Vasodilators independent

P2Y receptors that are found on endothelial cells elicit a Ca2+-dependent release of endothelium-dependent relaxing factor (EDRF) and vasodilation. A secondary activation of a Ca2+-sensitive phospholipase A2 increases the synthesis of endothelial prostacyclin, which limits the extent of intravascular platelet aggregation following vascular damage and platelet stimulation. The P2Y-mediated vasodilation opposes a vasoconstriction evoked by P2X receptors located on vascular smooth muscle cells. The latter elicit an endothelial-independent excitation (i.e. constriction). P2Y receptors are also found on adrenal chromaffin cells and platelets, where they modulate catecholamine release and aggregation respectively. 

In summary nitrosothiols are valuable vasodilators as they are water soluble and produce no toxic by-products. However there is considerable doubt about what prompts the release of NO from what, in vitro, are stable compounds. Release may be thermal and therefore a property of the compound and independent of tissue. On the other hand, Cu(I) ions are such powerful catalysts for NO release that their presence in tissue will greatly enhance the amount of NO formed. NO-delivery then becomes a property of the tissue as well as the compound, complicating interpretation of the results. The situation is further complicated by the suggestion that there is an enzyme responsible for NO-release from nitrosothiols [23]. 

Despite their successful use for at least 20 years, the mechanisms by which they lower the blood pressure remain uncertain. Theories to explain the antihypertensive effectiveness of the diuretic agents have included a) alteration of sodium and water content on arterial smooth muscle, b) the induction of a decreased vascular response to catecholamines, c) a decrease in blood volume and total extracellular fluid volume, and d) a direct vasodilator action independent from the diuretic effect(12). 

Tanaka M, Toknyasn M, Matsui T, Matsumoto K. (2008) Endothelium-independent vasodilation effect of di- and tri-peptides in thoracic aorta of Spragne-Dawley rats. Life Sci 82 869-875. 

Structure-activity relationship. The endothelium-independent vasodilator effects showed by flavonoids are related to the structure of the compound tested. Structure- activity relationships have been studied to flavonoids selected from five groups flavonols, flavones, flavanones, isoflavones, and flavanols in rat isolated aorta on the contractions induced by noradrenaline, KC1 and the phorbol ester derivative PMA, as well as the interactions of these flavonoids with isoprenaline and sodium nitroprusside, Table (2). 

In conclusion, flavonoids exert endothelium-independent vasodilator effects in isolated vascular smooth muscles that are related to the structure of the compound tested. The main vasodilator mechanism of flavonoids seems to be related to the inhibition of PKC, although an inhibitory effect on cyclic nucleotide PDEs and Ca2+ uptake and other protein kinases may also contribute to these actions, Fig. (4). 

Indapamidc has been shown to possess diuretic and independent vasodilators- effects. It lowers the elevated blood pressure and reduces inial peripheral resistance without an increase in heart rate. Indapamidc antagonizes die vasoconsiriciing effects of the catecholamines and angiotensin II. a property not shared by other thiazidc-lype diuretics. Tripumide is also reported to have direct vasodilators- effects. 

Perez-Vizcaino F, Ibarra M, Cogolludo AL, Duarte J, Zaragoza-Arnaez F, Moreno L, Tamargo J. 2002. Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries. J Pharmacol Exp Ther 302 66-72. 

Some diuretics have direct vasodilating effects in addition to their diuretic action. Indapamide is a nonthiazide sulfonamide diuretic with both diuretic and vasodilator activity. As a consequence of vasodilation, cardiac output remains unchanged or increases slightly. Amiloride inhibits smooth muscle responses to contractile stimuli, probably through effects on transmembrane and intracellular calcium movement that are independent of its action on sodium excretion. 

Kaiser DR, Billups K, Mason C, et al, Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease, J Am Coll Cardiol 2004 43 (2) 179-1 84,... 

Flow-dependent changes in vessel diameter contribute to the optimization of circulatory function and are mediated via shear stress-induced release of NO, vasodilator prostanoids, and a putative endothelium-derived hyperpolarization factor or EDHF (Griffith, 2002). There is growing evidence that NO/prostanoid-independent relaxations involve direct hetero-cellular signaling between endothelium and smooth muscle cells via gap junctions. 

Ghayurefo/. (2005)reportedthe hypotensive, endothelium-dependent and -independent vasodilator and cardio-suppressant and stimulant effects of aqueous extract (Zo. Cr) of ginger. Zo.Cr, which tested positive for saponins, flavonoids, amines, alkaloids and terpenoids, induced a dose-dependent... 

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