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PubMed1991

Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation.

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.

Animals↗
PubMed1991

Endothelium-dependent hyperpolarization elicited by adenine compounds in rabbit carotid artery.

Electrical responses of the membrane of intimal and adventitial smooth muscle cells of the rabbit carotid artery to ATP, ADP, AMP, and adenosine were recorded. In intimal cells, these compounds hyperpolarized the membrane. Mechanical removal of the endothelium altered the responses to ATP and ADP to one of a transient depolarization, with no alteration of the response to AMP and adenosine. In the adventitial cells, ATP and ADP produced a transient depolarization, whereas AMP and adenosine produced a sustained hyperpolarization, irrespective of the presence or absence of the endothelium. In tissues with an intact endothelium, 5'-adenylylimidodiphosphate tetralithium salt and alpha,beta-methylene ATP (mATP) transiently depolarized the membrane in these smooth muscles. In case of stabilization with mATP, only hyperpolarization was generated by ATP, in an endothelium-dependent manner. Our interpretation of these observations is that 1) ATP and ADP depolarize smooth muscle membrane by a direct action and hyperpolarize the membrane indirectly through the release of endothelium-derived hyperpolarizing factor, 2) AMP and adenosine hyperpolarize the membrane, independently of the endothelium, and 3) ATP receptors present on the endothelial cell membrane differ from those on smooth muscle membrane.

Adenine Nucleotides↗
PubMed1991

Dissociation between endothelium-dependent relaxations and increases in cGMP in systemic veins.

In canine systemic veins, in contrast to what is observed in mammalian systemic arteries, endothelium-dependent relaxations to the calcium ionophore A23187 are not diminished by the inhibitor of soluble guanylate cyclase, methylene blue. Therefore, experiments were designed to determine whether these relaxations in the veins are associated with the accumulation of guanosine 3',5'-cyclic monophosphate (cGMP). Rings of canine femoral arteries and veins with and without endothelium were suspended for the measurement of isometric force in organ chambers; cGMP was measured by radioimmunoassay. In arteries and veins contracted with norepinephrine, the tissue content of cGMP was greater in rings with than without endothelium. This difference was decreased by methylene blue (10(-5) M). A23187 (3 X 10(-7) M, for 1 min) increased the accumulation of cGMP, which was temporally related with the onset of relaxation in tissues with endothelium. Methylene blue inhibited the accumulation of cGMP in both blood vessels but inhibited the relaxations only in the arteries. In rings without endothelium, sodium nitroprusside (3 X 10(-7) and 10(-5) M) initiated increases in cGMP, which followed the onset of relaxation. Neither response to sodium nitroprusside was reduced by methylene blue. These results suggest that in canine femoral arteries and veins, relaxation of the smooth muscle to sodium nitroprusside are mediated by a mechanism distinct from changes in cGMP. Likewise, in canine systemic veins, endothelium-derived factor(s) released in response to A23187 also can initiate relaxation of the smooth muscle by a mechanism distinct from changes in cGMP.

Animals↗
PubMed1992

Role of superoxide anion and endothelium in vasoconstrictor action of prostaglandin endoperoxide.

The vasoconstrictor actions of prostaglandin (PG) endoperoxide, PGH2, were examined in isolated rabbit aortic rings suspended for measurement of isometric tension. In aortic rings with an intact endothelium, PGH2 caused concentration-dependent contractions which were blocked by SQ 29548 (a PGH2-thromboxane A2 receptor blocker) or superoxide dismutase (a superoxide anion scavenger) but not by carbethoxyhexyl imidazole (a thromboxane A2 synthase inhibitor) or catalase (a hydrogen peroxide scavenger). In contrast U 46619, a thromboxane A2 mimic, caused contractions, which were blocked by SQ 29548 but not by superoxide dismutase. PGH2 caused significantly greater contractions in aortic rings without endothelium or in those with intact endothelium treated with NG-nitro-L-arginine, a nitric oxide inhibitor; these contractions were inhibited by SQ 29548 but not by superoxide dismutase. In aortic rings with endothelium contracted with phenylephrine, a subthreshold concentration of PGH2, but not U 46619, impaired relaxations to acetylcholine; the inhibition was prevented by treatment with SQ 29548 or superoxide dismutase, indicating that the abnormality of endothelial cell function was specific for PGH2. These observations indicate that PGH2 causes contractions and inhibits endothelium-dependent relaxation by a mechanism involving formation of superoxide anion, which interacts with endothelium-derived nitric oxide.

