Signalling pathways in bradykinin- and nitric oxide-induced hypotension in the normotensive rat; role of K+-channels

1 Bradykinin and nitric oxide (NO) are potent hypotensive agents. In the present study, the role of K+-channels in the signalling pathways responsible for their hypotensive action was investigated in normotensive, anaesthetized rats. The rats were treated with ion-channel inhibitors before administration of bradykinin (2.8, 5.6, 28 and 56 nmol kg(-1), i.v.) followed in some of the protocols by nitroprusside (1.1, 3.5, 7, 14, and 28 nmol kg(-1), i.v.). 2 No attenuation of the hypotensive response to bradykinin was detected for inhibitors of the Na-K-Cl-cotransporter (30 mu mol kg(-1) furosemide), the ATP-sensitive K+-channel (40 mu mol kg(-1) glibenclamide), high conductance Ca2+-activated K+-channel (180 mu mol kg(-1) tetraethylammonium, 54 mu mol kg(-1) tetrabutylammonium, 35 nmol kg(-1) iberiotoxin, 35 nmol kg(-1) charybdotoxin) or the low conductance Ca2+-activated K+-channel (74 nmol kg(-1) apamin). 3 However, the voltage-sensitive K+-channel (I-A) inhibitor 4-aminopyridine (4.05-40.5 mu mol kg(-1)) induced a concentration-dependent (P<0.0001) attenuation of the hypotensive response (P<0.0001). Bradykinin had no effect on heart rate in anaesthetized rats and this observation was not altered by pretreatment with 4-aminopyridine. 4 4-Aminopyridine (53 mu mol kg(-1)) also significantly attenuated the hypotensive response to nitroprusside (P<0.0003) without altering the heart rate concentration-response curve. Of the two Ca2+-activated K+-channel inhibitors tested on nitroprusside-induced hypotension, tetrabutylammonium induced a slight attenuation (P<0.0101), whereas iberiotoxin had no effect. 5 We therefore concluded that, although the acute hypotensive response to bradykinin in the normotensive rat is not mediated through nitric oxide synthesis, the hypotensive response to both agents was mediated through opening of voltage-sensitive K+-channels (I-A), resulting in a decrease in peripheral vascular resistance.