Martın Aldasoro | Universitat de València (original) (raw)
Papers by Martın Aldasoro
Journal of Pharmacology and Experimental Therapeutics, Sep 1, 1998
We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 mul... more We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 multiorgan donors to investigate whether subpressor concentrations of vasopressin facilitate noradrenergic transmission in penile blood vessels. Vasopressin constricted penile dorsal arteries (pD 2 , 9.38 Ϯ 0.18) and deep dorsal veins (pD 2 , 9.40 Ϯ 0.14) by activating V 1 receptors. Vasopressin (10 Ϫ11 and 3 ϫ 10 Ϫ11 M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (15 V, 0.5-2 Hz, 0.2 msec duration for 15 sec) and produced leftward shifts of the concentrationresponse curve for norepinephrine. The V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (3 ϫ 10 Ϫ9 -10 Ϫ7 M) induced concentrationdependent inhibitions of potentiation caused by vasopressin. In
The American Journal of Physiology, Apr 1, 1997
Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may ... more Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal contractions. Vasopressin also potentiated KCl- and calcium-induced contractions. The V1-receptor antagonist 1-[beta-mercapto-beta,beta-cyclopentamethylenepropionic acid-2-O-methyl-tyrosine, 8-arginine]vasopressin (10(-6) M) prevented the potentiation evoked by vasopressin in all cases. The calcium antagonist nifedipine (10(-6) M) did not affect the potentiation of electrical stimulation and norepinephrine induced by vasopressin but abolished KCl-induced contractions. The results suggest that vasopressin, in addition to its direct vasoconstrictor effect, strongly potentiates the responses to adrenergic stimulation and KCl depolarization. Both the direct and indirect effects of vasopressin appear to be mediated by V1-receptor stimulation. The amplifying effect of vasopressin on constrictor responses may be relevant in those clinical situations characterized by increased plasma vasopressin levels.
European Journal of Pharmacology, Mar 1, 2001
To examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to ... more To examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline. Endothelin-1 (10(-10) M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ET(B) receptor antagonist (2,6-dimethylpiperidinecarbonyl-gamma-methyl-Leu-N(in)-[Methoxycarbonyl]-D-Trp-D-Nle) (BQ-788, 10(-6) M), but not the endothelin ET(A) receptor antagonist cyclo(D-Asp-Pro-D-Val-Leu-D-TRP) (BQ-123, 10(-6) M), inhibited the potentiating effects of endothelin-1. Pretreatment with the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate and the thromboxane receptor antagonist [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino] methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-30741) (all at 10(-5) M) prevented the potentiation induced by endothelin-1 on adrenergic stimulation. The Ca(2+) channel antagonist nifedipine (10(-6) M) did not affect the potentiation induced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endothelin ET(B) receptors. This potentiation depends on the production of cyclooxygenase-generated factors, probably thromboxane A(2).
PLOS ONE, 2015
Alzheimer´s disease (AD), a neurodegenerative illness involving synaptic dysfunction with extrace... more Alzheimer´s disease (AD), a neurodegenerative illness involving synaptic dysfunction with extracellular accumulation of Aβ 1-42 toxic peptide, glial activation, inflammatory response and oxidative stress, can lead to neuronal death. Endogenous cannabinoid system is implicated in physiological and physiopathological events in central nervous system (CNS), and changes in this system are related to many human diseases, including AD. However, studies on the effects of cannabinoids on astrocytes functions are scarce. In primary cultured astrocytes we studied cellular viability using MTT assay. Inflammatory and oxidative stress mediators were determined by ELISA and Western-blot techniques both in the presence and absence of Aβ 1-42 peptide. Effects of WIN 55,212-2 (a synthetic cannabinoid) on cell viability, inflammatory mediators and oxidative stress were also determined. Aβ 1-42 diminished astrocytes viability, increased TNF-α and IL-1β levels and p-65, COX-2 and iNOS protein expression while decreased PPAR-γ and antioxidant enzyme Cu/Zn SOD. WIN 55,212-2 pretreatment prevents all effects elicited by Aβ 1-42 . Furthermore, cannabinoid WIN 55,212-2 also increased cell viability and PPAR-γ expression in control astrocytes. In conclusion cannabinoid WIN 55,212-2 increases cell viability and anti-inflammatory response in cultured astrocytes. Moreover, WIN 55,212-2 increases expression of anti-oxidant Cu/Zn SOD and is able to prevent inflammation induced by Aβ 1-42 in cultured astrocytes. Further studies would be needed to assess the possible beneficial effects of cannabinoids in Alzheimer's disease patients.
The Journal of pharmacology and experimental therapeutics, 1998
We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 mul... more We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 multiorgan donors to investigate whether subpressor concentrations of vasopressin facilitate noradrenergic transmission in penile blood vessels. Vasopressin constricted penile dorsal arteries (pD2, 9.38 +/- 0.18) and deep dorsal veins (pD2, 9. 40 +/- 0.14) by activating V1 receptors. Vasopressin (10(-11) and 3 x 10(-11) M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (15 V, 0.5-2 Hz, 0.2 msec duration for 15 sec) and produced leftward shifts of the concentration-response curve for norepinephrine. The V1 receptor antagonist d(CH2)5Tyr(Me)AVP (3 x 10(-9)-10(-7) M) induced concentration-dependent inhibitions of potentiation caused by vasopressin. In contrast, the V2 receptor antagonist [d(CH2)5,D-Ile2, Ile4,Arg8]-vasopressin (10(-8)-10(-7) M) did not prevent the potentiation induced by vasopressin. The results demonstrate that vasopressin e...
