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Georg Kojda, Reply to Letter to the editor, Cardiovascular Research, Volume 44, Issue 1, October 1999, Page 224, https://doi.org/10.1016/S0008-6363(99)00209-6
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To the Editor:
We thank Dr. Pagliaro for his comments. In his letter Dr. Pagliaro focused on two points of the discussion of chronotropic effects of endogenous nitric oxide (NO) in our review [1]: (1) the use of Nω-nitro-l-arginine-methylester (l-NAME) and (2) a possible involvement of autonomic reflexes due to increases in blood pressure.
l-NAME is a widely used prodrug to inhibit NO-synthase (NOS) because of its convenient water solubility. To effectively inhibit NOS, l-NAME has to be deesterified to Nω-nitro-l-arginine, and in whole blood its halflife is 29 min [2]. Thus, it is unlikely that the intact ester has any considerable effect in-vivo. It is known that high concentrations of l-NAME can block muscarinergic receptors in-vitro [3]. In-vivo this blockade would result in an atropine like tachycardia, but there is no evidence of an antimuscarinergic effect of orally applied l-NAME.
The baroreceptor reflex balances sudden but not sustained changes in blood pressure. In hypertension there is a resetting of baroreceptors resulting in diminished baroreceptor induced pulse frequency (relatively diminished parasympathetic nerve activity) at any given blood pressure [4]. This was also observed in a chronically hypertensive transgenic mouse strain [5]. Thus, the bradycardia observed in normal mice treated for 3 weeks with l-NAME and in mice lacking the eNOS gene is most likely not a consequence of the concommitant mild increase in blood pressure. This interpretation is consistant with our observation that treatment of mice lacking the eNOS gene with l-NAME resulted in further bradycardia in the absence of any change of blood pressure [6]. It is also consistant with a recently published study demonstrating that isolated atria of mice lacking the eNOS gene have a normal response to muscarinergic stimulation [7].