Acetylcholine↗
PubMed1993

M3 and M1 receptors in cerebral arterioles in vivo: evidence for downregulated or ineffective M1 when endothelium is intact.

Pial arterioles of mice were monitored by intravital television microscopy. Responses to acetylcholine (ACh) and to McN-A-343, a selective M1 activator, were monitored before and after endothelial injury by a laser-dye technique in the presence or absence of different reference antagonists to the M1, M2, and M3 muscarinic receptors. ACh and McN-A-343 produced endothelium-dependent dilation that was blocked by 4-diphenyl-N-methyl-piperidine methiodide, an inhibitor of the M3 receptor. Dilations were not augmented by blocking the M1 receptor with pirenzepine. Endothelial injury unmasked a constricting effect of both ACh and McN-A-343. The constricting effect was blocked by pirenzepine. The results support the literature suggesting an action of McN-A-343 at more than one site. They indicate that ACh causes endothelium-dependent relaxation via the M3 receptor and directly constricts vascular smooth muscle via the M1 receptor. There does not appear to be continuous competition between endothelium-dependent relaxation and endothelium-independent constriction. Rather the M1 receptors mediating constriction in vascular smooth muscle appear downregulated and/or uncoupled from the contractile machinery as long as the overlying endothelium synthesizes/releases the mediator (endothelium-derived relaxing factor) of ACh's dilating action.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1993

Influence of endothelium on induction of the L-arginine-nitric oxide pathway in rat aortas.

The role of the endothelium in the onset and persistence of vascular hyporeactivity induced by bacterial lipopolysaccharide (LPS) and the implication of the L-arginine-nitric oxide (NO) pathway in this phenomenon were investigated in rat aortic rings exposed to LPS for different times. LPS (100 ng/ml) induced a decrease in the contractile response obtained by norepinephrine (NE) in rings without endothelium after a delay of 6 h. This delay was reduced to 4 h in the presence of the endothelium and corresponded temporally with the development of relaxation after addition of L-arginine (1 mM). This effect of L-arginine along with hyporeactivity to NE was reversed by both NG-nitro-L-arginine methyl ester (300 microM) and methylene blue (3 microM). The effects of LPS on reactivity, L-arginine-dependent relaxation, and tissue guanosine 3',5'-cyclic monophosphate content were prevented by cycloheximide (100 micrograms/ml) whether present throughout the experiment or added 6 h after LPS. Increasing the concentration of LPS to 1 mg/ml reduced the delay between addition of LPS and response to L-arginine in endothelium-denuded rings to 4 h but was without effect on the delay observed in rings with endothelium. These results demonstrate that the time course of development of hyporeactivity to NE corresponds to that of activation of the L-arginine-NO pathway after LPS challenge as assessed by development of sensitivity to L-arginine. The induction process was accelerated by the presence of the endothelium, which also increased the sensitivity of the preparation to LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Endothelin-1 and -3 cause endothelium-dependent hyperpolarization in the rat mesenteric artery.

