endothelin-1 and fenamic-acid

The direct effects of torasemide and furosemide on vasoconstriction and increases in intracellular free calcium concentration ([Ca(2+)]i) induced by endothelin-1 (ET-1) were investigated in the aorta of spontaneously hypertensive rats (SHR).. Vascular responses were assessed in endothelium-denuded aortic rings using an organ bath system. Changes of [Ca(2+)]i in cultured vascular smooth muscle cells (VSMCs) were assessed using fura-2 methodology.. ET-1-induced vasoconstriction was reduced in a dose-dependent way by torasemide and furosemide (IC(50) values: 4.3+/-1.4x10(-5) and 9.8+/-5.6 x10(-5) M, respectively). The ET-1-induced biphasic [Ca(2+)]i increase was blocked by torasemide (IC(50)=2.0+/-0.2x10(-8) and 2.7+/-0.6x10(-6) M, respectively). Furosemide inhibited the initial rise in [Ca(2+)]i induced by ET-1, with no effect on the second rise. The specific chloride (Cl(-)) channel blocker diphenylamine-2-carboxylate inhibits both ET-1-induced responses in VSMCs (IC(50)=8.0+/-0.3x10(-9) and 2.5+/-0.7x10(-7) M, respectively).. These results suggest that the ability of loop diuretics to interfere with the vascular actions of ET-1 may involve different molecular mechanisms. The ability of torasemide to block the vasoconstrictive action of ET-1 could include an inhibitory action on Cl(-) channels.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Bosentan; Calcium; Chloride Channels; Diuretics; Endothelin-1; Endothelium, Vascular; Furosemide; In Vitro Techniques; Kinetics; Muscle, Smooth, Vascular; ortho-Aminobenzoates; Rats; Rats, Inbred SHR; Sulfonamides; Torsemide; Vasoconstriction

We hypothesized that inhibition and activation of basolateral to luminal chloride transport mechanisms were associated with respective decreases and increases in basolateral to luminal water fluxes. The luminal to basolateral (J(W)(L-->B)) and basolateral to luminal (J(W)(B-->L)) water fluxes across ovine tracheal epithelia were measured simultaneously. The mean J(W)(L-->B) (6.5 microl/min/cm(2)) was larger than J(W)(B-->L) (6.1 microl/min/cm(2)). Furosemide reduced J(W)(B-->L) from 6.0 to 5.6 microl/min/cm(2). Diphenylamine-2-carboxylate (DPC) reduced J(W)(B-->L) from 7.9 to 7. 3 microl/min/cm(2) and reduced the membrane potential difference by 38%. Furosemide together with DPC decreased J(W)(L-->B) by 30% and J(W)(B-->L) by 15%. Norepinephrine increased J(W)(B-->L) from 4.9 to 6.0 microl/min/cm(2). Neuropeptide Y in the presence of norepinephrine decreased J(W)(L-->B) (6.4 to 5.2 microl/min/cm(2)) and returned J(W)(B-->L) to its baseline value. Vasopressin increased J(W)(B-->L) from 4.1 to 5.1 microl/min/cm(2). Endothelin-1 induced a simultaneous increase in J(W)(B-->L) (7.0 to 7.7 microl/min/cm(2)) and decrease in J(W)(L-->B) (7.4 to 6.4 microl/min/cm(2)); and decreased the membrane resistance. These data indicate that in tracheal epithelia under homeostatic conditions J(W)(B-->L) has a approximately 15% actively coupled component. Consistent with our hypothesis, inhibition and receptor-induced stimulation of chloride effluxes were associated with decreases and increases in J(W)(B-->L), respectively. However, as inhibition of transcellular chloride transport always decreased J(W)(L-->B) more than J(W)(B-->L), reducing transepithelial chloride transport did not result in less water being transported into the airway lumen.

Topics: Adrenergic alpha-Agonists; Animals; Biological Transport; Calcium Channel Blockers; Chlorides; Endothelin-1; Furosemide; In Vitro Techniques; Neuropeptide Y; Norepinephrine; ortho-Aminobenzoates; Respiratory Mucosa; Sheep; Trachea; Vasopressins; Water