The involvement of ATP‐sensitive potassium channels in β‐adrenoceptor‐mediated vasorelaxation in the rat isolated mesenteric arterial bed

1 Intracellular microelectrode recordings were performed to investigate the membrane K + conductances involved in smooth muscle hyperpolarization of lymphatic vessels in the guinea-pig mesentery. 2 Nitric oxide (NO), released either by the endothelium after acetylcholine (ACh; 10 mM) stimulation or by sodium nitroprusside (SNP; 50 ± 100 mM), hyperpolarized lymphatic smooth muscle. These responses were inhibited with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ, 10 mM). 3 ACh and SNP-induced hyperpolarizations were inhibited (by about 90%) upon application of the ATP-sensitive K + (K ATP ) channel blocker, glibenclamide (10 mM), or with 4-aminopyridine (2.5 mM), but were not aected by the Ca 2+ -activated K + channels blocker, penitrem A (100 nM). 4 Hyperpolarization caused by the K + channel opener, cromakalim (0.1 ± 10 mM), isoprenaline (0.1 mM) or forskolin (0.5 mM) were all signi®cantly blocked by glibenclamide. 5 Hyperpolarization evoked by ACh and SNP were inhibited with N-[2-(p-bromociannamylamino)-ethyl]-5-isoquinolinesulfonamide-dichloride (H89, 10 mM), suggesting the involvement of cyclic AMP dependent protein kinase (PKA). 6 These results suggest that K ATP channels play a central role in lymphatic smooth muscle hyperpolarization evoked by a NO-induced increase in cyclic GMP synthesis, as well as by badrenoceptor-mediated production of cyclic AMP. Interestingly, both pathways lead to K ATP channels opening through the activation of PKA.

Section: Role Of Protein Kinase a In No-induced Hyperpolarizationsupporting

confidence: 82%

ATP‐sensitive K⁺ channels in smooth muscle cells of guinea‐pig mesenteric lymphatics: role in nitric oxide and β‐adrenoceptor agonist‐induced hyperpolarizations

Weid

1998

“…These include prostanoids (Bouchard et al, 1994), fi-adrenoceptor agonists (Randall & McCulloch, 1995) and adenosine (Kirsch et al, 1990;Belloni & Hintze, 1991;Merkel et al, 1992;Dart & Standen, 1993). Accordingly, KATP activity may be highly regulated by a variety of systems.…”

Section: Introductionmentioning

confidence: 99%

The involvement of ATP‐sensitive potassium channels and adenosine in the regulation of coronary flow in the isolated perfused rat heart

Randall

1995

Self Cite

1 The roles of adenosine 5'-triphosphate (ATP)-sensitive potassium channels (KATp) and endogenous adenosine in the regulation of coronary flow have been assessed in the isolated, buffer-perfused heart of the rat.2 In the presence of glibenclamide 10 Mm there was a significant (P<0.001) reduction in coronary flow from a baseline value of 8.78 +0.76 ml min'`g'`to 3.89 +0.59 ml min'`g-. This change was accompanied by a significant (P< 0.01) reduction in cardiac mechanical performance as shown by the decrease in the pressure-rate product from 21,487+2,577 mmHg min-' to 6,950+ 1,104 mmHg min-m.3 The non-selective adenosine antagonist 8-phenyltheophylline (10 Mm) also caused a significant (P<0.001) reduction in coronary flow from a basal value of 10.4+0.6 ml min-' g-' to 6.32+0.60 ml min-I g-1. The subsequent addition of glibenclamide, in the presence of 8-phenyltheophylline, brought about a further significant (P<0.001) reduction in coronary flow to 3.05+0.55 ml min-I g1' and this value was similar to that in the presence of glibenclamide alone. 4 In hearts perfused under constant flow conditions, exogenous adenosine caused dose-related reductions in coronary perfusion pressure described by a maximum reduction in pressure of 30.7+ 3.9 mmHg and an ED50 of 977± 813 pmol. Addition of glibenclamide caused a significant (P<0.01) increase in coronary perfusion pressure of 44.7 + 7.2 mmHg and a significant (P< 0.05) rightward shift of the dose-response curve for the depressor effects of adenosine (ED50 = 13.5 ± 3.8 nmol), with a depression (P<0.05) of the maximum (16.3 ±2.4 mmHg). 5 In conclusion, both KATP and endogenous adenosine make major contributions towards coronary vascular tone and the regulation of coronary flow in the rat isolated heart. Furthermore, in the coronary vasculature a significant proportion of the vasodilator action of adenosine is mediated through the activation of KATP.

“…The potentiation appears to be speci®c to a 1 -adrenoceptor agonist stimulation, as similar results to those with PE were obtained for methoxamine, whereas the response in arteries constricted by a depolarizing solution containing 30 mM K + was identical to that in arteries constricted with PGF 2a (Figure 3). These results also suggest that the potentiation by PE and methoxamine is not related to any depolarizing in¯uence that these agents may have, and is therefore unrelated to the mechanisms described by Plane & Garland (1996) to account for di erences in ACh-induced relaxation in arteries constricted by noradrenaline or the thromboxane mimetic U46619, or to any possible hyperpolarizing action of b-adrenoceptor agonists (Randall & McCulloch, 1995).…”

Section: Discussionmentioning

confidence: 53%

Potentiation of cyclic AMP‐mediated vasorelaxation by phenylephrine in pulmonary arteries of the rat

Priest

Hucks

Ward

1999

1 a 1 -adrenoceptor agonists may potentiate relaxation to b-adrenoceptor agonists, although the mechanisms are unclear. We compared relaxations induced by b-adrenoceptor agonists and cyclic AMP-dependent vasodilators in rat pulmonary arteries constricted with prostaglandin F 2a (PGF 2a ) or the a 1 -adrenoceptor agonist phenylephrine (PE). In addition, we examined whether di erences were related to cyclic AMP-or nitric oxide (NO) and cyclic GMP-dependent pathways. 2 Isoprenaline-induced relaxation was substantially potentiated in arteries constricted with PE compared with PGF 2a . Methoxamine was similar to PE, whereas there was no di erence between PGF 2a and 30 mM KCl. The potentiation was primarily due to a marked increase in the NOindependent component of relaxation, from 9.1+1.7% for PGF 2a to 55.1+4.4% for PE. NOdependent relaxation was also enhanced, but to a lesser extent (*50%). Relaxation to salbutamol was almost entirely NO-dependent in both groups, and was potentiated *50% by PE. 3 Relaxation to forskolin (activator of adenylate cyclase) was also enhanced in PE constricted arteries. Part of this relaxation was NO-dependent, but the major e ect of PE was to increase the NO-independent component. Propranolol diminished but did not abolish the potentiation. There was no di erence in response to CPT cyclic AMP (membrane permeant analogue) between PE and PGF 2a , suggesting that mechanisms distal to the production of cyclic AMP were unchanged. 4 Relaxation to sodium nitroprusside (SNP) was the same for PE and PGF 2a , although relaxation to acetylcholine (ACh) was slightly depressed. This implies that potentiation by PE does not involve the cyclic GMP pathway directly. 5 Mesenteric arteries constricted with PE did not show potentiation of isoprenaline-induced relaxation compared to those constricted with PGF 2a , suggesting that this e ect may be speci®c to the pulmonary circulation. 6 These results clearly show that PE potentiates both the NO-independent and -dependent components of cyclic AMP-mediated relaxation in pulmonary arteries of the rat, although the e ect on the former is more profound. We suggest that potentiation of both components is largely due to direct activation of adenylate cyclase via a 1 -adrenoceptors, within the smooth muscle and endothelial cells respectively.