The present study was designed to determine whether endothelin (ET) induces endothelium-dependent hyperpolarization in the isolated rat mesenteric artery and, if so, to identify the receptor subtype involved. Main superior mesenteric arteries of Wistar-Kyoto and spontaneously hypertensive rats were used for the measurement of electrical responses of smooth muscle cells, using glass microelectrode. In tissues with endothelium of both strains, ET-1 (10(-8) M) caused an initial transient hyperpolarization followed by a sustained depolarization. In tissues without endothelium, only depolarization was observed. ET-3 (10(-8) M) produced transient hyperpolarizations only in preparations with endothelium. There was no significant difference in maximal amplitude of hyperpolarization between the two strains. BQ-123 (selective ETA-receptor antagonist) blocked the depolarization to ET-1 but did not inhibit hyperpolarizing responses to either isopeptide. IRL-1620 (specific ETB-receptor agonist) produced transient membrane hyperpolarizations in tissues with endothelium. The hyperpolarizations induced by ET were not affected by NG-nitro-L-arginine. These data suggest that both ET-1 and ET-3 can cause endothelium-dependent hyperpolarization in the rat mesenteric artery and that the endothelial receptor involved may belong to ETB subtype.

Animals↗
PubMed1994

Role of endothelium-derived nitric oxide in stimulation of Na(+)-K(+)-ATPase activity by endothelin in rabbit aorta.

An endothelium-derived factor with the properties of nitric oxide (NO) has recently been implicated in the regulation of basal Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity in vascular smooth muscle. To determine whether this factor also plays a role in the stimulation of ouabain-sensitive (OS) 86Rb uptake by specific agonists, studies were carried out using rabbit aortic rings. In endothelium-intact rings incubated for 3 h with Krebs-Henseleit solution containing 5.5 mM glucose, endothelin (ET) caused a concentration-dependent increase in OS 86Rb uptake (maximal increase = 205%, with 100 nM ET). Incubation with phenylephrine (Phe; 0.1 and 1 microM) or phorbol 12,13-dibutyrate (PDBu; 0.1 microM), under the same conditions, increased OS 86Rb uptake by 128, 144, and 140%, respectively. Removal of endothelium before incubation decreased the ability of ET to stimulate OS 86Rb uptake by 38-45%, but it did not diminish the stimulation of OS 86Rb uptake by Phe or PDBu. An increase in the concentration of glucose from 5.5 to 44 mM diminished ET-stimulated OS 86Rb uptake by 50% in endothelium-intact rings but had no effect on Phe- or PDBu-induced increases in OS 86Rb uptake. Addition of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 0.3 mM) to the medium decreased ET-stimulated OS 86Rb uptake by 40%. Guanosine 3',5'-cyclic monophophate (cGMP) formation in endothelium-intact rings was also increased (65%) by ET but not by Phe or PDBu. The increase in cGMP by ET was totally inhibited by L-NMMA or endothelium denudation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Administration of tumor necrosis factor-alpha in vivo depresses endothelium-dependent relaxation.

Although depressed endothelium-dependent relaxation occurs during early sepsis, the precise mechanism responsible for this remains unknown. Because the elevated levels of plasma tumor necrosis factor (TNF) play a major role in the pathophysiology of sepsis, we investigated whether TNF-alpha administration alters endothelium-dependent relaxation. To study this, recombinant TNF-alpha (1.2 x 10(7) U/mg) was infused intravenously (0.25 mg/kg body wt) for 0.5 h in normal rats, and mean arterial pressure was monitored. At 1 h after the completion of TNF-alpha or vehicle infusion, the aorta and a pulmonary artery were isolated, cut into 2.5-mm rings, and placed in organ chambers. Norepinephrine (2 x 10(-7) M) was applied to achieve near-maximal contraction, and dose responses for an endothelium-dependent vasodilator, acetylcholine, and an endothelium-independent vasodilator, nitroglycerine, were determined. In additional studies, aortic rings from normal animals were incubated with TNF-alpha for 2 h in vitro, and vascular reactivity was determined. The results indicate that TNF-alpha administration significantly reduced acetylcholine-induced vascular relaxation both in vivo and in vitro. Such a reduction was sustained at least 80 min after the completion of 2-h incubation with TNF-alpha. In contrast, TNF did not alter nitroglycerine-induced vascular relaxation. Thus TNF-alpha depresses endothelium-dependent relaxation in vitro as well as in vivo. Because TNF-alpha infusion increases plasma TNF levels without decreasing mean arterial pressure, the depressed endothelium-dependent relaxation observed during early sepsis may be due to the elevated circulating levels of TNF.

