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PubMed1992

Age, hypertension and hypercholesterolaemia alter endothelium-dependent vascular regulation.

As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoactive substances are nitric oxide, prostacyclin, endothelin-1 and contracting factors requiring the activity of cyclooxygenase. The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension and hypercholesterolaemia. All three conditions are associated with a decreased basal and simulated release of endothelium-derived nitric oxide. On the other hand, the release of endothelin-1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of a cyclooxygenase-dependent endothelium-derived contracting factor, most likely prostaglandin H2. The circulating levels of endothelin-1 on the other hand are not increased in experimental and human hypertension. In the porcine coronary circulation, oxidized low-density lipoproteins selectively reduced endothelium-dependent relaxations to aggregating platelets, serotonin and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension and hypercholesterolaemia may have important clinical implications for the pathogenesis of cardiovascular disease.

Aging↗
PubMed1991

Endothelium-dependent relaxation and effects of prostacyclin, endothelin and platelet-activating factor in human hand veins and arteries.

An altered release of endothelium-derived vasoactive factors has been implicated in several vasospastic conditions. Since the functional role of the endothelium in the hand vasculature is largely unknown, we examined the effects of 'endothelial removal' on vascular reactivity, and the effects of some 'endothelium-associated' substances in isolated human hand veins and arteries. Acetylcholine induced a large relaxation (Emax = 97 +/- 1%) in precontracted hand arteries. The relaxation was abolished by endothelial removal. In hand veins, acetylcholine induced a small relaxation (Emax = 13 +/- 4%), which was unaffected by endothelial removal. An endothelium-dependent relaxation was, however, obtained with high concentrations (greater than or equal to 10(-6) mol l-1) of the Ca2+ ionophore A23187. Contractile responses to noradrenaline, serotonin and prostaglandin F2 alpha did not differ between vein segments with and without endothelium. Endothelin was a potent constrictor of both veins and arteries. The potency and maximum response did not differ between the two types of vessel. Indomethacin pretreatment of veins did not influence the endothelin-induced contractions, suggesting that cyclo-oxygenase products are not involved in the response. In endothelin-contracted veins and arteries, the prostacyclin analogue iloprost elicited relaxation of similar potency and amplitude. The maximum relaxation in veins was, however, 3 times larger than that produced by prostacyclin itself. Platelet-activating factor was devoid of contractile and relaxant effects in both veins and arteries. The present study indicates differences between human hand veins and arteries regarding endothelial-dependent relaxation, and suggests that the modulatory role of endothelium-derived relaxing factor(s) is small in hand veins. The contractile and relaxant effects of endothelin and iloprost, however, did not differ between veins and arteries.

Acetylcholine↗
PubMed1993

Rhythmic contractions of isolated small arteries from rat: influence of the endothelium.

Small arteries of the mesenteric arcade from Wistar rats display rhythmic oscillations superimposed on the tonic contractile response when exposed to submaximal doses of noradrenaline. We have previously shown that mechanical removal of the endothelium abolishes these oscillations. In the present study different methods to eliminate or modify the influence of the endothelium were used in order to further characterize the mechanisms behind rhythmic contractions in these vessels. Endothelium was removed either mechanically or chemically by perfusing the vessels with 0.3% CHAPS. The absence of functional endothelium enhanced noradrenaline sensitivity and simultaneously abolished oscillations in tension and membrane potential, but did not affect resting membrane potential. The rhythmic activity was also reduced or abolished by exposure to haemoglobin, methylene blue, LY83583 or L-NNA. Indomethacin and propranolol were without effect. Sodium nitroprusside or the permeant analogue of cyclic GMP, 8-bromo cyclic GMP, restored rhythmic activity in precontracted endothelium-denuded vessels. The data suggest that release of nitric oxide from the endothelium, and subsequent generation of cyclic GMP in the smooth muscle, activates oscillations in membrane potential and tension; the oscillator itself appears to be located within the smooth muscle cells.

Aminoquinolines↗
PubMed1986

Role of efficacy in the assessment of the actions of alpha-adrenoceptor agonists in rat aorta with endothelium.