The American journal of physiology, 1997
Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may ... more Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal ...
Journal of andrology
The present study was designed to investigate general morphology and the response of human defere... more The present study was designed to investigate general morphology and the response of human deferential artery to constrictor and dilator substances with special emphasis on endothelium-dependent responses. Human deferential artery segments were obtained from patients undergoing radical cystectomy (n = 7), suprapubic prostatectomy (n = 6), or radical prostatectomy (n = 6). Light microscopy revealed that human deferential artery is of muscular type, and fluorescence microscopy showed a dense adrenergic innervation. Paired rings, one normal and the other de-endothelialized by gentle rubbing, were mounted for isometric recording of tension in organ baths. Vasopressin, endothelin, serotonin, and potassium chloride induced endothelium-independent contractions, whereas norepinephrine and electrical field stimulation caused frequency-dependent contractions that were of greater magnitude in arteries denuded of endothelium. In precontracted arterial rings, acetylcholine and substance P induce...
American Journal of Hypertension, 2007
We studied the participation of K(+) channels on the adrenergic responses in human saphenous vein... more We studied the participation of K(+) channels on the adrenergic responses in human saphenous veins as well as the intervention of dihydropyridine-sensitive Ca(2+) channels on modulation of adrenergic responses by K(+) channels blockade. Saphenous vein rings were obtained from 40 patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. Iberiotoxin (10(-7) mol/L), an inhibitor of large conductance Ca(2+)-activated K(+) channels, and charybdotoxin (10(-7) mol/L), an inhibitor of both large and intermediate conductance Ca(2+)-activated K(+) channels, enhanced the contractions elicited by electrical field stimulation and produced a leftward shift of the concentration-response curve to norepinephrine. In contrast, the inhibitor of small conductance Ca(2+)-activated K(+) channels apamin (10(-6) mol/L) did not modify the contractile response to electrical field stimulation or norepinephrine. In the presence of the dihydropyridine Ca(2+)-channel blocker nifedipine (10(-6) mol/L), iberiotoxin and charybdotoxin failed to enhance the contractile responses to electrical field stimulation and norepinephrine. The results suggest that large conductance Ca(2+)-activated K(+) channels are activated by stimulation with norepinephrine to counteract the adrenergic-induced contractions of human saphenous vein. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels.
American Journal of Hypertension, 2006
We recently reported that endothelium-dependent relaxation is impaired in forearm veins from pati... more We recently reported that endothelium-dependent relaxation is impaired in forearm veins from patients with chronic renal failure. However, assessment of responses to norepinephrine remains controversial. We examined the contractile response to norepinephrine in forearm veins from patients on chronic hemodialysis and the role of nitric oxide (NO), prostanoids, and Ca(2+)-activated K(+) channels in this response. Isometric contraction curves were obtained in rings of forearm vein from 21 dialyzed patients and 12 multiorgan donors in response to norepinephrine (1 nmol/L to 10 micromol/L) or KCl (5 to 100 mmol/L). Veins from uremic patients were markedly less responsive to norepinephrine (7.6 +/- 0.6 g) and KCl (6.0 +/- 0.3 g) than those from organ donors (12.0 +/- 0.7 g and 10.4 +/- 0.5 g, respectively, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05). Treatment with N(G)-monomethyl-l-arginine (100 micromol/L), an inhibitor of NO synthase, or indomethacin (10 micromol/L), an inhibitor of prostacyclin synthesis, increased the response to norepinephrine in veins from control subjects but not in veins from dialyzed patients. Additional blockade of Ca(2+)-activated K(+) channels did not correct the hyporesponsiveness. In veins incubated in Ca(2+)-free solution containing either 100 mmol/L KCl or 1 micromol/L norepinephrine, addition of calcium chloride (0.1 to 30 mmol/L) elicited contractile responses that were significantly lower in veins from dialyzed patients. The results demonstrate that norepinephrine-mediated contractions of forearm veins are markedly decreased in dialyzed patients. Endothelium-derived relaxing factors are not involved in this effect. The reduced contractile response is most likely caused by a decreased calcium entry through voltage- and receptor-dependent calcium channels.
American Journal of Hypertension, 2007
The aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostag... more The aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostaglandins in the responses of human gastroepiploic artery to sympathetic stimulation and norepinephrine. Rings of human gastroepiploic artery were obtained from 45 patients (26 men and 19 women) undergoing gastrectomy. The rings were suspended in organ baths for isometric recording of tension. We studied the responses to electrical field stimulation, norepinephrine, and acetylcholine, in the absence and presence of COX-1 or COX-2 inhibition. The COX-1 and COX-2 inhibitor aspirin at high concentrations (10(-6) to 10(-5) mol/L) and the COX-2 inhibitor nimesulide (10(-6) mol/L) potentiated the contractile responses of the arterial rings to sympathetic neurogenic stimulation and norepinephrine. In contrast, lower concentrations of aspirin (10(-8) to 10(-7) mol/L) or the COX-1 inhibitor SC-560 (3 x10(-8) mol/L) did not affect these responses. The vascular relaxation induced by acetylcholine was not affected by COX-1 and COX-2 inhibition. The results provide functional evidence that vasodilator prostaglandins are active components of the response of human gastroepiploic artery to neurogenic stimulation and norepinephrine. Aspirin at high concentrations and the COX-2 selective inhibitor nimesulide potentiated the contractile response of gastroepiploic artery to adrenergic stimulation by inhibiting COX-2-derived PGI(2). Aspirin at low concentrations and the COX-1 selective inhibitor SC-560 did not modify the contractile responses, possibly due to minor importance of vasoconstrictor prostaglandins (TXA(2)) as active components of the response of gastroepiploic artery to adrenergic stimulation.
