RESUMEN
This article reviews the body of work aimed at elucidating the mechanisms of action by which natural products of plant origin exert a vasodilatory effect at the level of the vasculature. The search was restricted to 4 mechanisms: the nitric oxide system and (or) reactive oxygen species, the eicosanoid system, potassium channel function, and calcium channel function. The National Library of Medicine database was searched using "PubMed" without restriction to language. The search generated 266 references on 15 November 2005. Most studies were in vitro in nature and of these, most involved studies in the rat aorta. Many of the natural products evoked vasodilatation through an endothelium-dependent mechanism. The vasodilatation was attenuated or abolished by a nitric oxide synthase inhibitor and, in some of these studies, by an inhibitor of guanylate cyclase. A few studies reported a cyclooxygenase component, but most found no effect of the cyclooxygenase inhibitor, indomethacin. The vasorelaxation evoked by several natural products was attenuated by various potassium channel blocking agents, suggesting that some natural products exerted their effect either directly or indirectly through activation of potassium channels. Finally, a significant number of natural products evoked vasodilatation either through blockade of calcium channels or by inhibiting the release of calcium from intracellular stores. Many natural products evoked vasodilatation through multiple mechanisms. The information in this review on mechanisms of action should facilitate good clinical practice by increasing the predictive capabilities of the practitioner, notably the ability to predict adverse effects and interactions among medications. The knowledge should also help to provide leads to the ultimate goal of developing new therapeutic medications.
Asunto(s)
Preparaciones de Plantas/farmacología , Vasodilatación/efectos de los fármacos , Animales , Calcio/fisiología , Eicosanoides/fisiología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Homeostasis , Humanos , Óxido Nítrico/fisiología , Canales de Potasio/fisiología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Several in vitro studies have shown that endothelium-dependent vasodilatation is maintained by endothelium-derived hyperpolarizing factor (EDHF) or prostacyclin in vessels isolated from endothelial nitric oxide synthase knockout mice. Since this has not been addressed by in vivo studies, we sought to define the magnitude and the onset time of this compensation by recording blood pressure responses to endothelium-dependent vasodilators in rats treated acutely or chronically with the NOS inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME). Groups of male Sprague-Dawley rats were given plain water (control) or L-NAME (0.7 mg/ml) in drinking water for 1 day, 5 days, 3 wks or 6 wks. Dose-dependent hypotensive responses to acetylcholine, bradykinin and sodium nitroprusside were determined in anesthetized rats before and after acute intravenous infusion of either L-NAME or a combination of apamin plus charybdotoxin that would selectively inhibit EDHF. Acute L-NAME treatment increased the mean arterial pressure and inhibited acetylcholine- and bradykinin-induced fall in blood pressure in control but not in chronic L-NAME treated rats. The endothelium-dependent hypotensive responses to acetylcholine and bradykinin were restored in rats treated with L-NAME after a time period of 24 h along with increased sensitivity to sodium nitroprusside and reduced plasma nitrate+nitrite levels. While apamin+charybdotoxin pretreatment inhibited the responses to acetylcholine and bradykinin in both acute and chronic L-NAME treated groups, it was more pronounced in the latter group. In conclusion, chronic inhibition of nitric oxide synthase results in the development of a compensatory hypotensive response to acetylcholine within 24 h and this is mediated by EDHF.
Asunto(s)
Acetilcolina/farmacología , Factores Biológicos/metabolismo , Hipotensión/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Vasodilatadores/farmacología , Animales , Apamina/farmacología , Factores Biológicos/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Caribdotoxina/farmacología , Relación Dosis-Respuesta a Droga , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Inhibidores Enzimáticos/farmacología , Hipotensión/fisiopatología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/metabolismo , Nitroglicerina/farmacología , Nitroprusiato/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio Calcio-Activados/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
This study was designed to evaluate the contribution of ATP-dependent potassium (KATP) channels to the changes in vascular reactivity and spontaneous tone observed in vessels isolated from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In phenylephrine preconstricted aortic rings, cromakalim induced concentration-dependent, glibenclamide-sensitive relaxation. The concentration response curve to cromakalim was shifted to the right in DOCA-salt hypertensive rats (EC50: 0.850 +/- 0.100 microM) compared with SHAM-normotensive rats (0.108 +/- 0.005 microM), and the maximum relaxation (Emax) evoked by cromakalim was significantly lower in aortic rings from the DOCA group (68 +/- 2%) compared with the SHAM group (108 +/- 5%). The results were similar in endothelium-denuded rings. Spontaneous tone was observed in aortic rings (5 g preload) from DOCA-salt but not SHAM rats. Cromakalim abolished spontaneous tone and the effect was blocked by glibencamide. In whole cell patch clamp studies, increasing extracellular K concentrations from 5.4 to 140 mM and the administration of cromakalim evoked dramatic increases in KATP channel currents in aortic cells isolated from SHAM rats. In contrast, in aortic cells from DOCA-salt hypertensive rats, KATP channel currents were either absent or weak in response to challenges by elevated extracellular K and by cromakalim. These findings suggest that the function of KATP channels is impaired in smooth muscle cells from aorta of DOCA-salt hypertensive rats, which may contribute to the impaired vasodilatation and spontaneous tone observed in these rats.
