RESUMEN
OBJECTIVE: We investigated the potentiating effect of U-46619, a synthetic analogue of thromboxane A(2) (TXA(2)), on the adrenergic responses in human saphenous vein. METHODS: Saphenous vein rings were obtained from 35 patients undergoing coronary artery bypass surgery. The rings were suspended in organ bath chambers for isometric recording of tension. RESULTS: U-46619 (10(-10)-3 x 10(-7) mol/l) produced concentration-dependent and endothelium-independent contractile responses. U-46619 (10(-10) mol/l) potentiated the contractions elicited by electrical stimulation and potassium chloride, and produced leftward shifts of the concentration-response curve for noradrenaline. The TXA(2) receptor antagonist SQ-30741 (10(-8) mol/l) prevented the potentiation evoked by U-46619. The dihydropyridine calcium antagonist nifedipine (10(-6) mol/l) did not affect the potentiation of electrical stimulation and noradrenaline induced by U-46619, but abolished the potentiation of U-46619 on KCl-induced contractions. CONCLUSIONS: U-46619 facilitates sympathetic neurotransmission and potentiates constrictor effects of noradrenaline in human saphenous veins through stimulation of TXA(2) receptors. These effects are independent of calcium entry through dihydropyridine calcium channels.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Endotelio Vascular/efectos de los fármacos , Norepinefrina/farmacología , Receptores de Tromboxanos/antagonistas & inhibidores , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacología , Vasoconstrictores/farmacología , Anciano , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/metabolismo , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Estimulación Eléctrica , Endotelio Vascular/metabolismo , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Nifedipino/farmacología , Cloruro de Potasio/farmacología , Vena Safena , Estimulación QuímicaRESUMEN
BACKGROUND: Sildenafil is currently used in the treatment of erectile dysfunction. However, assessment of direct effects of sildenafil on coronary arteries and on arteries used as coronary grafts is unknown. This study was designed to investigate the effects of sildenafil on contracted human coronary, internal mammary, and radial arteries obtained from multiorgan donors. The observations were extended to forearm veins. Zaprinast was included in this study for comparison. METHODS: Segments of left coronary, internal mammary, and radial arteries, and forearm veins were obtained from 16 multiorgan donors. Vascular rings were suspended in organ bath chambers and isometric tension was recorded. Then the effects of sildenafil, zaprinast, and sodium nitroprusside on precontracted vessels were studied. RESULTS: Sildenafil (10(-8) - 3 x 10(-5) mol/L) caused concentration-dependent relaxation in the internal mammary arteries, radial arteries, and forearm veins. In the coronary arteries, sildenafil had a modest relaxant effect. In addition, sildenafil amplified the relaxation induced by sodium nitroprusside in all four vessels. Relaxation was unaffected by the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (10(-4) mol/L). Compared with zaprinast, sildenafil was eight to ten times more potent in terms of EC50 values. CONCLUSIONS: The direct relaxant effects of sildenafil together with its synergistic interaction with nitric oxide donors should be considered in patients undergoing coronary bypass surgery, patients with low blood pressure, and patients receiving antihypertensive regimes.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Purinonas/farmacología , Vasodilatación/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Arterias Mamarias/efectos de los fármacos , Purinas , Arteria Radial/efectos de los fármacos , Citrato de Sildenafil , Sulfonas , Venas/efectos de los fármacosRESUMEN
OBJECTIVES: Plasma levels of endogenous guanidino-substituted analogues of L -arginine are increased in various pathologic conditions. In the present study we determined the effects of some of these compounds on basal and stimulated release of nitric oxide in human internal thoracic and radial arteries. METHODS: Rings of human internal thoracic and radial arteries were obtained from 16 multiorgan donors. The rings were suspended in organ baths for isometric recording of tension. RESULTS: N(G)-monomethyl L -arginine (10(-6) to 10(-3) mol/L) and N(G),N(G)-dimethyl L -arginine (10(-6) to 10(-3) mol/L) caused concentration- and endothelium-dependent contractions. Maximal force of contractions for N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine in the internal thoracic artery were 18.0% +/- 4.3% and 17.8% +/- 3.8%, respectively, of the contraction to 100 mmol/L KCl, and those found in the radial artery were 9.6% +/- 2.5% and 9.1% +/- 2.4%, respectively. Aminoguanidine (10(-5) to 3 x 10(-3) mol/L) and methylguanidine (10(-5) to 3 x 10(-3) mol/L) produced endothelium-independent contractions. L -Arginine (10(-3) mol/L) prevented the contractions by N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine but did not change contractions induced by aminoguanidine and methylguanidine. N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine inhibited, in a concentration-dependent manner, the endothelium-dependent relaxation to acetylcholine in the internal thoracic artery and had little attenuating effect in the radial artery; aminoguanidine and methylguanidine were without effect. CONCLUSIONS: The results suggest that the contractions induced by N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine are due to inhibition of both basal and stimulated nitric oxide production, whereas aminoguanidine and methylguanidine do not affect the synthesis of nitric oxide. An increase in the plasma concentration of N(G)-monomethyl L -arginine and N(G),N(G)-dimethyl L -arginine is likely to represent a risk factor for abnormal vasomotor tone in conduit arteries used as coronary grafts.