International Journal of Medical Sciences, 2015
One of the earliest neuropathological events in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp... more One of the earliest neuropathological events in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease is accumulation of astrocytes at sites of Aβ1-42 depositions. Our results indicate that Aβ1-42 toxic peptide increases lipid peroxidation, apoptosis and cell death in neurons but not in astrocytes in primary culture. Aβ1-42-induced deleterious neuronal effects are not present when neurons and astrocytes are mixed cultured. Stimulation of astrocytes with toxic Aβ1-42 peptide increased p-65 and decreased IκB resulting in inflammatory process. In astrocytes Aβ1-42 decreases protein expressions of sirtuin 1 (SIRT-1) and peroxisome proliferator-activated receptor γ (PPAR-γ) and over-expresses peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) and mitochondrial transcription factor A (TFAM), protecting mitochondria against Aβ1-42-induced damage and promoting mitochondrial biogenesis. In summary our data suggest that astrocytes may have a key role in protecting neurons, increasing neural viability and mitochondrial biogenesis, acquiring better oxidative stress protection and perhaps modulating inflammatory processes against Aβ1-42 toxic peptide. This might be a sign of a complex epigenetic process in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease development.
European Heart Journal, 2013
ABSTRACT Purpose: Physical activity is able to reduce cardiovascular morbidity and mortality. The... more ABSTRACT Purpose: Physical activity is able to reduce cardiovascular morbidity and mortality. These effects may be mediated in a number of ways including an enhancement of endothelial function. We investigated the effects of physical training on plasma levels of nitric oxide (NO) and vascular responses induced by sympathetic stimulation and acetylcholine. Methods: Eleven male New Zealand white rabbits were exercised during 6 weeks following a chronic exercise protocol on treadmill (trained group) and another twelve rabbits (control group) were stabulated during the same period. When the chronic exercise program was finished, rabbits were anaesthetized, killed and common carotid arteries were dissected. Arterial segments (3 mm long) were mounted for isometric recording of tension in organ baths containing Krebs-Henseleit solution. Electrical field stimulation (EFS, 4Hz, 20V, 0.25 ms duration for 30 s) was provided by a Grass S88 stimulator via two platinum electrodes positioned on each side and parallel to the axis of the arterial segment. Blood samples were drawn from the ear artery before anaesthesia for determination of plasma nitrite plus nitrate (NOx) using the Griess reaction. Results: Acetylcholine (3x10-6M) produced more relaxation in control group (Emax values: 93.8±2.1 for control group vs 83.5±3.2 for training group, n=10; p>0.05). The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME 10-4M) reduced the relaxation to acetylcholine in both trained (pD2 = 6.7±0.2, n=5; p<0.001) and control rabbits (pD2 = 6.9±0.2, n=5; p<0.001). The reduction of maximum effect by L-NAME was greater in control rabbits (44% vs 34%, p<0.05). The contractile responses to EFS were abolished by tetrodotoxin (10-6M), guanethidine (10-6M) and prazosin (10-6M) thus indicating that the contractile effect is due to noradrenaline acting on a1 adrenoceptors. EFS (1, 2 and 4 Hz) induced contraction was greater in trained groups. L-NAME 10-4M enhanced the contractions elicited by EFS in both groups with the similar magnitude. Plasma levels of NOx were similar in both control and trained groups (67±21 mM vs 62±20 mM, n=11; p>0.05). Conclusions: Although NO plasma levels were similar in the two groups, trained rabbits show a significant decrease in the NO component, sensitive to L-NAME, induced by acetylcholine but not by sympathetic stimulation.
BioMed Research International, 2013
The aim of this study was to analyze whether tyrosine phosphorylation in tumoral arteries may mod... more The aim of this study was to analyze whether tyrosine phosphorylation in tumoral arteries may modulate their vascular response. To do this, mesenteric arteries supplying blood flow to colorectal tumors or to normal intestine were obtained during surgery and prepared for isometric tension recording in an organ bath. Increasing tyrosine phosphorylation with the phosphatase inhibitor, sodium orthovanadate produced arterial contraction which was lower in tumoral than in control arteries, whereas it reduced the contraction to noradrenaline in tumoral but not in control arteries and reduced the relaxation to bradykinin in control but not in tumoral arteries. Protein expression of VEGF-A and of the VEGF receptor FLT1 was similar in control and tumoral arteries, but expression of the VEGF receptor KDR was increased in tumoral compared with control arteries. This suggests that tyrosine phosphorylation may produce inhibition of the contraction in tumoral mesenteric arteries, which may increase blood flow to the tumor when tyrosine phosphorylation is increased by stimulation of VEGF receptors.