Concentration-effect curves to phenylephrine are shifted to the right in the presence of endothelium in rat aorta while responses to clonidine are practically abolished. Analysis of the concentration-effect curves showed that the effect of endothelium could possibly be explained by a reduction in relative intrinsic efficacy of the two agonists by between 3.5- and 6-fold. Published observations on the modulatory effects of agonist-induced contractions by endothelium in the rat aorta tend to support this explanation. It is further concluded that this reduction in efficacy could be related to the basal release of an endothelium-derived substance and that changes in tissue contractility in the presence of endothelium cannot necessarily be taken as evidence for a stimulated liberation of endothelium-derived products by agonists.

Adrenergic alpha-Agonists↗
PubMed1990

The preservation of functional activity of smooth muscle and endothelium in pig coronary arteries after storage at -190 degrees C.

Pig coronary arteries have been investigated in-vitro using fresh tissue or after storage at -190 C in foetal calf serum containing 1.8 M dimethyl sulphoxide. Attention was paid to modulation of contractile activity and endothelium-dependent relaxation. After cryopreservation of the arteries maximal contractile responses to both 5-hydroxytryptamine (5-HT) and prostaglandin F2 alpha (PGF2 alpha) were markedly reduced and the pD2 values for both agonists were slightly, but significantly, diminished. Nevertheless, 5-HT antagonism by ketanserin and pizotifen was unchanged. Endothelium-independent relaxant responses of precontracted arteries to isoprenaline, forskolin, 3-isobutyl-1-methylxanthine, nitroprusside, atriopeptin III and cromakalim were generally unchanged after storage. Mechanical removal of the endothelium by rubbing enhanced the contractile response to PGF2 alpha in both fresh and stored arteries to a similar extent. In addition, endothelium-dependent relaxant responses to both 5-HT and substance P were well maintained, suggesting release of endothelium-derived relaxing factor by the stored arteries. The evidence suggests that after cryopreservation of pig coronary arteries at -190 degrees C mechanisms of relaxation, in particular those which are endothelium-dependent, are well maintained.

Animals↗
PubMed1995

Endothelium derived relaxing factor release from canine coronary artery by leukocytes.

Lectins, known to recognize endothelial cell adhesion molecules, have been shown to release endothelium-derived relaxing factor (EDRF) from blood vessels. We investigated the effects of different leukocyte-type cells to determine if these cells, by interacting with the endothelium, could release EDRF from the circumflex branch of the canine coronary artery. The following cells were investigated: human promyelocytic leukemia (HL-60), human monocyte (THP-1), and human Burkitt lymphoma (DAUDI). All of these cells produced a significant endothelium-dependent relaxation of the dog coronary artery in the presence of ibuprofen. The endothelium-dependent relaxations were reversed by hemoglobin (10 microM), methylene blue (3 microM), 6-anilino-5,8-quinolinedione (LY 83583, 30 microM), and NG-nitro-L-arginine methyl ester (L-NAME, 1 mM). HL-60 cells grown in the presence of 1 mM L-NAME retained their ability to cause endothelium-dependent relaxation of the canine coronary artery, suggesting that the source of the NO was the endothelium and not the HL-60 cells. The cell-induced vascular relaxation could be obtained in the absence of extracellular calcium. It is suggested that HL-60, THP-1, and DAUDI cells interact with a specific receptor on the endothelial cell and as a result of this interaction the endothelial cells are stimulated to release EDRF.

Aminoquinolines↗
PubMed1993

Endothelium-dependent vasorelaxation evoked by desmopressin and involvement of nitric oxide in rat aorta.

