doi: 10.1161/01.STR.0000012743.21379.33
(Stroke. 2002;33:1164.)
© 2002 American Heart Association, Inc.
Letters to the Editor |
Re: Slowly Activating Potassium Conductance (ID): A Potential Target for Stroke Therapy
Physiology Department, CHU, Limoges, France
Departments of Neurology, Pharmacology, and Nephrology Internal Medicine, CHU, Amiens, France
Pathology Department, Yale Medical School, New Haven, Connecticut
To the Editor:
We read with great interest the article by Bains et al1 in which they hypothesize that the blood pressure–independent susceptibility of spontaneous hypertensive rats (SHR) to stroke could be explained by increased angiotensin II levels in the brain nuclei. Indeed, they convincingly documented that resistance to death of magnocellular neurons of paraventricular nucleus (PVN) after injection of an N-methyl-D-aspartate receptor agonist (NMDAa) is present in normotensive rats but absent in SHR and that preadministration of saralasin into these nuclei of SHR generated resistance of these cells to NMDAa-induced death, by preventing the angiotensin II–mediated increase of neuronal excitability, which is secondary to inhibition of a D-type specific potassium conductance. Indeed, inhibition of this conductance results in higher frequency of depolarization in the penumbra surrounding a focal brain ischemia and, therefore, results in increased infarct size. However, while the authors stressed the potential pathophysiological significance of their observation by recalling that the AT1 receptor antagonist losartan protects SHR against stroke even at nonantihypertensive dose,2 they unfortunately did not examine the effect of specific AT1 receptor blockade in their experimental model, and we wonder why they have chosen saralasin, a nonspecific angiotensin II antagonist.
Preadministration of losartan and candesartan have been shown to be more stroke protective than angiotensin-converting enzyme inhibitor (ACEI) in the gerbil model of acute brain ischemia by unilateral carotid ligation, whereas preadministration of ACEI with these AT1 receptor antagonists resulted in the same mortality as with ACEI alone, suggesting that stimulation of non–AT1 receptors was responsible for the stroke protective effect of AT1 receptor antagonists.3,4 Indeed, AT1 receptors blockade blunts the angiotensin II–mediated suppression of renin secretion and stimulates angiotensin II formation and therefore the nonopposed non–AT1 receptors, whereas ACE inhibition prevents angiotensin II formation and therefore non–AT1 receptor stimulation. Furthermore, in the rat stroke model induced by transient middle cerebral artery occlusion, previous intracerebroventricular injection of irbesartan (at low doses leaving the systemic angiotensin II system unaffected) was able to improve the neurological outcome, in parallel with a decrease of the expression of AP-1 transcription factors associated with neuron apoptosis. Because these beneficial effects were canceled by preadministration of an AT2 receptor blocker, the PD123177, this suggests that they were mediated by the AT2 receptors.5
Because of the duality of its receptors, angiotensin II seems to act as the two-edge sword, with AT1 and AT2 mediating opposing effects.3 The crucial question as to whether, depending on the balance of the expression of these receptors, angiotensin II is protective during brain ischemia through stimulation of AT2 or deleterious through stimulation of AT1 is still pending. As the important results presented by Bains et al point to the regulation of the D-type potassium channel as to a central effector to neuron protection during ischemic insult, we would be very eager to know if the authors have examined the effects of preadministration of AT1 and AT2 receptor antagonists on the channel inhibition by angiotensin II. An AT1-mediated inhibitory effect but an AT2-mediated stimulatory effect of angiotensin II of the K channel–dependent neuroprotective effect would provide an important new experimental evidence supporting the idea that AT1 specific blockade is better suited than ACE inhibition for cerebral protection.
References
1.
Bains J, Follwelle M, Latchford K, Anderson J, Ferguson A. Slowly activating potassium conductance (ID): a potential target for stroke therapy. Stroke. 2001; 32: 2624–2634.