Life Sciences, 2013
Aims: In the present study we investigated the intervention of nitric oxide and prostacyclin in t... more Aims: In the present study we investigated the intervention of nitric oxide and prostacyclin in the responses to vasopressin of isolated thyroid arteries obtained from multi-organ donors. Main methods: Paired artery rings from glandular branches of the superior thyroid artery, one normal and the other deendothelised, were mounted in organ baths for isometric recording of tension. Concentrationresponse curves to vasopressin were determined in the absence and in the presence of either the vasopressin V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (10 −8 M), the nitric oxide synthase inhibitor N G -monomethyl-Larginine (L-NMMA, 10 −4 M), or the inhibitor of prostaglandins indomethacin (10 −6 M). Key findings: In artery rings under resting tension, vasopressin produced concentration-dependent, endotheliumindependent contractions. The vasopressin V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (10 −8 M) displaced the control curve to vasopressin 19-fold to the right in a parallel manner. The contractile response to vasopressin was unaffected by L-NMMA or by indomethacin. Significance: Vasopressin causes constriction of human thyroid arteries by stimulation of V 1 vasopressin receptors located on smooth muscle cells. These effects are not linked to the presence of an intact endothelium or to the release of nitric oxide or prostaglandins. The constriction of thyroid arteries may be particularly relevant in certain pathophysiological circumstances in which vasopressin is released in amounts that could interfere with the blood supply to the thyroid gland.
Journal of Vascular Surgery, 1997
P~rpose: The goal of this study was to determine the effects of vasopressin and the selective V2-... more P~rpose: The goal of this study was to determine the effects of vasopressin and the selective V2-receptor agonist desmopressin on human saphenous veins, with special emphasis on endothelium-mediated responses.
Journal of Pharmacy and Pharmacology, 1992
The effects of endothelin have been studied in isolated arterial segments (0.8-1 mm in external d... more The effects of endothelin have been studied in isolated arterial segments (0.8-1 mm in external diam.) of human omental arteries obtained during the course of abdominal operations (15 patients, 7 men and 8 women). Paired segments, one normal and the other de-endothelized, were mounted for isometric recording of tension in organ baths. Endothelin produced concentration-dependent contractions with an EC50 value of 5.4 x 10(-9) M. Removal of endothelium did not affect significantly endothelin-induced contractions (EC50, 6.7 x 10(-9) M). Removal of extracellular calcium or addition of the calcium channel blocker nicardipine (10(-6) M) diminished but did not abolish responses to endothelin. These results indicate that endothelin exerts powerful contractile effects on human isolated omental arteries which are independent of the presence of an intact endothelial cell layer; this contraction cannot be explained solely by voltage-dependent calcium channels.
Journal of Pharmacy and Pharmacology, 1991
The L-arginine analogues NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) and NG-nitro-L-arginine meth... more The L-arginine analogues NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) and NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), which specifically inhibit the synthesis of nitric oxide from L-arginine, significantly reduced acetylcholine-induced endothelium-dependent relaxations in rings of human omental arteries. The inhibitory potency of L-NMMA and L-NAME was similar. Addition of L-NMMA or L-NAME to the organ bath did not induce any significant changes in the resting tension of the tissues. The effects of L-NMMA were reversed by L-arginine (3 x 10(-4) M). The L-NMMA enantiomer, D-NMMA (10(-4) M), did not influence either the basal tone of the preparation or the relaxing effects of acetylcholine. Arterial relaxations induced by sodium nitroprusside (10(-6) M) were not influenced by incubation with L-NMMA or L-NAME. These results suggest that endothelium-dependent relaxations in human omental arteries are mediated by the endogenous and substrate-specific generation of nitric oxide from L-arginine.
Journal of Cerebral Blood Flow & Metabolism, 1996
The present study was designed to investigate the influence of the endothelium and that of the L-... more The present study was designed to investigate the influence of the endothelium and that of the L-arginine pathway on the contractile responses of isolated human cerebral arteries to electrical field stimulation (EFS) and norepinephrine. Rings of human middle cerebral artery were obtained during autopsy of 19 patients who had died 3-8 h before. EFS (1-8 Hz) induced frequency-dependent contractions that were abolished by tetrodotoxin, prazo sin, and guanethidine (all at 10-6 M). The increases in tension were of greater magnitude in arteries denuded of endothelium. NG-monomethyl L-arginine (L-NMMA \0 -4 M) potentiated the contractile response to EFS in artery rings with endothelium but did not influence re sponses of endothelium-denuded arteries. L-arginine (10-4 M) reversed the potentiating effects of L-NMMA on EFS-induced contractions. Norepinephrine induced Nitric oxide (or a substance containing nitric ox ide) synthesized from L-arginine accounts for the powerful vasodilator effects of endothelium-derived relaxing factor (Ignarro et aI., 1987; Palmer et al., 1987) and consequently plays a decisive role in de termining vasomotor tone (for review see Moncada et aI., 1991). Guanidino-substituted L-arginine de rivatives such as N G -nitro-L-arginine methyl ester (L-NAME) and N G -monomethyl-L-arginine (L NMMA) inhibit the formation of nitric oxide from L-arginine in endothelial cells and the endothelium dependent relaxation of various vascular beds (Rees et aI., 1989a; Rees et aI., 1990; Liu et aI., 1992). Histochemical studies have demonstrated the presence of nitric oxide synthase immunoreac-
International Journal of Medical Sciences, 2000
Journal of Pharmacology and Experimental Therapeutics, Sep 1, 1998
We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 mul... more We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 multiorgan donors to investigate whether subpressor concentrations of vasopressin facilitate noradrenergic transmission in penile blood vessels. Vasopressin constricted penile dorsal arteries (pD 2 , 9.38 Ϯ 0.18) and deep dorsal veins (pD 2 , 9.40 Ϯ 0.14) by activating V 1 receptors. Vasopressin (10 Ϫ11 and 3 ϫ 10 Ϫ11 M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (15 V, 0.5-2 Hz, 0.2 msec duration for 15 sec) and produced leftward shifts of the concentrationresponse curve for norepinephrine. The V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (3 ϫ 10 Ϫ9 -10 Ϫ7 M) induced concentrationdependent inhibitions of potentiation caused by vasopressin. In
The American Journal of Physiology, Apr 1, 1997
Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may ... more Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal contractions. Vasopressin also potentiated KCl- and calcium-induced contractions. The V1-receptor antagonist 1-[beta-mercapto-beta,beta-cyclopentamethylenepropionic acid-2-O-methyl-tyrosine, 8-arginine]vasopressin (10(-6) M) prevented the potentiation evoked by vasopressin in all cases. The calcium antagonist nifedipine (10(-6) M) did not affect the potentiation of electrical stimulation and norepinephrine induced by vasopressin but abolished KCl-induced contractions. The results suggest that vasopressin, in addition to its direct vasoconstrictor effect, strongly potentiates the responses to adrenergic stimulation and KCl depolarization. Both the direct and indirect effects of vasopressin appear to be mediated by V1-receptor stimulation. The amplifying effect of vasopressin on constrictor responses may be relevant in those clinical situations characterized by increased plasma vasopressin levels.