It is known that in vivo administration of desmopressin (DDAVP; a selective V2-vasopressin receptor agonist) results in prostacyclin-independent vasodilation. The in vitro effects of DDAVP and its mechanisms were examined using rat aortic strips. DDAVP from a concentration of 1 x 10(-9) M caused a concentration-dependent relaxation of the aorta precontracted with norepinephrine (10(-7) M) with intact endothelium. However, no relaxation was induced in aorta with the endothelium removed. The DDAVP-induced relaxation was not influenced by the presence of indomethacin but was inhibited by L-NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide (NO) synthesis. The inhibition by L-NMMA was reversed by the addition of L-arginine but not D-arginine. Further, the endothelium-dependent relaxation due to DDAVP was potentiated by superoxide dismutase, a scavenger of superoxide anions, and was inhibited by hemoglobin. DDAVP induced an increase in guanosine 3',5'-cyclic monophosphate levels in the aorta with endothelium but not in aorta without endothelium, and this was suppressed by L-NMMA and hemoglobin. The suppression by L-NMMA was also partially reversed by L-arginine but not by D-arginine. Two selective V2-receptor antagonists had no effect on the DDAVP-induced vasorelaxation. Selective V1-receptor antagonists (a peptidic and a nonpeptidic) caused a concentration-dependent but nonparallel shift to the right of the concentration-response curves to DDAVP. However, DDAVP did not affect the tension of the strip with or without endothelium in nonprecontracted aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Acetylcholine causes endothelium-dependent contraction of mouse arteries.

The goal of this study was to determine whether acetylcholine evokes endothelium-dependent contraction in mouse arteries and to define the mechanisms involved in regulating this response. Arterial rings isolated from wild-type (WT) and endothelial nitric oxide (NO) synthase knockout (eNOS(-/-)) mice were suspended for isometric tension recording. In abdominal aorta from WT mice contracted with phenylephrine, acetylcholine caused a relaxation that reversed at the concentration of 0.3-3 microM. After inhibition of NO synthase [with N(omega)-nitro-l-arginine methyl ester (l-NAME), 1 mM], acetylcholine (0.1-10 microM) caused contraction under basal conditions or during constriction to phenylephrine, which was abolished by endothelial denudation. This contraction was inhibited by the cyclooxygenase inhibitor indomethacin (1 muM) or by a thromboxane A(2) (TxA(2)) and/or prostaglandin H(2) receptor antagonist SQ-29548 (1 microM) and was associated with endothelium-dependent generation of the TxA(2) metabolite TxB(2.) Also, SQ-29548 (1 microM) abolished the reversal in relaxation evoked by 0.3-3 microM acetylcholine and subsequently enhanced the relaxation to the agonist. The magnitude of the endothelium-dependent contraction to acetylcholine (0.1-10 microM) was similar in aortas from WT mice treated in vitro with l-NAME and from eNOS(-/-) mice. In addition, we found that acetylcholine (10 microM) also caused endothelium-dependent contraction in carotid and femoral arteries of eNOS(-/-) mice. These results suggest that acetylcholine initiates two competing responses in mouse arteries: endothelium-dependent relaxation mediated predominantly by NO and endothelium-dependent contraction mediated most likely by TxA(2).

Acetylcholine↗
PubMed2006

In SHR aorta, calcium ionophore A-23187 releases prostacyclin and thromboxane A2 as endothelium-derived contracting factors.

In mature spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), acetylcholine and the calcium ionophore A-23187 release endothelium-derived contracting factors (EDCFs), cyclooxygenase derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine are most likely prostacyclin and prostaglandin (PG)H(2), whereas those released by A-23187 remain to be identified. Isometric tension and the release of PGs were measured in rings of isolated aortas of WKY and SHR. A-23187 evoked the endothelium-dependent release of prostacyclin, thromboxane A(2), PGF(2alpha), PGE(2), and possibly PGH(2) (PGI(2) >> thromboxane A(2) = PGF(2alpha) = PGE(2)). In SHR aortas, the release of prostacyclin and thromboxane A(2) was significantly larger in response to A-23187 than to acetylcholine. In response to the calcium ionophore, the release of thromboxane A(2) was significantly larger in aortas of SHR than in those of WKY. In both strains of rat, the inhibition of cyclooxygenase-1 prevented the release of PGs and the occurrence of endothelium-dependent contractions. Dazoxiben, the thromboxane synthase inhibitor, abolished the A-23187-dependent production of thromboxane A(2) and inhibited by approximately one-half the endothelium-dependent contractions. U-51605, an inhibitor of PGI synthase, reduced the release of prostacyclin elicited by A-23187 but induced a parallel increase in the production of PGE(2) and PGF(2alpha), suggestive of a PGH(2) spillover, which was associated with the enhancement of the endothelium-dependent contractions. These results indicate that in the aorta of SHR and WKY, the endothelium-dependent contractions elicited by A-23187 involve the release of thromboxane A(2) and prostacyclin with a most likely concomitant contribution of PGH(2).