Asunto(s)
Adenosina Trifosfato/fisiología , Hipertensión/patología , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Canales de Potasio/fisiología , Adenosina Trifosfato/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/lesiones , Aorta Torácica/patología , Presión Sanguínea/efectos de los fármacos , Canadá , Cromakalim/antagonistas & inhibidores , Cromakalim/farmacología , Desoxicorticosterona , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos/administración & dosificación , Electrofisiología/métodos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/lesiones , Endotelio Vascular/patología , Gliburida/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Músculo Liso Vascular/efectos de los fármacos , Nefrectomía/métodos , Fenilefrina/antagonistas & inhibidores , Fenilefrina/farmacología , Canales de Potasio/clasificación , Canales de Potasio/efectos de los fármacos , Cloruro de Potasio/metabolismo , Cloruro de Potasio/farmacología , Ratas , Ratas Sprague-Dawley , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
1. The roles of nitric oxide (NO), superoxide anion (O(2)(-)), and hydrogen peroxide (H(2)O(2)) in the modulation of spontaneous tone were investigated in isolated aorta from deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 2. Increases in preload from 1 to 5 g were accompanied by increases in spontaneous tone in aortic rings from DOCA-salt hypertensive rats but not from SHAM-normotensive rats. 3. Tone was higher in endothelium-denuded aortic rings than in endothelium-intact vessels. Inhibition of nitric oxide synthase (NOS) with 300 microM N(G)-nitro-L-arginine methyl ester (l-NAME) increased spontaneous tone. 4. Basal O(2)(-) generation was higher in aortic rings from DOCA-salt hypertensive rats than in those from SHAM-normotensive rats. Stretch increased O(2)(-) levels even further in the DOCA-salt group. In rings isolated from DOCA-salt hypertensive rats, administration of the O(2)(-) scavenger, superoxide dismutase (SOD, 150 U ml(-1)), or the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase inhibitor, apocynin (100 microM), completely abolished the development of spontaneous tone in endothelium-intact aortic rings but not in endothelium-denuded or in L-NAME-treated rings. SOD and apocynin decreased the generation of O(2)(-) in endothelium-intact, endothelium-denuded, and L-NAME-treated aortic rings. 5. Oral treatment of DOCA-salt hypertensive rats with the O(2)(-) scavengers, tempol or tiron, or with apocynin for 3 weeks prevented the development of hypertension and abolished the increases in O(2)(-) generation and spontaneous tone. 6. Administration of catalase (1000 U ml(-1)) to aortic rings increased spontaneous tone in vessels from DOCA-salt hypertensive rats. 7. Administration of the cyclooxygenase (COX) inhibitor, valeroyl salicylate, or the thromboxane/prostaglandin antagonist, SQ 29548, to aortic rings abolished tone. 8. The results suggest that NO plays a major role in preventing the generation of spontaneous tone in isolated aortic rings from DOCA-salt hypertensive rats. NADPH-oxidase-derived O(2)(-) enhanced spontaneous tone by inactivating NO. Endogenous H(2)O(2) appears to mitigate the increase in tone. In addition, a COX component may also contribute to spontaneous tone.
