Abstract-Hydrochlorothiazide has been shown to exert direct vasodilator effects by activation of calcium-activated potassium (K Ca ) channels in human and guinea pig isolated resistance arteries. Since hydrochlorothiazide binds to and inhibits the enzyme carbonic anhydrase and because K Ca channel activation is pH sensitive, we investigated the role of intracellular and extracellular carbonic anhydrase in the vascular effects of thiazide diuretics. Small arteries were isolated from guinea pig mesentery and studied by use of a microvascular myograph technique. In some experiments, tone and intracellular pH (pH i ) were measured simultaneously with 2Ј,7Ј-bis(2-carboxyethyl)-5(6)Ј-carboxyfluorescein (BCECF-AM). Bendroflumethiazide, a thiazide diuretic with minimal inhibitory effects on carbonic anhydrase, had little effect on noradrenaline-induced tone (16Ϯ8% relaxation) compared with hydrochlorothiazide (74Ϯ12% relaxation). In contrast to hydrochlorothiazide, the action of bendroflumethiazide was unaffected by 100 nmol/L charybdotoxin, a selective blocker of K Ca channels. All inhibitors of carbonic anhydrase relaxed noradrenaline-induced tone in a concentration-dependent manner, and this effect was blocked by charybdotoxin. Key Words: hydrochlorothiazide Ⅲ carbonic anhydrase inhibition Ⅲ muscle, smooth, vascular Ⅲ pH i Ⅲ potassium channels T hiazide diuretics were developed in the 1950s by chemical modification of carbonic anhydrase inhibitors. Although their blood pressure-lowering effects have been well documented, their mechanism of action is still not fully resolved. The principal site of action of thiazides is the early segment of the distal nephron, where they inhibit a luminal transmembrane-coupled NaCl transport system. In the long term, thiazides act by reducing peripheral resistance rather than by their diuretic effects, 1 and therefore a direct vascular effect has been proposed.Previous studies in isolated human and guinea pig resistance arteries have established a direct vasodilator activity of hydrochlorothiazide. This vasorelaxant response to hydrochlorothiazide was abolished by charybdotoxin and iberiotoxin, both selective blockers of large-conductance Ca 2ϩ -activated potassium (K Ca ) channels, but not by inhibitors of other vascular K ϩ channels. 2 On the basis of the fact that thiazide-like drugs such as cicletanine and diazoxide lead to hyperpolarization in vascular smooth muscle cells 3 and the fact that hydrochlorothiazide increases 86 Rb efflux as a marker of K ϩ efflux, 2,4 it was proposed that hydrochlorothiazide opens K Ca channels, thereby leading to K ϩ efflux and membrane hyperpolarization. The resultant closure of voltage-dependent Ca 2ϩ channels leads to a fall in [Ca 2ϩ ] i and vasorelaxation. 5 In addition to [Ca 2ϩ ] i , the open state probability of the K Ca channel is also modulated by intracellular pH (pH i ). Channel opening is inhibited by intracellular acidosis in carotid body cells, 6 while in isolated blood vessels intracellular alkalinization leads to relaxation asso...
Natriuretic peptides play an important role in sodium regulation and blood pressure (BP) control. We examined the effects of atrial natriuetic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) on human isolated resistance arteries and the mechanisms involved in vasorelaxation. Human subcutaneous resistance arteries were mounted in an isometric myograph and contracted with phenylephrine. CNP, but not ANP or BNP, relaxed arteries in a concentration dependent manner. The action of CNP was unaffected by removal of the endothelium, inhibition of nitric oxide synthase by NG-monomethyl-Larginine or inhibition of soluble guanylate cyclase by 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one. Blockade of cyclic GMPdependent kinase by 8-bromoguanosine-3', 5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS) inhibited CNP relaxation. CNP relaxation was also inhibited by high potassium or iberiotoxin, indicating that it was due to opening of BK Ca channels. Omapatrilat, a vasopeptidase inhibitor of neutral endopeptidase and angiotensin-converting enzyme, enhanced the effect of CNP and inhibited responses to Ang I. In summary, CNP, but not ANP or BNP, relaxes human resistance arteries by activating cyclic GMP-dependent kinase and BK Ca . The effects of CNP are enhanced by vasopeptidase inhibition and this may contribute to the vasodilator effects of these agents in vivo.
1 Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2 Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT 2 selective antagonist, PD123319, was without eect on responses to AII. The eects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3 Mechanical removal of the endothelium; pre-incubation with N o -nitro-L-arginine methyl ester hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or preincubation with BQ 485, an endothelin antagonist; had no signi®cant eect on contractions induced by AII. 4 Our results suggest AII contracts human isolated resistance arteries by an action on AT 1 receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT 1 antagonists without sacri®cing assumptions regarding the competitive nature of binding of these antagonists.
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