Animals↗
PubMed1982

Metabolism of norepinephrine in vitro by dog pulmonary arterial endothelium.

The importance of endothelial cells in the removal of norepinephrine from synaptic clefts in dog pulmonary artery was studied. Strips of artery cut helically were denuded of endothelium by gently stroking the intimal surface with a wooden applicator stick or were studied with endothelium intact. All strips were prelabeled in L-[3H]norepinephrine (2 X 10(-7) M) and mounted for superfusion. Superfusate was collected continuously before, during, and after electrical stimulation (10 V, 2 ms, 2 Hz). Measurements were made of the amounts of [3H]norepinephrine and its metabolites in superfusate and in tissue. These studies have established that 3,4-dihydroxyphenylglycol is of neuronal origin and O-methylated metabolites are of extraneuronal origin. The formation of extraneuronal metabolites in smooth muscle and endothelium was examined by either blocking uptake of norepinephrine into each, in turn, or by combining blockade of uptakes with the elimination of access of norepinephrine to endothelial tissue by completely removing it. Electrical stimulation elicited the overflow of large amounts of norepinephrine, 3,4-dihydroxyphenylglycol, and O-methylated metabolites into superfusate in strips with intact endothelium; in strips denuded of endothelium there were striking decreases in the amounts of O-methylated metabolites produced. These studies show that pulmonary arterial endothelium participates in the extraneuronal metabolism of norepinephrine released by sympathetic nerve stimulation.

Animals↗
PubMed1984

Endothelium and asymmetrical responses of the coronary arterial wall.

Changes in isometric tension due to intra- or extraluminal addition of vasoactive agents were determined in isolated perfused segments of canine left circumflex coronary artery. Segments denuded of endothelium were more sensitive to the contractile action of 5-hydroxytryptamine and potassium during intraluminal addition. In segments with intact endothelium, the sensitivity to intraluminal, but not extraluminal, 5-hydroxytryptamine was decreased in comparison to denuded segments; that to potassium was unchanged. In segments with intact endothelium contracted with prostaglandin F2 alpha, intraluminal, but not extraluminal, acetylcholine, adenosine diphosphate, or thrombin caused relaxation. Intraluminal 5-hydroxytryptamine and aggregating platelets caused relaxation or attenuated contractions in a majority of vessels studied; extraluminal addition caused only contractions. Thus the endothelium is responsible for opposite smooth muscle responses to intra- versus extraluminal vasoactive substances released from aggregating platelets. During intraluminal thrombosis the endothelium may inhibit smooth muscle contraction by responding to 5-hydroxytryptamine and adenosine diphosphate released from platelets and to thrombin; where the endothelium is damaged, the luminal aspect of the blood vessel wall, which is more sensitive to 5-hydroxytryptamine, may become the site of coronary spasm.

Acetylcholine↗
PubMed1985

Uptake and metabolism of norepinephrine by endothelium of dog pulmonary artery.

The contribution of endothelium of dog pulmonary artery to the extraneuronal metabolism of norepinephrine was determined. Pulmonary artery was cut into helical strips; the endothelium was removed from half of the strips by gently stroking them with a wooden applicator stick. All strips were immersed in l-[3H]norepinephrine (2 X 10(-7) M) and mounted for superfusion. Superfusate was collected continuously before, during, and after electrical stimulation (10 V, 2 ms, 2 Hz). Column chromatography was used to separate [3H]norepinephrine and its radiolabeled metabolites in superfusate. Quantitation was by liquid scintillation spectrometry. Previous studies have established that 3,4-dihydroxyphenylglycol is of neuronal origin and that O-methylated metabolites are of extraneuronal origin. Since cocaine prevented neuronal uptake of norepinephrine, the reduction in metabolites of norepinephrine of extraneuronal origin in arteries with endothelium removed represented the contribution of endothelium to extraneuronal metabolism. O-Methylated metabolites were decreased from 3.50 to 2.17 X 10(3) dpm/2 ml of superfusate during basal conditions preceding electrical stimulation and from 11.16 to 6.94 X 10(3) dpm/2 ml of superfusate during electrical stimulation when endothelium had been removed. Decreases in extraneuronal metabolite production continued throughout the basal periods following stimulation. These studies suggest that in small pulmonary artery a substantial amount of the total norepinephrine that is released at the neuroeffector junction may be metabolized following uptake into endothelium.