2. Stier CTJ, Adler LA, Levine S, Chander PN. Stroke prevention by losartan in stroke-prone spontaneously hypertensive rats. J Hypertens. 1993; 11: S37–S42.[CrossRef][Medline] [Order article via Infotrieve]
3. Achard JM, Fournier A, Mazouz H, Caride VJ, Penar PL, Fernandez L. Protection against ischemia: a physiological function of the renin angiotensin system. Biochem Pharmacol. 2001; 62: 261–271.[CrossRef][Medline] [Order article via Infotrieve]
4. Dalmay F, Mazouz H, Allard J, Pesteil F, Achard JM, Fournier A. Non AT 1-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil. JRAAS. 2001; 2: 103–106.
5. Blume A, Funk A, Gohlke P, Unger T, Culman J. AT2 receptor inhibition in the rat brain reverses the beneficial effects of AT1 receptor blockade on neurological outcome after focal brain ischemia. Hypertension. 2000; 36: 656.Abstract.
Department of Physiology, Queen’s University, Kingston, Ontario, Canada
Neuroscience Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada
Response
We are not surprised by the very sensible question from Achard et al as to why selective AT1 receptor antagonists were not used in our experiments reported in Stroke.1 The reason for this decision is academically somewhat disappointing while unfortunately very relevant in the current era, with an increased awareness of the real value of intellectual property. Our request for losartan to be used in these experiments was accompanied by the very familiar standard agreement to assign at minimum a portion of patent rights from any work coming from the use of this compound to the pharmaceutical supplier. Working with the technology transfer office at Queen’s University, PARTEQ, we decided not to give up our intellectual property rights at this time, as we felt that the primary question could be answered using the nonselective peptide antagonist saralasin. The data from these experiments are reported in our article and, as pointed out by Achard et al, do not allow us to differentiate between potential AT1 and AT2 receptor–mediated effects.
We agree that the issue is indeed an intriguing one, and our recent study unfortunately fails to provide a definitive answer. The literature does, however, provide some hints. While we have not assessed the effects of AT1 receptor blockade on the delay current directly, previous work from this laboratory has shown AT1-mediated inhibition of transient potassium currents at that time identified as IA, which in all probability included a component of ID.2 In addition, in cultured hypothalamic neurons, Kang et al3 have reported both AT1-mediated inhibition of net potassium currents (blocked by losartan), and AT2-mediated enhancement (blocked by PD123177 and PD123319) of these same net potassium currents. Again, caution is necessary in interpreting these data as they do not assess specific effects on isolated currents. It should be stressed, however, that even though these effects are in accordance with the hypothesis of Achard et al with regard to potential effects on ID, direct assessment of AT receptor subtypes responsible for effects on this current has not to our knowledge been carried out.
Finally, we would agree that the available data do suggest AT1 receptor antagonists to be more effective in achieving cerebral protection than ACE inhibition. The novelty of our data, we believe, rests in the suggestion of a potential mechanism underlying such protection, namely inhibition if transient potassium conductances. We believe that the strength of our study is that we have provided both in vivo and in vitro validation of this hypothesis using 2 separate pharmacological agents that both inhibit these currents and endow neuroprotection. Obviously, as Achard et al point out, future studies will be necessary to more completely test this hypothesis in a variety of stroke models.
References
1. Bains JS, Follwell MJ, Latchford KJ, Anderson JW, Ferguson AV. Slowly activating potassium conductance (ID): a potential target for stroke therapy. Stroke. 2001; 32: 2624–2634.
2. Li Z, Ferguson AV. Electrophysiological properties of paraventricular magnocellular neurons in rat brain slices: modulation of IA by angiotensin II. Neuroscience. 1996; 71: 133–145.[CrossRef][Medline] [Order article via Infotrieve]
3. Kang J, Sumners C, Posner P. Modulation of net outward current in cultured neurons by angiotensin II: involvement of AT1 and AT2 receptors. Brain Res. 1992; 580: 317–324.[CrossRef][Medline] [Order article via Infotrieve]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||