Acetylcholine↗
PubMed1994

Role of venular endothelium in control of arteriolar diameter during functional hyperemia.

This study was designed to determine the importance of the venular endothelium in the vasodilation of adjacent arterioles during functional hyperemia. The hamster cremaster muscle was prepared for in vivo microscopy. Two silver-silver chloride electrodes were placed across the pedicle of the cremaster muscle, and a square-wave pulse (10 V amplitude, 1 ms duration, and 1 Hz frequency) was used to elicit muscle contraction. Muscle stimulation for 1 min resulted in a vasodilation of the first-order arterioles from 74 +/- 2 to 91 +/- 2 microns (n = 9, P < 0.05). After perfusion of the venule with air to disrupt the venular endothelium, there was no significant effect on the resting diameter, 73 +/- 3 microns, but the vasodilation associated with the muscle stimulation was significantly attenuated to 82 +/- 3 microns (P < 0.01). After completion of these experiments, the disruption of venular endothelium was confirmed by electron microscopy. The functional vasodilation of arterioles adjacent to venules with an intact endothelium (venules in which air did not enter) was retained after air perfusion (n = 6). These results suggest that the presence of the venular endothelium is important for the arteriolar vasodilation during functional hyperemia. We propose that the venular endothelium releases a relaxing factor responsible for a portion of the functional arteriolar vasodilation.

Air↗
PubMed1995

Connexin 43 and connexin 40 gap junctional proteins are present in arteriolar smooth muscle and endothelium in vivo.

The distributions of connexin 43 (Cx43) and connexin 40 (Cx40) in smooth muscle and endothelium of resistance vessels were examined using indirect immunofluorescence techniques coupled with confocal microscopy. Cx43 and Cx40 were found in smooth muscle and endothelium. Similar staining patterns were found in microvessel samples from brain and cremaster of the rat and from arterioles of the hamster cheek pouch. Double-labeling studies showed a high degree of colocalization of Cx40 with Cx43, suggesting the presence of multiple connexins within a single junctional plaque. Quantitative comparisons were made of the fluorescent patterns in the endothelium and smooth muscle of rat brain arterioles. Cx43 and Cx40 plaque diameters were 0.9 +/- 0.1 and 0.8 +/- 0.1 (SE) microns, respectively, in the endothelial layer and 0.5 +/- 0.1 and 0.5 +/- 0.1 microns, respectively, in the smooth muscle. There was no difference between mean plaque diameters of Cx43 and Cx40 in endothelium or smooth muscle. However, plaques were significantly larger in endothelium than in smooth muscle (P < 0.05). These findings demonstrate the potential for cell-cell communication in both cell types of the wall of arterioles from three different tissues. The data also suggest a greater level of coupling within the endothelium.

Animals↗
PubMed1999

Inhibition of NO synthesis or endothelium removal reveals a vasoconstrictor effect of insulin on isolated arterioles.

