) skeletal muscle of sedentary (SED) and exercised (EX) rats to increases in perfusate flow (PF, range 0-30 microl/min). Rats were run on a treadmill, once daily for 3 to 4 weeks (with gradually increasing intensity up to 40 min at 28 m/min; a total of 15-19 sessions on the treadmill). The passive diameters of arterioles (obtained in Ca2+-free solution) were similar ( approximately 140 microm) but the pressure-induced active diameter (at 80 mmHg) of skeletal muscle arterioles was significantly smaller than that of mesenteric arterioles. The basal diameter of MES arterioles of SED and EX rats was: 83.5 +/- 3.6 and 83.9 +/- 2.9 microm, respectively; increases in PF increased the diameter of SED and EX arterioles to a similar degree by 33.2 +/- 4. 7 and 31.9 +/- 6.1 microm, respectively). The diameters of PL muscle arterioles of SED and EX rats were 62.1 +/- 6.2 and 68.0 +/- 5.5 microm. In contrast to arterioles of MES, the highest PF increased the diameters of arterioles of PL muscle from EX rats to a significantly greater extent than those from SED rats (52.4 +/- 7.8 vs 30.3 +/- 3.9 microm). Thus, there is a functional adaptation to exercise activity in arterioles of skeletal muscle but not in those of arterioles of mesentery. We speculate that the intermittent increase in blood flow/shear stress in arterioles of skeletal muscle during the periods of exercise activity may be the underlying mechanism responsible for this adaptation.

Adaptation, Physiological↗
PubMed1998

Flow-induced responses in skeletal muscle venules: modulation by nitric oxide and prostaglandins.

Skeletal muscle arterioles dilate in response to increases in flow velocity/wall shear stress (WSS). The effect of flow/WSS on the diameter of skeletal muscle venules and the possible endothelial mediation of the response, however, have not yet been characterized. Thus changes in diameter of pressurized (10 mmHg) and norepinephrine-preconstricted venules (179 +/- 8 micron in diameter) to increases in perfusate flow before and after endothelium removal or application of inhibitors of NO and prostaglandin (PG) synthesis, Nomega-nitro-L-arginine (L-NNA, 10(4) M) and indomethacin (Indo, 2.8 x 10(5) M), respectively, were measured. Increases in perfusate flow [elicited by increases in the pressure difference (Pdiff) between proximal and distal cannulas] evoked with a delay of 17 +/- 2 s dilations, up to 36 +/- 9 micron at the highest flow, a response that was completely eliminated by removal/disruption of the venular endothelium. Calculation of WSS indicated that in endothelium-intact venules, the midpoint of the shear stress-diameter curve was at approximately 8 dyn/cm2, whereas in endothelium-denuded vessels, shear stress increased in a linear fashion with increases in flow, up to 40 dyn/cm2. L-NNA significantly reduced flow-induced dilations (from 38 +/- 11 to 17 +/- 9 micron at 14 mmHg Pdiff), whereas in the additional presence of Indo, flow elicited constriction of venules decreasing basal diameter (by 21 +/- 8 micron at Pdiff 12 mmHg). Thus in skeletal muscle venules an increase in shear stress due to increases in perfusate flow stimulates the release of endothelium-derived NO and PGs eliciting dilation, which in turn, regulates WSS, albeit at a lower value than what is observed in arterioles. In the absence of NO and PGs, flow-induced constriction is revealed, the cause of which remains obscure. From these data, we propose that shear stress-related responses of venules are involved in the regulation of venular resistance, especially during high flow conditions, such as reactive and exercise hyperemia.

Animals↗
PubMed1998

Regulation of the vasomotor activity of lymph microvessels by nitric oxide and prostaglandins.