Animals↗
PubMed1986

Enhanced adrenergic constriction of iliac artery with removal of endothelium in conscious dogs.

We studied, in conscious dogs, the effects of removal of endothelium on the responses of iliac artery diameter and iliac blood flow to intra-arterial infusions of adrenergic agonists. With endothelium intact, iliac diameter increased with intra-arterial infusion of nitroglycerin (4.7 +/- 0.4%), acetylcholine (4.2 +/- 0.6%), and epinephrine (4.5 +/- 1.3%), and decreased with norepinephrine (-7.5 +/- 1.7%), phenylephrine (-6.6 +/- 1.0%), and B-HT 920 (-2.1 +/- 0.6%). One- to-five days following removal of endothelium with a balloon-tipped catheter, base-line iliac diameter was unchanged, and still increased with nitroglycerin (4.6 +/- 0.5%), but not with acetyl-choline, and epinephrine actually decreased diameter (-3.5 +/- 1.3%). Removal of the endothelium also enhanced the constriction observed with norepinephrine (-12.5 +/- 2.0%) and phenylephrine (-11.4 +/- 1.6%), but not with B-HT 920 (-1.8 +/- 0.5%). The changes in arterial pressure, iliac blood flow, iliac vascular resistance, and heart rate induced by any of the agonists did not differ before and after removal of the endothelium. These results indicate that the endothelium mediates the dilation in response to epinephrine and also serves an important role in protecting against alpha 1-adrenergic vasoconstriction of large iliac arteries.

Animals↗
PubMed1986

Modulation of endothelium-dependent responses by chronic alterations of blood flow.

To determine whether the blood flow and O2 tension to which a blood vessel is chronically exposed could modulate endothelium-dependent responses, these parameters were altered in the dog either by causing partial occlusion of the femoral artery or by creating a fistula between the femoral artery and vein. Blood flow was reduced by 75% in the clamped artery; mean arterial pressure was unchanged. In the vessels proximal to the fistula, blood flow was elevated and O2 tensions were similar in the vein and artery. After 6 wk the femoral arteries and veins were excised, and their endothelium-dependent responses were studied in vitro. The endothelium-dependent relaxations to acetylcholine, adenosine diphosphate, and alpha 2-adrenergic stimulation were augmented in fistula-operated compared with sham-operated arteries. The responses to these agents in the clamp-operated vessels were not different from those of the sham-operated ones. Relaxation to arachidonic acid in the arteries showed an inverse relationship to blood flow. In the veins proximal to the fistula, the endothelium-dependent relaxations to acetylcholine were augmented and an endothelium-dependent relaxation to alpha 2-adrenergic stimulation was present; only a contractile response was observed in veins from the sham-operated limb in response to the latter. These studies suggest a pattern of increased endothelium-dependent relaxation in vessels exposed to chronically elevated blood flow.

Animals↗
PubMed1988

Endothelium-dependent pressure-induced contraction of isolated canine carotid arteries.

Experiments were conducted in a bioassay system, where a canine coronary artery ring without endothelium (bioassay tissue) was superfused by the effluent from a perfused canine carotid artery segment with endothelium (donor segment). A rapid increase in transmural pressure (from near 0 to 32-38 mmHg) triggered active contraction of the donor segment and simultaneously of the bioassay tissue. These contractions were prevented by removal of the endothelium from the donor segment but not by treatment of the segment with indomethacin. Exposure to elevated pressure depressed basal, acetylcholine-, and flow-induced release of endothelium-derived relaxing factor(s). Methylene blue prevented the pressure-induced contraction of the bioassay ring. These data show that pressure-induced contraction of isolated carotid arteries is endothelium dependent and is mediated by the depression of the synthesis and/or release of endothelium-derived relaxing factor(s).

Acetylcholine↗
PubMed1989

Endothelium-dependent and -independent responses to vasoactive substances of isolated human coronary arteries.