European Journal of Pharmacology, Mar 1, 2001
To examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to ... more To examine whether low concentrations of endothelin-1 potentiate the vasoconstrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline. Endothelin-1 (10(-10) M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ET(B) receptor antagonist (2,6-dimethylpiperidinecarbonyl-gamma-methyl-Leu-N(in)-[Methoxycarbonyl]-D-Trp-D-Nle) (BQ-788, 10(-6) M), but not the endothelin ET(A) receptor antagonist cyclo(D-Asp-Pro-D-Val-Leu-D-TRP) (BQ-123, 10(-6) M), inhibited the potentiating effects of endothelin-1. Pretreatment with the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate and the thromboxane receptor antagonist [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino] methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid (SQ-30741) (all at 10(-5) M) prevented the potentiation induced by endothelin-1 on adrenergic stimulation. The Ca(2+) channel antagonist nifedipine (10(-6) M) did not affect the potentiation induced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endothelin ET(B) receptors. This potentiation depends on the production of cyclooxygenase-generated factors, probably thromboxane A(2).
PLOS ONE, 2015
Alzheimer´s disease (AD), a neurodegenerative illness involving synaptic dysfunction with extrace... more Alzheimer´s disease (AD), a neurodegenerative illness involving synaptic dysfunction with extracellular accumulation of Aβ 1-42 toxic peptide, glial activation, inflammatory response and oxidative stress, can lead to neuronal death. Endogenous cannabinoid system is implicated in physiological and physiopathological events in central nervous system (CNS), and changes in this system are related to many human diseases, including AD. However, studies on the effects of cannabinoids on astrocytes functions are scarce. In primary cultured astrocytes we studied cellular viability using MTT assay. Inflammatory and oxidative stress mediators were determined by ELISA and Western-blot techniques both in the presence and absence of Aβ 1-42 peptide. Effects of WIN 55,212-2 (a synthetic cannabinoid) on cell viability, inflammatory mediators and oxidative stress were also determined. Aβ 1-42 diminished astrocytes viability, increased TNF-α and IL-1β levels and p-65, COX-2 and iNOS protein expression while decreased PPAR-γ and antioxidant enzyme Cu/Zn SOD. WIN 55,212-2 pretreatment prevents all effects elicited by Aβ 1-42 . Furthermore, cannabinoid WIN 55,212-2 also increased cell viability and PPAR-γ expression in control astrocytes. In conclusion cannabinoid WIN 55,212-2 increases cell viability and anti-inflammatory response in cultured astrocytes. Moreover, WIN 55,212-2 increases expression of anti-oxidant Cu/Zn SOD and is able to prevent inflammation induced by Aβ 1-42 in cultured astrocytes. Further studies would be needed to assess the possible beneficial effects of cannabinoids in Alzheimer's disease patients.
The Journal of pharmacology and experimental therapeutics, 1998
We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 mul... more We have used in vitro preparations of human penile dorsal artery and deep dorsal vein from 20 multiorgan donors to investigate whether subpressor concentrations of vasopressin facilitate noradrenergic transmission in penile blood vessels. Vasopressin constricted penile dorsal arteries (pD2, 9.38 +/- 0.18) and deep dorsal veins (pD2, 9. 40 +/- 0.14) by activating V1 receptors. Vasopressin (10(-11) and 3 x 10(-11) M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (15 V, 0.5-2 Hz, 0.2 msec duration for 15 sec) and produced leftward shifts of the concentration-response curve for norepinephrine. The V1 receptor antagonist d(CH2)5Tyr(Me)AVP (3 x 10(-9)-10(-7) M) induced concentration-dependent inhibitions of potentiation caused by vasopressin. In contrast, the V2 receptor antagonist [d(CH2)5,D-Ile2, Ile4,Arg8]-vasopressin (10(-8)-10(-7) M) did not prevent the potentiation induced by vasopressin. The results demonstrate that vasopressin e...