It was shown previously that the presence of endothelium modulates spontaneous vasomotion of small lymphatic vessels. In the present study, we aimed to elucidate the nature of endothelium-derived factors, produced in basal conditions and in response to agonists, that affect the smooth muscle tone of lymph microvessels in vitro. Afferent lymph microvessels were isolated from rat iliac lymph nodes, cannulated with glass micropipettes, and pressurized (6 cmH2O), and changes in their diameter were investigated with video microscopy. In resting conditions, isolated lymph vessels exhibited spontaneous constrictions and dilations. The maximum and minimum diameters (Dmax and Dmin) were 149.8 +/- 2.9 and 85.8 +/- 3.6 microns, respectively. Acetylcholine (ACh, 10(-7) to 10(-5) M) and sodium nitroprusside (SNP, 10(-8) to 10(-6) M) temporarily abolished diameter oscillations, increasing the diameter of lymphatics dose dependently. For example, 10(-5) M ACh and 10(-6) M SNP increased the diameter (Dmax) by 15.2 +/- 2.2 and 25.0 +/- 2.7 microns, respectively. Treatment of vessels with NG-nitro-L-arginine (10(-4) M) significantly reduced the amplitude of diameter oscillations and nearly completely eliminated ACh-induced dilation of lymph microvessels, whereas SNP (10(-6) M) elicited a significantly greater dilation (55.6 +/- 7.5 microns). Arachidonic acid (AA, 10(-8) to 10(-6) M) constricted (up to 50 microns), whereas prostaglandin E2 (PGE2, 10(-9) to 10(-7) M) dilated (up to 40 microns), lymphatic vessels. Indomethacin (10(-5) M) increased both Dmax and Dmin and completely inhibited AA-induced constrictions, but did not affect PGE2-induced dilations of lymph microvessels. AA-induced constrictions of lymphatics were converted into dilations after treatment with SQ-29,548, a selective PGH2-thromboxane A2 (PGH2-TxA2, 10(-6) M) receptor antagonist, whereas PGE2-induced dilations were not affected. We conclude that endothelial nitric oxide and prostaglandins are important modulators of lymphatic vasomotion, hence pumping activity of lymph microvessels in vivo.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide.

Previous studies show that agonist-induced, nitric oxide (NO)-mediated arteriolar dilations are greater in female than in male rats. Thus we hypothesized that flow-dependent arteriolar dilation, which is in part mediated by NO, is also greater in females than in males. Gracilis muscle arterioles from 12-wk-old female and male Wistar rats were isolated, cannulated, and pressurized. At 80 mmHg of perfusion pressure, the active diameter and passive diameter (PD) of arterioles of female and male rats were 58.3 +/- 3.4 and 53.2 +/- 2.6 micrometer as well as 103.6 +/- 4.0 and 115.3 +/- 4.8 micrometer, respectively. Dilations to step increases in perfusate flow from 0 to 25 microliter/min were significantly greater in arterioles of female rats and ovariectomized rats with estrogen replacement (OVE) than in male and ovariectomized female (OV) rats (98.6 +/- 0.6 and 97.4 +/- 1.1% vs. 72.6 +/- 3.3 and 72.5 +/- 3.6% of PD at 25 microliter/min). Calculation of wall shear stress (WSS) revealed that the maintained WSS was significantly lower in arterioles of female than in those of male rats (approximately 20 vs. approximately 35 dyn/cm2). After indomethacin pretreatment, Nomega-nitro-L-arginine methyl ester (L-NAME; 10(-4) M) eliminated flow-dependent dilation in arterioles of male and OV rats but only attenuated (by approximately 50%) the responses in arterioles of female and OVE rats. In vessels of these latter two groups of rats, the remaining flow-induced dilation was completely eliminated by administration of 10(-5) M Hb or 10(-3) M L-NAME. The greater flow/shear stress-induced dilation of arterioles of female rats indicates a gender difference in the regulation of WSS, which is likely to be due to the greater release of NO in female vessels requiring the chronic presence of estrogen. These findings suggest an important role for estrogen in the regulation of peripheral resistance in females.

Animals↗
PubMed1998

Estrogen preserves regulation of shear stress by nitric oxide in arterioles of female hypertensive rats.