In this study we tested the hypothesis that insulin may differentially affect isolated arterioles from red (RGM) and white gastrocnemius muscles (WGM) because of their differences in function and metabolic profile. We also determined whether the responses of these arterioles are endothelium dependent and mediated by either prostaglandins or nitric oxide (NO). Arterioles were isolated, pressurized to 85 mmHg, equilibrated in Krebs bicarbonate-buffered solution (pH 7.4) gassed with 10% O2 (5% CO2-85% N2), and studied in a no-flow state. Control diameters for first-order arterioles from RGM averaged 77 +/- 8 micrometers and from WGM averaged 77 +/- 5 micrometers. Cumulative dose-response curves to insulin (10 microU/ml, 100 microU/ml, 1 mU/ml, and 10 mU/ml) were obtained in arterioles before and after endothelium removal or administration of either indomethacin (Indo, 10(-5) M) or NG-nitro-L-arginine (L-NNA, 10(-4) M). Insulin evoked concentration-dependent increases in control diameter of intact RGM and WGM arterioles of 6-26% and 9-28%, respectively. Indo was without any effect on insulin-induced dilation in RGM and WGM arterioles. Insulin-evoked dilation in both RGM and WGM arterioles was completely inhibited and converted to vasoconstriction by endothelium removal and administration of L-NNA. These results indicate that in endothelium-intact arterioles from RGM and WGM, insulin evokes an endothelium-dependent dilation that is equivalent and mediated by NO. In contrast, in the absence of a functional endothelium, insulin evokes arteriolar constriction. The finding that insulin can constrict arterioles, at physiological concentrations, suggests that insulin may play a more significant role in the regulation of vascular tone and total peripheral resistance than previously appreciated.

Animals↗
PubMed2000

Alterations of endothelium and smooth muscle function in monocrotaline-induced pulmonary hypertensive arteries.

We examined how monocrotaline (MCT), which impairs the endothelium and causes pulmonary hypertension, altered the endothelial regulation of pulmonary artery functions. Rats were given a single injection of MCT (60 mg/kg sc). Pulmonary arteries were depolarized to -48.3 +/- 2.6 and -39.8 +/- 2.2 mV at 2 and 3 wk after treatment with MCT, respectively (control arteries -59.9 +/- 1.9 mV). The basal tone in the resting state was only slightly elevated at 3 wk in endothelium-intact arteries. Removal of the endothelium caused further depolarization in MCT-affected arteries at 2 wk, but not at 3 wk, and greatly elevated the basal tone at 2 and 3 wk. N(omega)-nitro-L-arginine (200 microM), a nitric oxide synthase inhibitor, also caused depolarization in endothelium-intact arteries in both groups and elevated the basal tone of MCT-affected arteries. The relaxant responses of pulmonary arteries to ACh and A-23187 were depressed at 2 and 3 wk after MCT treatment. Thus chronic impairment of the endothelium altered the property of the pulmonary artery leading to depolarization. During the early stage of depolarization, a rise in the basal tone was offset by nitric oxide released from the injured endothelium.

Animals↗
PubMed1990

Effects of hypoxia on endothelium-dependent relaxation of rat pulmonary artery.

We have previously reported that the isolated rat branch pulmonary artery (PA) contracts when made hypoxic and that the contraction is dependent in large part on the presence of a functioning endothelium. This study tested if the hypoxic contraction was caused by reduced endothelium-derived relaxing factor (EDRF) activity. To do so we tested if chemical inhibitors of EDRF mimicked the effect of hypoxia, if PA guanosine 3',5'-cyclic monophosphate (cGMP) fell during hypoxic contraction, and if stimulation of smooth muscle cGMP attenuated hypoxic contraction. We found that the EDRF inhibitors hemoglobin and methylene blue caused a concentration-dependent increase in PA force that equaled that produced by hypoxia. PA cGMP decreased in endothelium-intact rings from 105 +/- 14 pM/g (wet wt) during normoxia to 41 +/- 9 pM/g during hypoxia. In endothelium-denuded rings normoxic cGMP was reduced to 32 +/- 10 pM/g with no further decrease during hypoxia. The endothelium-independent stimulators of cGMP, nitric oxide, and 8-bromo-cGMP, reduced maximum hypoxic contraction by 80 +/- 11 and 93 +/- 3%, respectively, whereas the endothelium-dependent stimulator acetylcholine did not. PA adenosine 3',5'-cyclic monophosphate (cAMP) fell only slightly during hypoxia and cAMP inhibitors failed to mimic the hypoxic contraction. We conclude that the hypoxic contraction of isolated rat PA is caused largely by decreased EDRF activity.

