Biomedical subjects

E Bassenge

Publications and source records attributed to E Bassenge.

At least 55 records · Page 3Linked to original sources

PubMed1994

Reduced nitric oxide formation causes coronary vasoconstriction and impaired dilator responses to endogenous agonists and hypoxia in dogs.

We investigated the relative contribution of basal and agonist stimulated EDRF/NO release to the adjustment of coronary tone and myocardial perfusion in conscious dogs by inhibiting coronary endothelial NO formation with NG-nitro-L-arginine methyl ester (L-NAME). Chronically instrumented conscious dogs (n = 9) were prepared for measurement of mean arterial blood pressure (MAP), heart rate (HR), coronary blood flow (CF) and diameter of the left circumflex (CDLC) and left anterior descending (CDLAD) coronary artery, respectively. Intracoronary infusions of L-NAME (30.3 mM; 0.25 ml x min-1) caused significant increases in MAP and decreases in HR. CDLC decreased by 3.8% from 3.01 +/- 0.04 to 2.90 +/- 0.04 mm and CF decreases by 30% from 12.9 +/- 0.2 to 9.1 +/- 0.2 (aU). Peak reactive hyperemia (CFmax) evoked by 20-s-lasting occlusions of the left circumflex coronary artery decreased from 29.9 +/- 0.8 to 25.8 +/- 1.0 aU and maximal flow-dependent coronary dilation were reduced from 2.04 +/- 0.08 to 0.91 +/- 0.12% after inhibition of NO-synthesis. Intracoronary infusions of acetylcholine (ACh), adenosine (Ado), bradykinin (Bk), and papaverine (Pap) caused dose-dependent increases in CDLC and CF. Infusion of L-NAME nearly abolished the dilator effect of Ado on CDLC and reduced those to ACh, Bk and Pap. Increases in CF to ACh, Ado and Bk but not to Pap were reduced by L-NAME. Subsequent intracoronary infusions of L-arginine (303 mM; 0.25 ml x min-1) reduced L-NAME-induced CF-changes partly, but did not reverse coronary constriction. These results suggest that inhibition of the continuous release of nitric oxide markedly reduces myocardial perfusion in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Low dose calcium-antagonism compensates for impaired myocardial blood supply resulting from deficient nitric oxide synthesis.

Coronary artery disease (CAD) has been documented to be usually associated with endothelial dysfunction. Thus, the present experiments were performed to investigate whether non-hypotensive doses of calcium antagonists can compensate for the effects of deficient endogenous formation of nitric oxide (NO) in the coronary vascular bed in vivo. In chronically instrumented conscious dogs (n = 6) which were prepared for the measurement of coronary blood flow (CBF), coronary diameter of the left circumflex artery (LCX), mean arterial blood pressure (MAP) and heart rate (HR), continuous intravenous infusions of 0.2 micrograms/kg/min nisoldipine (NI) or 2.0 micrograms/kg/min diltiazem (DT) were performed after intracoronary pretreatment with either vehicle or the inhibitor of NO synthesis NG-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg). NI dose-dependently increased CBF up to a maximum of +74 +/- 7.5% from control, while LCX diameter and HR were not significantly affected. MAP fell slightly (-5 +/- 3 mmHg). The maximum CBF increase in response to diltiazem at 10-fold higher doses was +39 +/- 13% while MAP fell -12 +/- 2 mmHg at the highest cumulative dose (100 micrograms/kg). HR and LCX diameter remained unaltered. Pretreatment with L-NAME caused marked hypertension and bradycardia, associated with reduction in CBF (-34 +/- 16%) and LCX diameter (-9.5 +/- 0.8%). Subsequent infusion of NI or DT increased CBF up to the control values obtained before L-NAME. In contrast, both calcium antagonists failed to reverse the effects on MAP or HR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Coronary vasomotor responses: role of endothelium and nitrovasodilators.