The American journal of physiology, 1997
Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may ... more Vasopressin not only acts directly on blood vessels through V1-receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vitro and in vivo. The aim of the present study was to investigate whether subpressor concentrations of vasopressin could modify the constrictor responses to norepinephrine and electrical stimulation of the perivascular nerves in human mesenteric arteries. Human mesenteric artery rings (3-3.5 mm long, 0.8-1.2 mm OD) were obtained from 38 patients undergoing abdominal operations. The arterial rings were suspended in organ bath chambers for isometric recording of tension. Vasopressin (3 x 10(-11) M) enhanced the contractions elicited by electrical stimulation at 2, 4, and 8 Hz (by 100, 100, and 72%, respectively) and produced a leftward shift of the concentration-response curves to norepinephrine (half-maximal effective concentration decreased from 2.2 x 10(-6) to 5.0 x 10(-7) M; P < 0.05) without any alteration in maximal ...
Journal of andrology
The present study was designed to investigate general morphology and the response of human defere... more The present study was designed to investigate general morphology and the response of human deferential artery to constrictor and dilator substances with special emphasis on endothelium-dependent responses. Human deferential artery segments were obtained from patients undergoing radical cystectomy (n = 7), suprapubic prostatectomy (n = 6), or radical prostatectomy (n = 6). Light microscopy revealed that human deferential artery is of muscular type, and fluorescence microscopy showed a dense adrenergic innervation. Paired rings, one normal and the other de-endothelialized by gentle rubbing, were mounted for isometric recording of tension in organ baths. Vasopressin, endothelin, serotonin, and potassium chloride induced endothelium-independent contractions, whereas norepinephrine and electrical field stimulation caused frequency-dependent contractions that were of greater magnitude in arteries denuded of endothelium. In precontracted arterial rings, acetylcholine and substance P induce...
American Journal of Hypertension, 2007
We studied the participation of K(+) channels on the adrenergic responses in human saphenous vein... more We studied the participation of K(+) channels on the adrenergic responses in human saphenous veins as well as the intervention of dihydropyridine-sensitive Ca(2+) channels on modulation of adrenergic responses by K(+) channels blockade. Saphenous vein rings were obtained from 40 patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. Iberiotoxin (10(-7) mol/L), an inhibitor of large conductance Ca(2+)-activated K(+) channels, and charybdotoxin (10(-7) mol/L), an inhibitor of both large and intermediate conductance Ca(2+)-activated K(+) channels, enhanced the contractions elicited by electrical field stimulation and produced a leftward shift of the concentration-response curve to norepinephrine. In contrast, the inhibitor of small conductance Ca(2+)-activated K(+) channels apamin (10(-6) mol/L) did not modify the contractile response to electrical field stimulation or norepinephrine. In the presence of the dihydropyridine Ca(2+)-channel blocker nifedipine (10(-6) mol/L), iberiotoxin and charybdotoxin failed to enhance the contractile responses to electrical field stimulation and norepinephrine. The results suggest that large conductance Ca(2+)-activated K(+) channels are activated by stimulation with norepinephrine to counteract the adrenergic-induced contractions of human saphenous vein. Thus, inhibition of these channels increases significantly the contraction, an effect that appears to be mediated by an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels.
American Journal of Hypertension, 2006
We recently reported that endothelium-dependent relaxation is impaired in forearm veins from pati... more We recently reported that endothelium-dependent relaxation is impaired in forearm veins from patients with chronic renal failure. However, assessment of responses to norepinephrine remains controversial. We examined the contractile response to norepinephrine in forearm veins from patients on chronic hemodialysis and the role of nitric oxide (NO), prostanoids, and Ca(2+)-activated K(+) channels in this response. Isometric contraction curves were obtained in rings of forearm vein from 21 dialyzed patients and 12 multiorgan donors in response to norepinephrine (1 nmol/L to 10 micromol/L) or KCl (5 to 100 mmol/L). Veins from uremic patients were markedly less responsive to norepinephrine (7.6 +/- 0.6 g) and KCl (6.0 +/- 0.3 g) than those from organ donors (12.0 +/- 0.7 g and 10.4 +/- 0.5 g, respectively, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05). Treatment with N(G)-monomethyl-l-arginine (100 micromol/L), an inhibitor of NO synthase, or indomethacin (10 micromol/L), an inhibitor of prostacyclin synthesis, increased the response to norepinephrine in veins from control subjects but not in veins from dialyzed patients. Additional blockade of Ca(2+)-activated K(+) channels did not correct the hyporesponsiveness. In veins incubated in Ca(2+)-free solution containing either 100 mmol/L KCl or 1 micromol/L norepinephrine, addition of calcium chloride (0.1 to 30 mmol/L) elicited contractile responses that were significantly lower in veins from dialyzed patients. The results demonstrate that norepinephrine-mediated contractions of forearm veins are markedly decreased in dialyzed patients. Endothelium-derived relaxing factors are not involved in this effect. The reduced contractile response is most likely caused by a decreased calcium entry through voltage- and receptor-dependent calcium channels.
American Journal of Hypertension, 2007
The aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostag... more The aim of the present study was to evaluate the intervention of COX-1- and COX-2-derived prostaglandins in the responses of human gastroepiploic artery to sympathetic stimulation and norepinephrine. Rings of human gastroepiploic artery were obtained from 45 patients (26 men and 19 women) undergoing gastrectomy. The rings were suspended in organ baths for isometric recording of tension. We studied the responses to electrical field stimulation, norepinephrine, and acetylcholine, in the absence and presence of COX-1 or COX-2 inhibition. The COX-1 and COX-2 inhibitor aspirin at high concentrations (10(-6) to 10(-5) mol/L) and the COX-2 inhibitor nimesulide (10(-6) mol/L) potentiated the contractile responses of the arterial rings to sympathetic neurogenic stimulation and norepinephrine. In contrast, lower concentrations of aspirin (10(-8) to 10(-7) mol/L) or the COX-1 inhibitor SC-560 (3 x10(-8) mol/L) did not affect these responses. The vascular relaxation induced by acetylcholine was not affected by COX-1 and COX-2 inhibition. The results provide functional evidence that vasodilator prostaglandins are active components of the response of human gastroepiploic artery to neurogenic stimulation and norepinephrine. Aspirin at high concentrations and the COX-2 selective inhibitor nimesulide potentiated the contractile response of gastroepiploic artery to adrenergic stimulation by inhibiting COX-2-derived PGI(2). Aspirin at low concentrations and the COX-1 selective inhibitor SC-560 did not modify the contractile responses, possibly due to minor importance of vasoconstrictor prostaglandins (TXA(2)) as active components of the response of gastroepiploic artery to adrenergic stimulation.