In epicardial conduit coronary artery strips obtained during autopsy within 2.5 h after death, relaxations induced by low concentrations of histamine were reversed to contractions by removal of endothelium, whereas those caused by bradykinin, substance P, and Ca2+ ionophore A23187 were almost abolished. In the artery strips with intact endothelium, which responded to histamine, bradykinin, and substance P with moderate or marked relaxations, acetylcholine elicited contractions. Endothelium denudation failed to potentiate the contractile response to acetylcholine and serotonin. Relaxant responses to histamine, bradykinin, and substance P did not significantly differ in coronary arteries from adults (35-48 yr old) and seniors (63-82 yr old). Two strips from a 2-mo-old male responded to acetylcholine only with contractions, and their responses to the vasodilators were not greater than those seen in the adult and senior arteries. Histamine increased guanosine 3',5'-cyclic monophosphate (cGMP); the increments did not differ in the arteries from adults and seniors. It may be concluded that endothelium is a major site for relaxant actions of histamine, bradykinin, and substance P, whereas muscarinic receptors, if any, in endothelium do not play an important role in the generation of relaxing factor from human coronary arteries. The endothelium-dependent relaxations do not appear to be altered with increasing age or in the arteries with slight atherosclerotic changes.

Acetylcholine↗
PubMed1990

Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway.

Endothelial cells modulate vascular tone by releasing endothelium-derived relaxing (EDRF) and contracting factors. An imbalance of these factors in hypertension could contribute to increased peripheral vascular resistance. Mesenteric resistance arteries of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were suspended in a myograph filled with physiological salt solution (37 degrees C; 95% O2-5% CO2). In WKY rings contracted with norepinephrine, acetylcholine (10(-9)-10(-4) M) evoked endothelium-dependent relaxations (88 +/- 2%, IC50 7.3 +/- 0.1; n = 31). Hemoglobin (10(-5) M) but not meclofenamate (10(-5) M) reversed the relaxations delineating EDRF as the mediator. Nitric oxide (3 X 10(-9)-10(-5) M) induced comparable relaxations as acetylcholine. In SHRSP, relaxations to acetylcholine but not those to nitric oxide were impaired (61 +/- 5%, IC50 greater than 6.6 +/- 0.4; n = 24; P less than 0.005). In SHRSP, meclofenamate but not the thromboxane synthetase inhibitor CGS 13080 normalized endothelium-dependent relaxations. Relaxations to sodium nitroprusside were enhanced in SHRSP both in rings with and without endothelium. Thus our results are compatible with the concept that endothelium-dependent relaxations in resistance arteries are mediated by nitric oxide. In SHRSP, endothelium-dependent relaxations are impaired because of a cyclooxygenase-dependent substance interfering with the release and/or action of EDRF.

Animals↗
PubMed1991

Importance of endothelium-derived nitric oxide in porcine coronary resistance arteries.

Endothelial cells regulate vascular tone through the release of nitric oxide and other relaxing factors. The role of these substances was studied in isolated intramyocardial porcine coronary resistance arteries suspended in myographs for isometric tension recording. The inhibitor of nitric oxide formation NG-monomethyl-L-arginine (L-NMMA; 10(-7)-10(-4)M), but not D-NMMA, caused endothelium-dependent contractions that could be reversed by L-arginine but not by D-arginine. In preparations with endothelium, L-NMMA potentiated the contractions induced by acetylcholine and the relaxations to 3-morpholino-sydnonimine. Under both conditions, the effect of endothelial removal was slightly more pronounced than that of L-NMMA. Bradykinin, serotonin, and the alpha 2-adrenergic agonist clonidine evoked endothelium-dependent relaxations. L-NMMA as well as the inhibitor of guanylate cyclase methylene blue (10(-5) M) prevented the relaxations induced by clonidine, reduced those to serotonin, but hardly affected those to bradykinin. Thus, in porcine coronary resistance arteries, endothelium-derived nitric oxide is continuously produced from L-arginine. Endothelium-dependent relaxations to clonidine are fully mediated and those to serotonin partially mediated by nitric oxide; its release does not involve a Gi protein. An endothelium-derived relaxing factor different from nitric oxide must mediate the relaxations to bradykinin and contribute to those evoked by serotonin.

Animals↗