Potassium channel blockade of atrial negative inotropic responses to P1-purinoceptor and muscarinic receptor agonists and to cromakalim.
The negative inotropic responses of guinea pig isolated left atria to the P1-receptor agonists adenosine and L-N6-phenylisopropyladenosine (L-PIA), the muscarinic receptor agonist carbachol, and the potassium channel activator cromakalim were examined. The potassium channel blocker 4-aminopyridine (4-AP, 10 mM) decreased the concentration-response curve for L-N-6-phenylisopropyladenosine (L-PIA) so that the maximum reduction in atrial tension was significantly reduced from 77.8 to 61.9%. The concentration-response curve for the negative inotropic response to carbachol was displaced to the right by a substantially greater amount (521-fold), partly due to the muscarinic receptor blocking activity of 4-AP. The response to a single submaximum dose of L-PIA (520 nM) was slow in onset and monophasic, whereas adenosine induced a rapid reduction in tension followed by a gradual return toward the resting level. In the presence of 4-AP (10 mM), the peak response to L-PIA was significantly reduced from a 59.7 to 31.0% inhibition of tension. In addition, the rate of development of the response was significantly slowed. The peak inhibition of tension by adenosine (112 microM) (60.0%) was also significantly reduced to 37.4% in the presence of 4-AP (10 mM). Furthermore, there was no rapid decrease in tension but a gradual decrease to a peak effect which was no different from that in the absence of 4-AP. These results suggest that the P1-receptor agonists exert negative inotropy through a K+ channel-dependent component which is blocked by 4-AP and a slower-onset K+ channel-independent component. The potassium channel blocker, bromobenzoylmethyladamantylamine (BMA 100 microM) also shifted (11-fold) the concentration-response curve for the negative inotropic response to adenosine, and to a lesser extent that to cromakalim (2.1-fold) and carbachol. Glibenclamide (0.3, 3, and 30 microM), a selective antagonist of ATP-regulated potassium channels, was a potent antagonist of the negative inotropic responses to cromakalim. However, 30 microM failed to antagonize the responses to L-PIA, adenosine, or carbachol, indicating that they do not mediate their responses through ATP-regulated potassium channels. 4-AP (10 mM) caused a slight shift (2.3-fold) of the concentration-response curve for cromakalim, indicating weak activity against ATP-regulated potassium channels in the left atrium. This study showed that P1-receptor agonists exert negative inotropic responses in guinea pig left atria only in part through activation of potassium channels. These channels differ from the ATP-regulated potassium channels activated by cromakalim.
Urquhart
R A
RA
Department of Pharmacology, Welsh School of Pharmacy, University of Wales College of Cardiff.
Ford
W R
WR
Broadley
K J
KJ
D015761:4-Aminopyridine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D019806:Cromakalim; D003864:Depression, Chemical; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects*; D006851:Hydrochloric Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010276:Parasympatholytics / Q000494:pharmacology*; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D011983:Receptors, Purinergic / Q000187:drug effects*; D012414:Rubidium Radioisotopes
D001578:Benzopyrans; D010276:Parasympatholytics; D015221:Potassium Channels; D011758:Pyrroles; D011976:Receptors, Muscarinic; D011983:Receptors, Purinergic; D012414:Rubidium Radioisotopes; D019806:Cromakalim; D010660:Phenylisopropyladenosine; D002217:Carbachol; D015761:4-Aminopyridine; D000241:Adenosine; D006851:Hydrochloric Acid; D005905:Glyburide