International Journal of Medical Sciences, 2015
One of the earliest neuropathological events in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp... more One of the earliest neuropathological events in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease is accumulation of astrocytes at sites of Aβ1-42 depositions. Our results indicate that Aβ1-42 toxic peptide increases lipid peroxidation, apoptosis and cell death in neurons but not in astrocytes in primary culture. Aβ1-42-induced deleterious neuronal effects are not present when neurons and astrocytes are mixed cultured. Stimulation of astrocytes with toxic Aβ1-42 peptide increased p-65 and decreased IκB resulting in inflammatory process. In astrocytes Aβ1-42 decreases protein expressions of sirtuin 1 (SIRT-1) and peroxisome proliferator-activated receptor γ (PPAR-γ) and over-expresses peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) and mitochondrial transcription factor A (TFAM), protecting mitochondria against Aβ1-42-induced damage and promoting mitochondrial biogenesis. In summary our data suggest that astrocytes may have a key role in protecting neurons, increasing neural viability and mitochondrial biogenesis, acquiring better oxidative stress protection and perhaps modulating inflammatory processes against Aβ1-42 toxic peptide. This might be a sign of a complex epigenetic process in Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease development.
European Heart Journal, 2013
ABSTRACT Purpose: Physical activity is able to reduce cardiovascular morbidity and mortality. The... more ABSTRACT Purpose: Physical activity is able to reduce cardiovascular morbidity and mortality. These effects may be mediated in a number of ways including an enhancement of endothelial function. We investigated the effects of physical training on plasma levels of nitric oxide (NO) and vascular responses induced by sympathetic stimulation and acetylcholine. Methods: Eleven male New Zealand white rabbits were exercised during 6 weeks following a chronic exercise protocol on treadmill (trained group) and another twelve rabbits (control group) were stabulated during the same period. When the chronic exercise program was finished, rabbits were anaesthetized, killed and common carotid arteries were dissected. Arterial segments (3 mm long) were mounted for isometric recording of tension in organ baths containing Krebs-Henseleit solution. Electrical field stimulation (EFS, 4Hz, 20V, 0.25 ms duration for 30 s) was provided by a Grass S88 stimulator via two platinum electrodes positioned on each side and parallel to the axis of the arterial segment. Blood samples were drawn from the ear artery before anaesthesia for determination of plasma nitrite plus nitrate (NOx) using the Griess reaction. Results: Acetylcholine (3x10-6M) produced more relaxation in control group (Emax values: 93.8±2.1 for control group vs 83.5±3.2 for training group, n=10; p>0.05). The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME 10-4M) reduced the relaxation to acetylcholine in both trained (pD2 = 6.7±0.2, n=5; p<0.001) and control rabbits (pD2 = 6.9±0.2, n=5; p<0.001). The reduction of maximum effect by L-NAME was greater in control rabbits (44% vs 34%, p<0.05). The contractile responses to EFS were abolished by tetrodotoxin (10-6M), guanethidine (10-6M) and prazosin (10-6M) thus indicating that the contractile effect is due to noradrenaline acting on a1 adrenoceptors. EFS (1, 2 and 4 Hz) induced contraction was greater in trained groups. L-NAME 10-4M enhanced the contractions elicited by EFS in both groups with the similar magnitude. Plasma levels of NOx were similar in both control and trained groups (67±21 mM vs 62±20 mM, n=11; p>0.05). Conclusions: Although NO plasma levels were similar in the two groups, trained rabbits show a significant decrease in the NO component, sensitive to L-NAME, induced by acetylcholine but not by sympathetic stimulation.
BioMed Research International, 2013
The aim of this study was to analyze whether tyrosine phosphorylation in tumoral arteries may mod... more The aim of this study was to analyze whether tyrosine phosphorylation in tumoral arteries may modulate their vascular response. To do this, mesenteric arteries supplying blood flow to colorectal tumors or to normal intestine were obtained during surgery and prepared for isometric tension recording in an organ bath. Increasing tyrosine phosphorylation with the phosphatase inhibitor, sodium orthovanadate produced arterial contraction which was lower in tumoral than in control arteries, whereas it reduced the contraction to noradrenaline in tumoral but not in control arteries and reduced the relaxation to bradykinin in control but not in tumoral arteries. Protein expression of VEGF-A and of the VEGF receptor FLT1 was similar in control and tumoral arteries, but expression of the VEGF receptor KDR was increased in tumoral compared with control arteries. This suggests that tyrosine phosphorylation may produce inhibition of the contraction in tumoral mesenteric arteries, which may increase blood flow to the tumor when tyrosine phosphorylation is increased by stimulation of VEGF receptors.
