Differential cardiovascular responses to blockade of nNOS or iNOS in rostral ventrolateral medulla of the rat

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Abstract
We investigated the contribution of neuronal or inducible nitric oxide synthase (nNOS or iNOS) at the rostral ventrolateral medulla (RVLM) to central cardiovascular regulation by endogenous nitric oxide (NO), using Sprague‐Dawley rats anaesthetized and maintained with propofol. Microinjection bilaterally into the RVLM of a NO trapping agent, carboxy‐2‐phenyl‐4,4,5,5‐tetramethylimidazoline‐l‐oxy‐l‐3‐oxide (10, 50 or 100 nmoles) resulted in significant hypotension and bradycardia. Similar application of a selective antagonist of nNOS, 7‐nitroindazole (1, 2.5 or 5 pmoles), or selective antagonists of iNOS, aminoguanidine (125, 250 or 500 pmoles), N6‐(l‐iminoethyl)‐L‐lysine (250 pmoles) or S‐methylisothiourea (250 pmoles), induced respectively a reduction or an enhancement in systemic arterial pressure, heart rate and power density of the vasomotor components in the spectrum of arterial blood pressure signals, the experimental index for sympathetic neurogenic vasomotor tone. Both hypotension and bradycardia induced by the NO precursor, L‐arginine (100 nmoles), were significantly blunted when aminoguanidine (250 pmoles) was co‐microinjected bilaterally into the RVLM. On the other hand, co‐administered 7‐nitroindazole (2.5 pmoles) was ineffective. Whereas low doses of S‐nitro‐N‐acetylpenicillamine (0.25 or 0.5 nmoles) elicited hypertension and tachycardia, high doses of this non‐nitrate NO donor (5 nmoles) induced hypotension and bradycardia. Reverse transcription – polymerase chain reaction analysis revealed that both iNOS and nNOS mRNA were expressed in the ventrolateral medulla. We conclude that the prevalence of nNOS over iNOS activity at the RVLM and the associated dominance of sympathoexcitation over sympathoinhibition may underlie the maintenance of sympathetic vasomotor outflow and stable systemic arterial pressure by the endogenous NO. British Journal of Pharmacology (2001) 133, 606–614; doi:10.1038/sj.bjp.0704105