Asunto(s)
Guanidinas/farmacología , Óxido Nítrico/metabolismo , Arteria Radial/efectos de los fármacos , Arterias Torácicas/efectos de los fármacos , Vasoconstrictores/farmacología , Adolescente , Adulto , Análisis de Varianza , Arginina/análogos & derivados , Arginina/farmacología , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Arteria Radial/metabolismo , Análisis de Regresión , Arterias Torácicas/metabolismoRESUMEN
OBJECTIVES: To investigate the effects of sildenafil on human penile blood vessels and evaluate the interaction of sildenafil with neurogenic-mediated responses. Sildenafil is currently used in the treatment of erectile dysfunction. METHODS: Penile dorsal arteries and deep dorsal veins were obtained from 14 multiorgan donors. Vascular rings were suspended in organ bath chambers, and the isometric tension was recorded. We then studied the effects of sildenafil on precontracted vessels and the neurogenic (noradrenergic and nitrergic) responses. RESULTS: Sildenafil (10(-9) to 3 x 10(-6) M) caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside. Relaxation was unaffected by the inhibitor of nitric oxide synthase N(G)-monomethyl-L-arginine (10(-4) M). Compared with zaprinast, sildenafil was 8 to 10 times more potent in terms of the median effective concentration (EC(50)) values. Electrical field stimulation of the vessels under resting tension caused frequency-dependent contractions that were attenuated in the presence of sildenafil. When penile vessels were contracted after blockade of norepinephrine release with guanethidine (10(-6) M), electrical stimulation induced frequency-dependent, nitric oxide-dependent relaxations that were enhanced by sildenafil. CONCLUSIONS: These results indicate that the relaxation of human penile arteries and veins induced by sildenafil involves inhibition of noradrenergic contraction, enhancement of neurogenic nitric oxide-mediated relaxation, and inhibition of smooth muscle contraction.
Asunto(s)
Pene/irrigación sanguínea , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Adolescente , Adulto , Arterias/efectos de los fármacos , Arterias/inervación , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Relajación Muscular/efectos de los fármacos , Relajación Muscular/fisiología , Purinas , Citrato de Sildenafil , Sulfonas , Vasoconstricción/fisiología , Vasodilatación/fisiología , Venas/efectos de los fármacos , Venas/inervaciónRESUMEN
The present study was designed to characterize the response of human penile dorsal artery and deep dorsal vein to dilator drugs used in the diagnosis and treatment of erectile dysfunction with special emphasis on the effects on sympathetic neurotransmission. Ring segments of penile dorsal artery and deep dorsal vein were obtained from 20 multi-organ donors during procurement of organs for transplantation. The rings (3 mm long) were suspended in organ bath chambers for isometric recording of tension. We then studied the relaxant responses to prostaglandin E1 (PGE1), vasoactive intestinal peptide (VIP), papaverine (PV), sodium nitroprusside (SNP) and linsidomine chlorhydrate (SIN-1), and analysed the effects of these drugs on contractions induced by stimulation of perivascular sympathetic nerves. In artery and vein rings contracted by noradrenaline, all the drugs tested caused concentration-dependent relaxation. The order of potencies in terms of IC50 values (concentration of agonist causing 50% of the maximal relaxation) was PGE1=VIP>SNP>SIN-1=PV. Both arteries and veins contracted to electrical field stimulation (15 V, 0.5-2 Hz, 0.2 ms duration for 15 s) in a frequency-dependent manner. All relaxant drugs caused concentration-dependent inhibition of neurogenic contractions; the relative order of potencies was PGE1>VIP>SNP>SIN-1=PV. It is concluded that inhibition of sympathetic activity constitutes an effective relaxing mechanism in penile dorsal artery and vein. Modulation of sympathetic activity together with the direct effects on smooth muscle should be considered to evaluate adequately the efficacy of relaxant drugs to increase human penile blood supply.