Life Sciences, 2013
Aims: In the present study we investigated the intervention of nitric oxide and prostacyclin in t... more Aims: In the present study we investigated the intervention of nitric oxide and prostacyclin in the responses to vasopressin of isolated thyroid arteries obtained from multi-organ donors. Main methods: Paired artery rings from glandular branches of the superior thyroid artery, one normal and the other deendothelised, were mounted in organ baths for isometric recording of tension. Concentrationresponse curves to vasopressin were determined in the absence and in the presence of either the vasopressin V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (10 −8 M), the nitric oxide synthase inhibitor N G -monomethyl-Larginine (L-NMMA, 10 −4 M), or the inhibitor of prostaglandins indomethacin (10 −6 M). Key findings: In artery rings under resting tension, vasopressin produced concentration-dependent, endotheliumindependent contractions. The vasopressin V 1 receptor antagonist d(CH 2 ) 5 Tyr(Me)AVP (10 −8 M) displaced the control curve to vasopressin 19-fold to the right in a parallel manner. The contractile response to vasopressin was unaffected by L-NMMA or by indomethacin. Significance: Vasopressin causes constriction of human thyroid arteries by stimulation of V 1 vasopressin receptors located on smooth muscle cells. These effects are not linked to the presence of an intact endothelium or to the release of nitric oxide or prostaglandins. The constriction of thyroid arteries may be particularly relevant in certain pathophysiological circumstances in which vasopressin is released in amounts that could interfere with the blood supply to the thyroid gland.
Journal of Vascular Surgery, 1997
P~rpose: The goal of this study was to determine the effects of vasopressin and the selective V2-... more P~rpose: The goal of this study was to determine the effects of vasopressin and the selective V2-receptor agonist desmopressin on human saphenous veins, with special emphasis on endothelium-mediated responses.
Journal of Pharmacy and Pharmacology, 1992
The effects of endothelin have been studied in isolated arterial segments (0.8-1 mm in external d... more The effects of endothelin have been studied in isolated arterial segments (0.8-1 mm in external diam.) of human omental arteries obtained during the course of abdominal operations (15 patients, 7 men and 8 women). Paired segments, one normal and the other de-endothelized, were mounted for isometric recording of tension in organ baths. Endothelin produced concentration-dependent contractions with an EC50 value of 5.4 x 10(-9) M. Removal of endothelium did not affect significantly endothelin-induced contractions (EC50, 6.7 x 10(-9) M). Removal of extracellular calcium or addition of the calcium channel blocker nicardipine (10(-6) M) diminished but did not abolish responses to endothelin. These results indicate that endothelin exerts powerful contractile effects on human isolated omental arteries which are independent of the presence of an intact endothelial cell layer; this contraction cannot be explained solely by voltage-dependent calcium channels.
Journal of Pharmacy and Pharmacology, 1991
The L-arginine analogues NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) and NG-nitro-L-arginine meth... more The L-arginine analogues NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) and NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), which specifically inhibit the synthesis of nitric oxide from L-arginine, significantly reduced acetylcholine-induced endothelium-dependent relaxations in rings of human omental arteries. The inhibitory potency of L-NMMA and L-NAME was similar. Addition of L-NMMA or L-NAME to the organ bath did not induce any significant changes in the resting tension of the tissues. The effects of L-NMMA were reversed by L-arginine (3 x 10(-4) M). The L-NMMA enantiomer, D-NMMA (10(-4) M), did not influence either the basal tone of the preparation or the relaxing effects of acetylcholine. Arterial relaxations induced by sodium nitroprusside (10(-6) M) were not influenced by incubation with L-NMMA or L-NAME. These results suggest that endothelium-dependent relaxations in human omental arteries are mediated by the endogenous and substrate-specific generation of nitric oxide from L-arginine.
Journal of Cerebral Blood Flow & Metabolism, 1996
The present study was designed to investigate the influence of the endothelium and that of the L-... more The present study was designed to investigate the influence of the endothelium and that of the L-arginine pathway on the contractile responses of isolated human cerebral arteries to electrical field stimulation (EFS) and norepinephrine. Rings of human middle cerebral artery were obtained during autopsy of 19 patients who had died 3-8 h before. EFS (1-8 Hz) induced frequency-dependent contractions that were abolished by tetrodotoxin, prazo sin, and guanethidine (all at 10-6 M). The increases in tension were of greater magnitude in arteries denuded of endothelium. NG-monomethyl L-arginine (L-NMMA \0 -4 M) potentiated the contractile response to EFS in artery rings with endothelium but did not influence re sponses of endothelium-denuded arteries. L-arginine (10-4 M) reversed the potentiating effects of L-NMMA on EFS-induced contractions. Norepinephrine induced Nitric oxide (or a substance containing nitric ox ide) synthesized from L-arginine accounts for the powerful vasodilator effects of endothelium-derived relaxing factor (Ignarro et aI., 1987; Palmer et al., 1987) and consequently plays a decisive role in de termining vasomotor tone (for review see Moncada et aI., 1991). Guanidino-substituted L-arginine de rivatives such as N G -nitro-L-arginine methyl ester (L-NAME) and N G -monomethyl-L-arginine (L NMMA) inhibit the formation of nitric oxide from L-arginine in endothelial cells and the endothelium dependent relaxation of various vascular beds (Rees et aI., 1989a; Rees et aI., 1990; Liu et aI., 1992). Histochemical studies have demonstrated the presence of nitric oxide synthase immunoreac-
International Journal of Medical Sciences, 2000