Previously we found that flow-induced arteriolar dilation in male spontaneously hypertensive rats (SHR) is significantly impaired, due to the absence of the nitric oxide (NO)-mediated portion of the response, resulting in an elevation of maintained wall shear stress. Since estrogen has been shown to affect NO-mediated responses, we hypothesized that in female SHR (fSHR) the NO-mediated portion of flow-induced responses is preserved. Gracilis muscle arterioles (approximately 45 to 55 microm) from 12-week-old fSHR, ovariectomized fSHR (OV fSHR), or ovariectomized and supplemented with estrogen fSHR (OVE fSHR) were isolated, cannulated, and pressurized at 80 mm Hg of perfusion pressure. Arteriolar dilations elicited by step increases in perfusate flow from 0 to 25 microL/min were significantly less (by approximately 30%) in OV fSHR compared with fSHR and OVE fSHR (delta19.4+/-1.5 versus 26.0+/-0.9 and 26.8+/-2.0 microm, respectively at maximum flow rate). Inhibition of prostaglandin synthesis with indomethacin elicited a approximately 50% reduction in flow-dependent dilation in all three groups of rats. N(omega)-nitro-L-arginine (L-NNA) significantly inhibited flow-induced responses in arterioles of fSHR and OVE fSHR (by approximately 50%) but not in those of OV fSHR. Constrictions to norepinephrine (10(-7)-3 x 10(-7) mol/L) were significantly greater (up to approximately 40%) in arterioles of OV fSHR compared with those of fSHR and OVE fSHR; these differences, however, were abolished in the presence of L-NNA. In conclusion, estrogen seems to preserve the NO-mediated portion of flow/shear stress-induced dilation in female hypertensive rats resulting in a lower maintained wall shear stress in female than in male SHR. The lower wall shear stress may contribute to the mechanisms by which estrogen lowers systemic blood pressure and the incidence of cardiovascular diseases in women.

Animals↗
PubMed1997

Angiotensin-converting enzyme inhibitors promote nitric oxide production in coronary microvessels from failing explanted human hearts.

We have previously shown that nitric oxide (NO) release by the coronary circulation in the failing and nonfailing human heart is, in part, regulated by local kinin production in coronary microvessels. Angiotensin-converting enzyme (ACE) also known as kininase II, inactivates kinins. ACE inhibitors prevent kinin breakdown by ACE, thereby increasing the concentration of bradykinin (BK) and related kinins. The goal of this study was to determine if kinins contribute to the therapeutic action of ACE inhibitors. Six hearts from end-stage heart failure patients were harvested at the time of orthotopic cardiac transplantation. Microvessels were prepared as previously described, and nitrite production, a metabolic product of NO in vitro, was determined by the Griess reaction. Microvessels were incubated in the presence of kininogen and bradykinin, and with the ACE inhibitors ramiprilat, enalaprilat, or captopril. All caused dose-dependent increases in nitrite. For instance, ramiprilat increased nitrite from 76 +/- 5.6 to 155 +/- 15 pmol/min per mg wet weight. Nitrite production in response to ACE inhibition was blocked by N-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, and icatibant (HOE 140), a B2-kinin receptor-specific antagonist. Furthermore, NO production was prevented by 3 different serine protease inhibitors, which block kallikrein, the enzyme responsible for conversion of kininogen to kinins. Our results indicate that ACE/kininase inhibitors increase NO production by the coronary microvasculature in the failing human heart, through increased available active kinins. The therapeutic action of ACE inhibition in the failing human heart may result in part from increased NO production by coronary microvessels.

Adolescent↗
PubMed1997

Nitric oxide and prostaglandins mediate vasodilation to 5,6-EET in rabbit lung.

We have previously found that 5,6-EET (epoxyeicosatrienoic acid)(50 nM) significantly dilates the vascular bed(42%) of the isolated, constantly perfused rabbit lung, which has been constricted with U46619(5-8 pM). We studied the role of EDRF-NO and prostaglandins in the 5,6-EET-induced vascular relaxation. Dilation to 5,6-EET was evident only when the pulmonary vascular tone was increased. L-NNA (N omega-nitro-L-arginine, 10(-4) M), an inhibitor of NO synthase(NOS); U46619(5-10 pM), a thromboxane mimetic; and L-NNA + INDO(indomethacin, 10(-5) M), a cyclooxygenase inhibitor, all increased the pressure of pulmonary artery(PPa) from baseline, to a peak range of 28-38mmHg(32.75 [symbol: see text] 2.2), whereas INDO alone increased Ppa only by 10mmHg. L-NNA + INDO,L-NNA alone, and INDO + U46619 attenuated the 5,6-EET relaxing effect by 100%, 88% and 64.5%, respectively. In the presence of L-NNA and 5,6-EET, SNAP(S-nitroso-N-acetyl-D,L-penicillamine, 10(-6) M), a NO donor, reduced Ppa by 75%. We conclude that the mechanism of vasodilation to 5,6-EET in the rabbit pulmonary circulation is via both EDRF-NO and PG pathways and that the vasodilation is largely EDRF-NO dependent.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Gender difference in myogenic tone of rat arterioles is due to estrogen-induced, enhanced release of NO.