The endogenous nitrovasodilator endothelium-derived nitric oxide (EDNO) is continuously synthetized enzymatically by NO synthase from L-arginine and is released from endothelial cells. Enhanced, superimposed EDNO release can be stimulated by various local and circulating factors, such as bradykinin, ATP, etc., but also most importantly by viscous drag-induced shear stress of the bloodstream acting on the endothelial lining. Thus luminal release suppresses leukocyte adhesion (expression of adhesion molecules), platelet activation, platelet adhesion, and platelet aggregation, and abluminal release counteracts myogenic and neurogenic coronary constrictor tone, thereby increasing myocardial perfusion and dilating large coronary artery calibers. Thus endothelial impairment and denudation (hypercholesterolemia, atheromatosis, balloon catheter interventions) favor excessive constrictor tone and myocardial ischemia. Under these conditions EDNO can be supplemented by compounds (e.g., nitroglycerin, isosorbide dinitrate) converted by biological systems into NO. In addition, it can be supplemented by compounds that even spontaneously release NO (e.g., sydnonimines such as SIN-1 and sodium nitroprusside). EDNO and exogenously supplemented NO stimulate soluble guanylyl cyclase, increase cGMP levels, and bring about vascular relaxation, particularly in those still compliant sections in which EDNO production is impaired and cGMP levels are thus diminished. Exogenous nitrovasodilators are preferentially converted (in the presence of cysteine) enzymatically in large coronary arteries, improving coronary conductance, and in the venous bed (preload reduction), resulting in an improved O2 supply/demand ratio. During chronic, continuous application, neurohormonal counterregulation and diminished enzymatic biotransformation into NO may reduce their effectiveness, resulting in tolerance, particularly in the most sensitive vascular sections, such as veins and coronary arteries. This drawback can be overcome by applying spontaneously NO-releasing compounds, intermittent therapy, or intermittent interposition of other vasodilator principles.

Amino Acid Oxidoreductases↗

PubMed1994

Endothelium dependent vasomotor responses to endogenous agonists are potentiated following ACE inhibition by a bradykinin dependent mechanism.

OBJECTIVE: The aim was to investigate the effects of angiotensin converting enzyme inhibition on agonist induced endothelium dependent vasodilatation in vivo. METHODS: Chronically instrumented conscious dogs (n = 8) were prepared for the measurement of coronary blood flow, diameter of the left circumflex coronary artery, mean arterial blood pressure, and heart rate. Intracoronary infusions of acetylcholine, adenosine, and bradykinin that induced dose dependent increases in coronary blood flow and diameter were performed with and without intracoronary administration of captopril (1 mg.kg-1) and enalapril (0.4 mg.kg-1). The effects were studied of concomitant inhibition of bradykinin actions by the specific B2 kinin antagonist HOE-140 (10(-7) M), NO-synthesis by NG-nitro-L-arginine-methyl ester (L-NAME, 2 x 10(-5) M), or cyclo-oxygenase by indomethacin (10(-7) M) (all intracoronary). RESULTS: Neither captopril nor enalapril had significant vasodilating effect on the coronary vasculature when given alone. In contrast, both ACE inhibitors potentiated the agonist induced increases in coronary blood flow by bradykinin and acetylcholine (p < or = 0.01). HOE-140 strongly antagonised the effects of infused bradykinin and prevented the potentiation of acetylcholine responses by ACE inhibition. L-NAME caused hypertension and bradycardia and abolished the responses to acetylcholine and adenosine, but only partially attenuated the bradykinin induced increases in coronary blood flow. Simultaneous ACE inhibition reduced the hypertensive effect of L-NAME and partially restored the responses to bradykinin. Indomethacin reduced the responses to bradykinin but did not affect acetylcholine and adenosine induced coronary vasodilatation. The potentiation of the response to acetylcholine induced by ACE inhibition was, however, diminished by indomethacin. CONCLUSIONS: In the coronary vasculature of the dog, ACE inhibitors enhance vasomotor responses to endothelium dependent agonists by facilitating the release of both NO and PGI2, a mechanism which is coupled to endogenously formed bradykinin. ACE inhibitors may thus mediate their effects in vivo partly by increasing the capacity of the endothelium to release autacoids.

Acetylcholine↗

PubMed1994

Attenuation of coronary autoregulation in the isolated rabbit heart by endothelium derived nitric oxide.