Asunto(s)
Aorta Torácica/fisiología , Hipertensión/fisiopatología , Tono Muscular/fisiología , Músculo Liso Vascular/fisiología , Óxido Nítrico/fisiología , Estrés Oxidativo/fisiología , Tirosina/análogos & derivados , Acridinas/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Western Blotting , Calcio/fisiología , Catalasa/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Desoxicorticosterona , Endotelio Vascular/fisiología , Peróxido de Hidrógeno/farmacología , Hipertensión/inducido químicamente , Inmunohistoquímica , Técnicas In Vitro , Mediciones Luminiscentes , Masculino , Contracción Muscular/efectos de los fármacos , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III , Oligopéptidos/farmacología , Oxígeno/metabolismo , Péptidos Cíclicos/farmacología , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Tromboxanos/antagonistas & inhibidores , Superóxidos/metabolismo , Tirosina/metabolismo , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
This article reviews data at the in vivo whole animal and human level. The importance of both flow and pressure recordings and of the methods used to record these variables is emphasized. Exogenous administration of endothelin-1 evokes a transient depressor response mediated by endothelial endothelinB receptors, but the predominate effect of endothelin-1 is a sustained increase in blood pressure resulting from increases in total peripheral resistance. Resistance in the superior mesenteric, renal, and hindquarter vascular beds of animals and forearm resistance in humans is increased. Both endothelinA and, to a lesser extent, endothelinB receptors on vascular smooth muscle mediate the increases in resistance. Endothelin-1 evokes decreases in the precapillary/postcapillary resistance ratio, resulting in increased capillary pressure and net transcapillary filtration. Endothelin-1 evokes increases in mean circulatory filling pressure in animals and in constriction of the human dorsal hand vein. This venoconstrictor activity is mediated primarily through endothelinA and to a lesser extent endothelinB receptors. Endogenously generated endothelin contributes to the hemodynamic effects of angiotensin and vasopressin in certain animal models of hypertension. Antagonists of endothelin evoke modest hemodynamic changes in healthy humans and in some healthy animals, and they decrease vascular resistance dramatically in several salt-sensitive rat models of hypertension and also in some hypertensive human subjects. Thus, endogenously generated ET appears to play a modest role in the healthy organism, but it likely plays a major role in many pathophysiological states as described in companion articles in this issue.
Asunto(s)
Circulación Sanguínea/fisiología , Endotelinas/fisiología , Capacitancia Vascular/fisiología , Resistencia Vascular/fisiología , Animales , Circulación Sanguínea/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores de Endotelina , Endotelinas/agonistas , Endotelinas/antagonistas & inhibidores , Humanos , Receptores de Endotelina/agonistas , Receptores de Endotelina/fisiología , Capacitancia Vascular/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
The changes in blood pressure, cardiac output, and total peripheral conductance evoked by the novel hypotensive arginine vasopressin (AVP) - like peptide, d(CH2)5[D-Tyr(Et)2,Arg3,Val4,Arg7,Eda9]AVP (HYPO-AVP), were recorded in conscious unrestrained Sprague-Dawley rats implanted with radiotelemetry pressure transducers and ultrasonic transit-time flowprobes. Intravenous infusions of 0.6, 1.0, 2.0, and 4.0 microg x kg(-1) x min(-1) of HYPO-AVP evoked dose-related decreases in blood pressure. At the lowest dose of 0.6 microg x kg(-1) x min(-1), the fall in blood pressure was associated with a small but significant increase in total peripheral conductance. Cardiac output was unchanged. In contrast, at the three higher doses of 1.0, 2.0, and 4.0 microg x kg(-1) x min(-1), the fall in blood pressure was related to a dramatic fall in cardiac output. Indeed, total peripheral conductance decreased, preventing blood pressure from falling further. These hemodynamic findings should help to direct future research into the mechanism of the putative hypotensive property of vasopressin, a property that attenuates the well established blood pressure elevating actions of the peptide.
Asunto(s)
Antihipertensivos/farmacología , Arginina Vasopresina/farmacología , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Animales , Arginina Vasopresina/análogos & derivados , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacosRESUMEN
The effect of tiron (4,5-dihydroxy-1,3-benzene disulfonic acid) on the binding of Ca2+ and its effect on vascular responses of the rat perfused mesenteric bed was studied at concentrations of tiron that are used widely to scavenge superoxide anion. In competition assays in buffered solutions with no tissue present, tiron decreased the fluorescence ratio of fura-FF, a measure of [Ca2+]: the inhibition constant (Ki) of tiron with Ca2+ was 0.692 +/- 0.036 mM. In the mesenteric bed perfused at constant flow and preconstricted with 90 mM KCl, tiron evoked decreases in perfusion pressure of the mesenteric bed in a concentration-dependent manner (Rmax = 43.58 +/- 2.6 mmHg; EC50 = 1.46 +/- 0.33 mM). This vasodilator effect of tiron was similar in the presence of the superoxide anion scavenger, tempol (Rmax = 46.12 +/- 1.87 mmHg; EC50 = 1.34 +/- 0.27 mM). In the presence of 90 mM KCl, increasing concentrations of Ca2+ increased perfusion pressure and tiron shifted the concentration-response curve to Ca2+ to the right. In freshly drawn blood from rats, tiron increased clotting time. The data indicate that tiron binds Ca2+ at concentrations at or below those commonly used to scavenge superoxide anion, an action that may be responsible for a variety of biological responses. The interpretation of effects of tiron in previous work on the role of superoxide anion may need to be re-evaluated.