Acetylcholine↗
PubMed1994

Mechanisms of hypoxic vasoconstriction in the canine isolated pulmonary artery: role of endothelium and sodium pump.

Contraction of canine pulmonary artery to hypoxia in vitro is both endothelium dependent and independent. The mechanisms which underlie this phenomenon were studied. Rings of canine pulmonary artery were suspended for isometric force recording in tissue baths containing modified Krebs-Ringer bicarbonate solution. Tissues were first contracted with norepinephrine [effective dose at 35% (ED35) concentration]. Subsequent exposure to hypoxia induced a triphasic response: an initial phasic transient contraction (phase 1), a transient reduction in force (phase 2), followed by a sustained tonic contraction (phase 3). In the absence of endothelium, all phases of the hypoxic response were reduced, and phase 2 was reversed from a contraction to a relaxation (with endothelium: 0.68 +/- 0.2 g; without endothelium: -0.34 +/- 0.1 g). Similar data were obtained in the presence of nitro-L-arginine (3 x 10(-5) M). In the absence of endothelium, indomethacin (10(-5) M) abolished the phase 2 relaxation and converted phase 3 from a contraction to a relaxation (control: 0.99 +/- 0.2 g; indomethacin: -0.44 +/- 0.1 g); and ONO-3708 (thromboxane A2/prostaglandin H2 receptor antagonist) diminished phase 3 (control: 0.99 +/- 0.2 g; ONO-3708: 0.3 +/- 0.04 g). In the absence of endothelium, but in the presence of indomethacin (10(-5) M), K(+)-free solution diminished phase 1 (contraction) and converted phase 2 (relaxation) to a contraction (control: -0.74 +/- 0.1 g; K(+)-free solution: 0.1 +/- 0.06 g). Similar results were obtained with ouabain (4 x 10(-7) M), and cooling of the bathing medium (20 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Inhaled NO reaches distal vasculatures to inhibit endothelium- but not leukocyte-dependent cell adhesion.

Nitric oxide (NO), in addition to being a potent vasodilator, also prevents leukocyte adhesion in the microvasculature. Based on the antiadhesive properties of NO and work suggesting that NO is transported by proteins in the circulation, we tested the possibility that inhaled NO could impart antiadhesive effects in peripheral microvessels. We also determined the underlying mechanisms of actions. Three well-established models that induce local microvascular changes (either endothelium or leukocyte) were used. Hydrogen peroxide (H(2)O(2); 100 microM) was superfused onto the cat mesentery to induce an endothelium-derived, P-selectin- and platelet-activating factor-dependent, oxidant-dependent leukocyte recruitment. In a second series of experiments, the cat mesentery was superfused with histamine (100 microM) to induce rapid endothelium-derived, P-selectin- and platelet-activating factor-dependent, oxidant-independent leukocyte recruitment. Finally, in a third series of experiments to target the leukocyte (but not the endothelium) directly in the periphery, the chemotactic molecule leukotriene B(4) (20 nM) was superfused onto the cat mesentery. The above experiments were performed with and without cats breathing NO (80 parts/million). Intravital microscopy was used to visualize the mesenteric microcirculation. Inhaled NO reduced the increased leukocyte rolling and adhesion associated with H(2)O(2) superfusion of the feline mesentery via a cGMP-dependent mechanism. In contrast, inhaled NO had no effect on the histamine-induced increase in leukocyte rolling flux but partially inhibited the subsequent adhesion. The leukocyte chemotactic mediator leukotriene B(4) induced a significant increase in leukocyte adhesion, but NO inhalation did not impair this chemotactically induced leukocyte recruitment. These data suggest that inhaled NO can reach the endothelium in the distal microvasculature and alter the response to an oxidative and a nonoxidative activator of endothelium but imparts no antiadhesive effect directly on circulating leukocytes.