OBJECTIVE: The aim was to investigate the role of endothelium derived nitric oxide (EDNO/EDRF) in the control of coronary autoregulation. METHODS: In isolated saline perfused rabbit hearts coronary flow responses to stepwise increases in perfusion pressure were studied under control conditions, during maximum dilatation with sodium nitroprusside, and in the presence of the inhibitor of EDNO synthesis, NG-nitro-L-arginine (L-NNA), or the vasoconstrictors endothelin-1 and arginine vasopressin. RESULTS: At a constant perfusion pressure of 60 mm Hg, infusion of L-NNA (30 microM), but not D-NNA, reduced the coronary flow from 24.7(SEM 2) to 13.6(2.2) ml.min-1 and abolished flow increases induced by the EDRF stimulator acetylcholine. Under these conditions, pressure induced coronary flow increases were reduced (p < 0.05 compared to control) over the whole range of perfusion pressures studied (45 to 120 mm Hg). Arginine vasopressin [2(0.6) nM] and endothelin-1 [1.5(1) nM] induced similar reductions of coronary resting flow but the pressure induced flow increases were significantly greater than in the presence of L-NNA. Moreover, inhibition of EDRF synthesis reduced the peak reactive hyperaemia after a 30 s interruption of coronary flow from 47(2) to 32(2) ml.min-1. These changes occurred in spite of a decrease in the myocardial oxygen uptake from 5.1(0.6) to 3.4(0.5) ml.100 g-1.min-1 (p < 0.01) and a concomitant increase in the lactate release from 46(7) to 95(54) mumol.min.100 g-1 (p < 0.01), indicating myocardial ischaemia. CONCLUSIONS: EDNO attenuates coronary autoregulatory responses which, if unopposed, potentially impair a functionally adequate myocardial perfusion. It is suggested that the modulator role of EDNO is, at least in part, specific and most likely to be due to shear dependent alterations of EDNO release.

Acetylcholine↗

PubMed1994

Long term increases in coronary arterial conductance during five day infusion of low dose nicorandil.

OBJECTIVE: The aim was to test the effects of nicorandil on coronary arterial conductance and on a possible development of tolerance or cross tolerance with glyceryl trinitrate during a 5 d continuous intravenous infusion of this hybrid molecule (consisting of a combination of potassium channel activation and simultaneous nitro-ester induced soluble guanylyl-cyclase activation). METHODS: Continuous intravenous infusions of nicorandil at 2.5 micrograms.kg-1.min-1 and 10 micrograms.kg-1.min-1 into conscious chronically instrumented dogs were carried out for 5 d using a special portable infusion system. Employing additional short term infusions, dose-response curves were obtained by giving nicorandil or glyceryl trinitrate at increasing dosages both in the preinfusion control state and 4 h after terminating the nicorandil infusion. RESULTS: The 5 d infusion of 2.5 or 10.0 micrograms.kg-1.min-1 nicorandil resulted in a significant increase in large coronary artery diameter by 4.21 (SEM 0.14)% or 9.20(0.28)%, respectively. At the lower dose no significant tolerance or cross tolerance with glyceryl trinitrate was observed. However, at the higher dose there was a shift of the dose-response curve of both nicorandil and glyceryl trinitrate to the right, indicating some tolerance. The smaller dose did not induce hypotension or reflex increase in heart rate, whereas the larger resulted in a 42(2.5)% increase in heart rate. CONCLUSIONS: A dose regimen of 2.5 micrograms.kg-1.min-1 continuously administered for 5 d is capable of inducing a significant increase in coronary arterial conductance which was well maintained over the whole infusion period. Thus nicorandil can exert a selective large coronary artery dilatation and may bring about a well maintained increase in epicardial coronary conductance, especially when applied as a low dose slow release preparation which circumvents hypotension and increase in heart rate.

Animals↗

PubMed1994

Novel organic nitrates are potent dilators of large coronary arteries with reduced development of tolerance during long-term infusion in dogs: role of the sulfhydryl moiety.