Asunto(s)
Pene/irrigación sanguínea , Sistema Nervioso Simpático/efectos de los fármacos , Vasodilatadores/farmacología , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Disfunción Eréctil/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/efectos de los fármacos , Análisis de RegresiónRESUMEN
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 exerts powerful constrictor action in human penile arteries and veins by direct stimulation of V1 receptors. In addition, vasopressin strongly potentiates the contractions to norepinephrine and stimulation of perivascular adrenergic nerves. Consequently, the direct contractile effects of vasopressin together with its amplifying effects on adrenergic-mediated constriction should be taken into consideration in the overall regulation of penile erection and in those states characterized by increased plasma vasopressin levels.
Asunto(s)
Norepinefrina/metabolismo , Pene/irrigación sanguínea , Vasoconstricción/efectos de los fármacos , Vasopresinas/farmacología , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/farmacología , Receptores de Vasopresinas/fisiologíaRESUMEN
1. The aim of the present study was to characterize neurogenic and pharmacological responses of human penile deep dorsal vein and to determine whether the responses are mediated by nitric oxide from neural or endothelial origin. 2. Ring segments of human penile deep dorsal vein were obtained from 22 multiorgan donors during procurement of organs for transplantation. The rings were suspended in organ bath chambers for isometric recording of tension. We then studied the contractile and relaxant responses to electrical field stimulation and to vasoactive agents. 3. Electrical field stimulation (0.5-2 Hz) and noradrenaline (3 x 10(-10)-3 x 10(-5) M) caused frequency- and concentration-dependent contractions that were of greater magnitude in veins denuded of endothelium. The inhibitor of nitric oxide synthesis NG-nitro-L-arginine methyl ester hydrochloride (L-NAME, l0(-4) M) increased the adrenergic responses only in rings with endothelium. 4. In preparations contracted with noradrenaline in the presence of guanethidine (10(-6) M) and atropine (10(-6) M), electrical stimulation induced frequency-dependent relaxations. This neurogenic relaxation was prevented by L-NAME, methylene blue (3 x 10(-5) M) and tetrodotoxin (10(-6) M), but was unaffected by removal of endothelium. 5. Acetylcholine (10(-8)-3 x 10(-5) M) and substance P (3 x 10(-11) -3 x 10(-7) M) induced endothelium-dependent relaxations. In contrast, sodium nitroprusside (10(-9)-3 x 10(-5) M) and papaverine (10(-8) 3 x 10(-5) M) caused endothelium-independent relaxations. 6. The results provide functional evidence that the human penile deep dorsal vein is an active component of the penile vascular resistance through the release of nitric oxide from both neural and endothelial origin. Dysfunction in any of these sources of nitric oxide should be considered in some forms of impotence.