Administration, Inhalation↗
PubMed2004

Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats.

IL-6 is elevated in plasma of preeclamptic women, and twofold elevation of plasma IL-6 increases vascular resistance and arterial pressure in pregnant rats, suggesting a role of the cytokine in hypertension of pregnancy. However, whether the hemodynamic effects of IL-6 reflect direct effects of the cytokine on the mechanisms of vascular contraction/relaxation is unclear. The purpose of this study was to test the hypothesis that IL-6 directly impairs endothelium-dependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. Active stress was measured in aortic strips isolated from virgin and late pregnant Sprague-Dawley rats and then nontreated or treated for 1 h with IL-6 (10 pg/ml to 10 ng/ml). In endothelium-intact vascular strips, phenylephrine (Phe, 10(-5) M) caused an increase in active stress that was smaller in pregnant (4.2 +/- 0.3) than virgin rats (5.1 +/- 0.3 x 10(4) N/m(2)). IL-6 (1,000 pg/ml) caused enhancement of Phe contraction that was greater in pregnant (10.6 +/- 0.7) than virgin rats (7.5 +/- 0.4 x 10(4) N/m(2)). ACh and bradykinin caused relaxation of Phe contraction and increases in vascular nitrite production that were greater in pregnant than virgin rats. IL-6 caused reductions in ACh- and bradykinin-induced vascular relaxation and nitrite production that were more prominent in pregnant than virgin rats. Incubation of endothelium-intact strips in the presence of N(omega)-nitro-L-arginine methyl ester (10(-4) M) to inhibit nitric oxide (NO) synthase, or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10(-5) M) to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in nontreated but to a lesser extent in IL-6-treated vessels, particularly those of pregnant rats. Removal of the endothelium enhanced Phe-induced stress in nontreated but not IL-6-treated vessels, particularly those of pregnant rats. In endothelium-denuded strips, relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was not different between nontreated and IL-6-treated vessels of virgin or pregnant rats. Thus IL-6 inhibits endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of virgin and pregnant rats. The greater IL-6-induced inhibition of vascular relaxation and enhancement of contraction in systemic vessels of pregnant rats supports a direct role for IL-6 as one possible mediator of the increased vascular resistance associated with hypertension of pregnancy.

Acetylcholine↗
PubMed1991

Progesterone and modulation of endothelium-dependent responses in canine coronary arteries.

Chronic treatment with estrogens enhances some endothelium-dependent relaxations. Whether or not progesterone would exert a similar effect is unknown. Experiments were designed to determine the effect of chronic treatment with progesterone on endothelium-dependent responses. Adult female dogs were ovariectomized and pellets containing carrier substance, estrogen, progesterone, or estrogen plus progesterone were implanted subcutaneously. After 14-21 days coronary arteries were removed, cut into rings, and suspended for the measurement of isometric force in organ chambers in the presence of indomethacin. Endothelium-dependent relaxations to ADP, bradykinin, or the calcium ionophore did not differ among groups. However, relaxations to acetylcholine and to the alpha 2-adrenergic agonist BHT-920 were greater in the estrogen-treated group than in the estrogen plus progesterone-treated group. In rings without endothelium, relaxations to nitric oxide and isoproterenol did not differ among groups. However, relaxations of the smooth muscle to ADP were greater in the progesterone-treated group than in the progesterone plus estrogen group. These results suggest that progesterone alone minimally affects endothelium-dependent responses. However, progesterone seems to antagonize the stimulatory effects of estrogen on two endothelium-dependent responses that are associated with pertussis toxin-sensitive guanine nucleotide regulatory proteins and the production of nitric oxide. These studies suggest that a specific receptor/second messenger system can be modulated by female reproductive steroid hormones.

Acetylcholine↗