The vasodilator action of organic nitrates can be severely impaired by induction of drug tolerance. A critical depletion of sulfhydryl groups has been proposed to play a key role in impairment of the biotransformation of organic nitrates to nitric oxide (NO). We studied the effects of the new cysteine-containing nitrate SPM-5185 and the corresponding cysteine-free compound SPM-4744 on hemodynamics and large coronary artery dilation in chronically instrumented conscious dogs. Both nitrates caused dose-dependent increases of the diameter of the left circumflex artery (LCX); the cysteine-containing compound SPM-5185 however, caused such increases at < or = 30-fold lower doses as compared with SPM-4744. Coinfusion of the cysteine-containing analogue of SPM-5185 lacking the nitrate group (SPM-5267) did not alter the dose-response relationship to SPM-4744. Continuous infusion of SPM-5185 (4 micrograms/kg/min, n = 6) and SPM-4744 (2.7 micrograms/kg/min, n = 5) elicited LCX diameter increases of 0.24 +/- 0.06 and 0.17 +/- 0.07 mm, respectively, representing 60-70% of maximal dilator capacity. In contrast to classic organic nitrates, both SPM-5185 and SPM-4744 caused LCX diameter to decrease only slightly during 5-day infusions. Both compounds elicited sustained dilation even at day 5 (p < or = 0.05). SPM-5185 caused an initial decrease in mean arterial pressure (MAP) and evoked sustained increases in heart rate (HR), whereas SPM-4744 had no significant peripheral effects. On withdrawal of SPM-5185, LCX diameter was decreased below pretreatment values for several hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1993

Dual action of angiotensin II on coronary resistance in the isolated perfused rabbit heart.

We studied the functional role of angiotensin II (AII) receptor subtypes and vasodilatory endothelial autacoid release in response to AII in isolated perfused rabbit hearts. AII infusion induced biphasic changes in coronary perfusion pressure (CPP): an initial increase was followed by a decrease until a plateau was reached. At higher concentrations of AII (> or = 10 nmol/l) this plateau phase was lower than the initial CPP level. AII infusion elicited inverse changes in peak left ventricular pressure (LVP): coronary constriction was associated with a transient decline, and during the plateau phase LVP was clearly increased. AII also moderately augmented prostacyclin (PGI2) release from the coronary vascular bed. The AII-induced changes in CPP, LVP, and PGI2 release were effectively inhibited by the AT1 receptor subtype antagonist ICI D8731 (30 nmol/l), but not by the AT2 receptor antagonist CGP 42112 (30 nmol/l). The adenosine A1 receptor antagonist 8-phenyltheophylline (0.1 mumol/l) attenuated the decline in CPP following the constriction phase without affecting the changes in LVP during AII infusion. The cyclooxygenase inhibitor diclofenac (1 mmol/l) had no effect on the AII-induced changes in CPP, whereas the nitric oxide-synthase inhibitor NG-nitro-L-arginine (30 mumol/l) markedly potentiated the vasoconstriction but was without effect on the plateau phase of the response. In contrast to AII, the thromboxane analogue U46619 elicited sustained increases in CPP which were associated with slight decreases in LVP.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1993

Arterial size determines the enhancement of contractile responses after suppression of endothelium-derived relaxing factor formation.

We studied the effect of endothelium-derived relaxing factor (EDRF) on norepinephrine-induced contractile responses and on the tissue guanosine-3',5'-phosphate (cGMP) concentration of isolated rabbit arteries with an increasing endothelium to smooth muscle cell ratio (aorta, femoral and mesenteric arteries). After suppression of EDRF formation (either by NG-nitro-L-arginine or, in mesenteric arteries, by saponin), contractions elicited by cumulative doses of norepinephrine were unaltered in aorta but were enhanced by 22.5% in femoral arteries and by 44.3% in mesenteric arteries (at the highest norepinephrine concentration). The cGMP concentration (pmol/mg protein) of unstimulated, endothelium-intact vessels decreased after suppression of EDRF formation from 1.09 +/- 0.24 to 0.74 +/- 0.28 in aortic, from 2.86 +/- 0.4 to 0.61 +/- 0.19 in femoral and from 6.3 +/- 0.9 to 0.7 +/- 0.15 in mesenteric arterial segments. The basal cGMP concentration did not differ in endothelium-denuded segments of these arteries, suggesting a similar basal activity of soluble guanylate cyclase (sGC). A higher sensitivity of sGC may have contributed to the higher cGMP concentration observed in the smaller arteries, since in the presence of sodium nitroprusside the cGMP concentration of endothelium-denuded segments increased 1.8-fold in aortic, 2.9-fold in femoral and 2.4-fold in mesenteric arterial segments. However, these differences in sGC activation cannot be solely responsible for the high basal cGMP concentration in endothelium-intact mesenteric arteries. The greater ratio of endothelium to smooth muscle cell layers in the smaller arteries might result in a higher EDRF concentration in the vascular wall and subsequently in a higher cGMP concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Vasoconstriction and increased flow: two principal mechanisms of shear stress-dependent endothelial autacoid release.