Asunto(s)
Músculo Liso Vascular/inervación , Músculo Liso Vascular/fisiología , Pene/irrigación sanguínea , Acetilcolina/farmacología , Adolescente , Adulto , Anciano , Estimulación Eléctrica , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiología , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico/metabolismo , Nitroprusiato/farmacología , Norepinefrina/farmacología , Papaverina/farmacología , Sustancia P/farmacología , Vasoconstrictores/farmacología , Vasodilatadores/farmacología , Venas/efectos de los fármacos , Venas/inervación , Venas/fisiologíaRESUMEN
BACKGROUND: Arginine vasopressin (AVP) not only acts directly on blood vessels through V1 receptor stimulation but also may modulate adrenergic-mediated responses in animal experiments in vivo and in vitro. The aim of the present study was to investigate whether AVP can contribute to an abnormal adrenergic constrictor response of human saphenous veins. METHODS AND RESULTS: Saphenous vein rings were obtained from 32 patients undergoing coronary artery bypass surgery. The vein rings were suspended in organ bath chambers for isometric recording of tension. AVP (3x10[-9] mol/L) enhanced the contractions elicited by electrical field stimulation at 1, 2, and 4 Hz (by 80%, 70%, and 60%, respectively) and produced a leftward shift of the concentration-response curve to norepinephrine (half-maximal effective concentration decreased from 6.87x10[-7] to 1.04x10[-7] mol/L; P<.05). The V1 vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP (10[-6] mol/L) prevented the potentiation evoked by AVP. The selective V1 receptor agonist [Phe,2 Orn8]-vasotocin (3x[-10]-9 mol/L) induced potentiation of electrical stimulation-evoked responses, which was also inhibited in the presence of the V1 receptor antagonist (10[-6] mol/L). In contrast, the V2 receptor agonist desmopressin (10[-9] to 10[-7] mol/L) did not modify neurogenic responses, and the V2 receptor antagonist [d(CH2)5, D-Ile,2 Ile,4 Arg8]-vasopressin (10[-8] to 10[-6] mol/L) did not prevent the potentiation induced by AVP. The dihydropyridine calcium antagonist nifedipine (10[-6] mol/L) did not affect the potentiating effect of AVP. CONCLUSIONS: The results suggest that low concentrations of AVP facilitate sympathetic neurotransmission and potentiate constrictor effects of norepinephrine in human saphenous veins. These effects appear to be mediated by V1 receptor stimulation and are independent of calcium entry through dihydropyridine calcium channels. Thus, AVP may contribute to vascular mechanisms involved in acute ischemic syndromes associated with venous grafts, particularly if the sympathetic nervous system is activated.
Asunto(s)
Arginina Vasopresina/fisiología , Receptores de Vasopresinas/fisiología , Vena Safena/fisiología , Anciano , Antagonistas de los Receptores de Hormonas Antidiuréticas , Bloqueadores de los Canales de Calcio/farmacología , Técnicas de Cultivo , Estimulación Eléctrica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nifedipino/farmacología , Norepinefrina/farmacología , Cloruro de Potasio/farmacología , Receptores de Vasopresinas/efectos de los fármacosRESUMEN
PURPOSE: 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. METHODS: Human saphenous vein segments were obtained from 35 patients undergoing coronary bypass surgery. Paired segments, one normal and the other deendothelized by gentle rubbing, were mounted for isometric recording of tension in organ baths. Concentration-response curves to vasopressin and desmopressin were determined in the presence and in the absence of either the V1-receptor antagonist d(CH2)5Tyr (Me)AVP (10(-6) mol/L), the V1-V2-receptor antagonist desGly-d(CH2)5D-Tyr(Et)ValAVP (10(-6) mol/L), indomethacin (10(-6) mol/L), or NG-nitro-L-arginine methyl ester hydrochloride (L-NAME, 10(-4) mol/L). RESULTS: In vein rings under resting tension, vasopressin produced concentration-dependent, endothelium-independent contractions with a concentration of vasopressin producing half-maximal contractions (EC50) of 3.44 x 10(-8) mol/L. The vasopressin V1-receptor antagonist (10(-6) mol/L) displaced the control curve to vasopressin 9.86-fold to the right in a parallel manner. In precontracted vein rings previously treated with the V1-antagonist (10(-6) mol/L) vasopressin caused endothelium-dependent relaxations. This relaxation was reduced significantly by indomethacin (10(-6) mol/L) and unaffected by the V1-V2-receptor antagonist (10(-6) mol/L) or by L-NAME (10(-4) mol/L). Desmopressin caused endothelium-dependent relaxations in precontracted vein rings that were inhibited by the mixed V1-V2-receptor antagonist and by indomethacin, but not by the V1-antagonist or by pretreatment with L-NAME. CONCLUSIONS: These observations indicate that vasopressin exerts contractile effects on human saphenous vein by V1-receptor stimulation. Vasopressin causes dilatation of human saphenous vein only if V1-receptor blockade is present. This relaxation appears to be mediated by the release of relaxant prostaglandins, probably derived from endothelial cells, and is independent of V2-receptor stimulation or release of nitric oxide. Desmopressin elicits relaxation that is largely dependent on V2-receptor stimulation, which may bring about the release of dilating prostaglandins from the endothelial cells.