The characteristics of arteriolar myogenic responses of female rats have not been investigated. Thus experiments were conducted on isolated gracilis muscle arterioles (approximately 55 microm diameter) of four groups of 12-wk-old rats: male rats, female rats, ovariectomized female rats with no estrogen replacement (OV), and ovariectomized female rats with estrogen replacement (OV + E2, 50 microg/kg s.c. injection of 17beta-estradiol benzoate every 48 h). Diameter changes in response to increases in perfusion pressure from 20 to 140 mmHg and to various concentrations of substance P (SP, 10(-9)-5 x 10(-8) M) and sodium nitroprusside (SNP, 10(-8)-10(-6) M) were measured before and after administration of N(omega)-nitro-L-arginine (L-NNA, 10(-4) M), an inhibitor of NO synthase. Arteriolar diameters of male and OV female rats were significantly less at 60-140 mmHg pressure than those of normal female and OV + E2 female rats (at 80 mmHg, 45.4 +/- 1.8 and 43.1 +/- 2.2 vs. 58.4 +/- 1.6 and 57.3 +/- 1.3%). L-NNA elicited a significantly greater downward shift of pressure-diameter curves in arterioles of normal female and OV + E2 female rats than in arterioles of male and OV female rats (28.6 +/- 4.6 and 30.6 +/- 4.7 vs. 13.2 +/- 0.9 and 10.4 +/- 2.6%). Dilations of arterioles from normal female and OV +/- E2 female rats to SP were significantly greater (by 50-60%) than those from male and OV female rats (20.8 +/- 1.8 and 22.3 +/- 1.9 vs. 13.8 +/- 1.4 and 13.8 +/- 0.6% at 10(-8) M). L-NNA did not affect dilations to SNP but significantly reduced the dilation of arterioles in all groups to SP, more so in arterioles of male and OV female rats than in arterioles of the other two groups. We conclude that pressure-induced myogenic constriction of arterioles of female rats is less pronounced than that of male rats; this is, most likely, due to the enhanced release and/or activity of NO related to the presence of estrogen.

Animals↗
PubMed1997

Release of nitric oxide and prostaglandin H2 to acetylcholine in skeletal muscle venules.

The role of endothelium in regulating venular resistance is not well characterized. Thus we aimed to elucidate the endothelium-derived factors involved in the mediation of responses of rat gracilis muscle venules to acetylcholine (ACh) and other vasoactive agents. Changes in diameter of perfusion pressure (7.5 mmHg)- and norepinephrine (10(-6) M)-constricted venules (approximately 225 microns in diam) to cumulative doses of ACh (10(-9) to 10(-4) M) and sodium nitroprusside (SNP, 10(-9) to 10(-4) M), before and after endothelium removal or application of various inhibitors, were measured. Lower doses of ACh elicited dilations (up to 42.1 +/- 4.7%), whereas higher doses of ACh resulted in smaller dilations or even constrictions. Endothelium removal abolished both ACh-induced dilation and constriction. In the presence of indomethacin (2.8 x 10(-5) M), a cyclooxygenase blocker, or SQ-29548 (10(-6) M), a thromboxane A2-prostaglandin H2 (PGH2) receptor antagonist, higher doses of ACh caused further dilation (up to 72.7 +/- 7%) instead of constriction. Similarly, lower doses of arachidonic acid (10(-9) to 10(-6) M) elicited dilations that were diminished at higher doses. These reduced responses were, however, reversed to substantial dilation by SQ-29548. The nitric oxide (NO) synthase blocker, N omega-nitro-L-arginine (L-NNA, 10(-4) M), significantly reduced the dilation to ACh (from 30.6 +/- 5.5 to 5.4 +/- 1.4% at 10(-6) M ACh). In contrast, L-NNA did not affect dilation to SNP. Thus ACh elicits the release of both NO and PGH2 from the venular endothelium.

Acetylcholine↗