The mechanisms of which nitric oxide (NO) and prostacyclin (PGI2) are released from endothelium-intact rabbit femoral arteries under resting conditions and after stimulation by either shear stress or acetylcholine (ACh) were investigated. The concentration of NO in the effluate was determined by monitoring the NO-mediated stimulation of purified soluble guanylyl cyclase, and that of PGI2 was done using a specific radioimmunoassay for its stable hydrolysis product, 6-ketoprostaglandin F1 alpha, NO release under static (no-flow) conditions and in the absence of a stimulus accounted for 10-15% of the maximum release of NO from luminally perfused segments stimulated with ACh and was attenuated by removal of extracellular Ca2+. A six- to sevenfold increase in shear stress (from 0.15 to 1 dyn/cm2), generated either by vasoconstriction at constant flow or by an increase in flow at constant diameter, elicited a five- to sevenfold increase in NO release, which was correlated with increasing shear stress. The same increase in shear stress also enhanced the release of PGI2 from the femoral artery segments by 11- to 12-fold. Removal of extracellular Ca2+ abolished the shear stress-dependent PGI2 released but did not affect that of NO. In contrast, the ACh-stimulated NO release was strongly inhibited in the absence of extracellular Ca2+ (78% inhibition). Charybdotoxin, an inhibitor of Ca(2+)-activated K+ channels, and glibenclamide, an inhibitor of the ATP-sensitive K+ channel, had no effect on the shear stress-dependent release of NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1993

Effectiveness of an NO-releasing pirsidomine derivative on coronary conductance during long-term administration.

Nitrovasodilators have long been used in the treatment of myocardial ischemia. One of the limitations of their chronic administration is loss of drug action over time. Nitrovasodilator-induced drug tolerance results from either the loss of cyclic guanosine monophosphate-dependent dilator effects, or from biological counterregulatory processes, usually neurohormonal adaptations. C87-3754, a derivative of pirsidomine, is a new nitric oxide-releasing sydnonimine. Continuous 5-day infusion of C87-3754 in dogs did not result in a substantial loss of drug action. There was long-lasting dilation evident in the large coronary arteries and venous bed, resulting in improved coronary conductance. Administration of C87-3754 was associated with reduction in cardiac preload, wall stress, and subendocardial tissue pressure.

Animals↗

PubMed1993

Coronary vasodilation to acetylcholine, adenosine and bradykinin in dogs: effects of inhibition of NO-synthesis and captopril.

We investigated the effects of inhibition of both nitric oxide (NO) synthesis and angiotensin converting enzyme (ACE) on agonist-induced relaxations in the coronary system. Chronically instrumented conscious dogs (n = 4) were prepared for the measurement of coronary blood flow (CBF), coronary diameter of the left circumflex artery (LCX), mean arterial blood pressure (MAP) and heart rate (HR). Intracoronary infusions of acetylcholine, adenosine and bradykinin were performed after intracoronary pretreatment of either vehicle, L-NAME (6 mg.kg-1), captopril (1 mg.kg-1) or both L-NAME+captopril. Acetylcholine bradykinin and adenosine caused dose-dependent increases in CBF and LCX. HR increased concomitantly. Captopril potentiated the vasodilating effects of bradykinin and acetylcholine on LCX and CBF significantly (P < or = 0.05) and those of adenosine slightly. L-NAME caused vasoconstriction, hypertension and bradycardia. The effects of acetylcholine on CBF were abolished during L-NAME treatment while bradykinin and adenosine responses were markedly reduced. When captopril and L-NAME were given simultaneously, the vasodilator responses to bradykinin but not to acetylcholine or adenosine were partially restored (P < or = 0.05). We conclude that in vivo, (a) adenosine possibly elicits endothelium-dependent dilation; (b) adenosine and bradykinin act in part independently of the L-arginine/NO pathway; (c) vasodilation to acetylcholine is potentiated by acute ACE inhibition via NO-dependent mechanisms.

Acetylcholine↗

PubMed1992

Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function.

The favorable anti-ischemic effect of nitrates is based on the unique distribution pattern of vascular relaxation that they evoke in different vascular sections. Nitrovasodilators reduce cardiac preload and wall tension, and thus myocardial oxygen consumption. They increase precollateral coronary perfusion pressure, thereby augmenting oxygen delivery to ischemic sections, especially to the subendocardial layers. These vasodilator actions are caused by the nitric oxide (NO)-induced activation of soluble guanylyl cyclase, which augments vascular cyclic guanosine monophosphate (cGMP) levels to suppress intracellular Ca2+ concentrations. After some metabolic steps NO is finally cleaved from all nitrovasodilators and is probably identical with, or very closely related to, endothelium-derived relaxing factor (EDRF). A dinitrosyl-iron complex may serve under biologic conditions to stabilize the NO- radical, which has an extremely short half-life. NO derived from nitrovasodilators is used therapeutically to substitute for a deficient endothelium-mediated vascular control and autacoid production.

Animals↗

PubMed1992

Effects of long-term nicorandil application on coronary arteries in conscious dogs.

Nicorandil acting as both nitrovasodilator and K(+)-channel opener was analyzed with regard to its dilator activity in large coronary arteries. In addition, it was tested for potential development of tolerance in six chronically instrumented conscious dogs that received a 5-day continuous i.v. infusion. Increasing dosages of nicorandil (3, 10, and 30 micrograms.kg-1.min-1) caused dose-dependent strong increases in left circumflex coronary artery diameter (1.3 +/- 0.4%, 5.3 +/- 2.2%, and 8.4 +/- 2.8% above control, respectively). However, 100 micrograms.kg-1.min-1 nicorandil produced substantial hypotension, reflex tachycardia, and reduction of the dilator response in large coronary arteries. During long-term nicorandil administration (10 micrograms.kg-1.min-1 i.v. for 5 days), the diameter of the left circumflex coronary artery was increased by 8.8 +/- 2.5%. This was accompanied by a decrease in mean arterial pressure of 13.3 +/- 6.4% and an increase in heart rate by 41.5 +/- 21.0% compared with controls. On the fifth day of continuous nicorandil infusion, dose-response relations for both nicorandil- and nitroglycerin-induced epicardial artery dilations were shifted to 3.5-fold higher doses. We conclude that nicorandil dilates large coronary arteries in dogs, long-term nicorandil administration does not cause a development of tolerance, long-term nicorandil administration is not associated with the development of cross-tolerance to nitroglycerin, and the small shift of the dose-response relations is considered to reflect a hemodynamic adaptation process due to long-term nicorandil exposure.

Animals↗

PubMed1992

Prostacyclin and nitric oxide contribute to the vasodilator action of acetylcholine and bradykinin in the intact rabbit coronary bed.

The relative contribution of nitric oxide (NO) and cyclo-oxygenase products in the dilator response to equieffective doses of acetylcholine (ACh) and bradykinin (Bk) was studied in the isolated, saline-perfused rabbit heart under constant flow conditions. ACh (1 microM) and Bk (10 nM) induced a similar vasodilation, with a maximum reduction in coronary perfusion pressure (CPP) of 27 +/- 2%. The vasodilation induced by both agonists was associated with an enhanced release of 6-keto-PGF1 alpha from the coronary bed, with the Bk-induced increase in 6-keto-PGF1 alpha being threefold greater than that induced by ACh. The angiotensin converting enzyme (ACE) inhibitor ramiprilat (0.3 microM) selectively enhanced both the 6-keto-PGF1 alpha outflow and the dilator response to Bk. The B2-receptor antagonist Hoe 140 (0.1 microM) blocked both Bk effects. The cyclo-oxygenase inhibitor diclofenac (1 microM) halved the dilator response to Bk, but did not affect the vasodilation to ACh. Both agonists induced the release of NO, as assessed by the increase in cyclic GMP content of platelets passing through the vascular bed. However, ACh induced a 2.5-fold greater increase in platelet cyclic GMP content, compared to Bk. Treatment of hearts with NG-nitro-L-arginine (L-NNA, 30 microM) halved the ACh- and Bk-induced maximum reduction in CPP. Combined infusion of L-NNA and diclofenac completely blocked the dilator response to Bk, and inhibited the vasodilation to ACh more efficiently than L-NNA alone. We conclude that both NO and PGI2 contribute to the coronary dilator response to Bk and ACh in the rabbit Langendorff heart.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Clinical relevance of endothelium-derived relaxing factor (EDRF).

1. In addition to metabolic and neurohumoral factors endothelium-derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L-arginine by a Ca2+/calmodulin-dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium-dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L-arginine supplementation is effective in a few instances.

Animals↗

PubMed1992

Inhibition of cyclic AMP- and cyclic GMP-mediated dilations in isolated arteries by oxidized low density lipoproteins.

We studied the effects of native (N) and oxidized (Ox) low density lipoproteins (LDLs) on adenosine 3',5'-cyclic monophosphate (cAMP)-mediated and on guanosine 3',5'-cyclic monophosphate (cGMP)-mediated dilator mechanisms in isolated, perfused human mammary and rabbit femoral arteries. Dilations were induced in preconstricted, deendothelialized segments by either forskolin (Fo) or sodium nitroprusside (SNP) (intraluminal or adventitial application). Lipoproteins (0.5 mg/ml) were administered to the segments from the intraluminal side. N-LDL had no effect on Fo-induced dilation and caused a weak attenuation of SNP-induced dilation only when SNP was also administered into the intraluminal perfusate. In contrast, Ox-LDL inhibited both Fo- and SNP-induced dilation, independent of the route of dilator application. The effects of Ox-LDL were specific for dilation mediated by cyclic nucleotides. Dilation elicited by the Ca2+ antagonist nitrendipine was inhibited neither by N-LDL nor by Ox-LDL. Determination of basal and stimulated (SNP, Fo) cGMP and cAMP content in rabbit femoral segments after preincubation with N-LDL and Ox-LDL revealed a significant decrease of stimulated vascular cGMP and cAMP content by Ox-LDL, whereas N-LDL had no effect. These data indicate that Ox-LDL selectively inhibits vascular smooth muscle relaxation elicited by increases in cyclic nucleotides. This inhibition might contribute to the attenuation of vasodilation in hypercholesterolemia and atherosclerosis.

Animals↗

PubMed1992

Mechanisms of interaction between the sulfhydryl precursor L-methionine and glyceryl trinitrate.

BACKGROUND: L-Methionine potentiates systemic hemodynamic effects of intravenous glyceryl trinitrate (GTN) in tolerant and nontolerant patients to a similar extent as N-acetylcysteine (NAC). This potentiation of GTN action by L-methionine has been attributed to enhanced intracellular formation of nitrosothiols, known to be potent stimulators of soluble guanylyl cyclase. This study was performed to analyze directly the effects of L-methionine on GTN-induced dilation of large epicardial arteries and the venous capacitance system of the dog in the tolerant and nontolerant states. Cultured rat aortic vascular smooth muscle cells and purified guanylyl cyclase were used to study potential intracellular and extracellular mechanisms responsible for this interaction. METHODS AND RESULTS: In awake nontolerant dogs, L-methionine (100 mg/kg) potentiated the tachycardic response to GTN (5.0 and 15 micrograms/kg/min) and enhanced the hypotensive action of GTN (1.5 and 5.0 micrograms/kg/min) in anesthetized, nonreflexic dogs. In nontolerant and tolerant dogs, however, L-methionine did not alter the dose-response of large epicardial artery dilation to intravenous GTN challenges and did not modify nitrate tolerance of the low pressure system of the dog. The infusion of L-methionine (100 mg/kg) significantly increased plasma methionine levels (from 52 +/- 12 to 1,141 +/- 239 microM), cystine levels (from 12 +/- 4 to 26 +/- 7 microM), but not homocystine levels. In vitro, the L-methionine conversion product L-cysteine (0.1-1.0 mM) but not homocysteine significantly enhanced the augmentation of purified guanylyl cyclase activity by GTN (100 microM). Incubation of cultured rat aortic smooth muscle cells with L-methionine (10 microM or 1 mM) did not result in a significant increase of free intracellular sulfhydryl group content. CONCLUSIONS: The L-methionine conversion product L-cysteine mediates tolerance independent the potentiation of GTN action. This may result from an L-cysteine-induced formation of a vasoactive metabolite of GTN (nitric oxide) or nitrosothiol. This effect occurs primarily in the resistance vessel circulation, not in large epicardial arteries and veins. The lack of effect of L-methionine on sulfhydryl group content in large conductance vessels indicates that hepatic L-methionine metabolism constitutes the significant source of L-cysteine. These findings strongly suggest that administration of sulfhydryl-group precursor L-methionine does not represent a therapeutic alternative to a nitrate-free interval to restore nitrate sensitivity in tolerant large epicardial arteries and veins.

Animals↗