Increased counteracting effect of eNOS and nNOS on an alpha1-adrenergic rise in total peripheral vascular resistance in spontaneous hypertensive rats.
OBJECTIVE
The hypertension in spontaneous hypertensive rats (SHR) may result from a hyperactive sympathetic nervous system or from insufficient bioactive nitric oxide (NO) due to increased oxidative stress. The present investigation aimed to elucidate the balance between these two systems by studying the ability of NO to oppose an adrenergic rise in total peripheral vascular resistance (TPVR).


METHODS
In anesthetized, open-chest SHR and normotensive controls (WKY) on a respirator, blood pressure was recorded in the femoral artery and cardiac output measured by ascending aorta flow. Tyramine infusion (15 min, intravenously) was used to stimulate neuronal noradrenaline release.


RESULTS
Tyramine induced an immediate but transient increase in TPVR, which was 4.5 times greater in SHR. After the non-selective NO synthase (NOS) inhibitor (L-NAME: N(omega)-nitro-L-arginine methyl ester), DeltaTPVRimm was 8.6 and 5.3 times increased in SHR and WKY, respectively, and TPVR remained elevated throughout the infusion period. Addition of alpha1-adrenoceptor antagonist (prazosin+L-NAME) abolished the TPVR response to tyramine. Neuronal NOS inhibitor (7-introindazole) increased DeltaTPVRimm only in SHR (2.1 times), and TPVR remained elevated. Inducible NOS inhibitor (1400W), free radical scavenger (tempol), NAD(P)H oxidase inhibitor (apocynin), angiotensin AT1 receptor antagonist (losartan), and ganglion blocker (hexamethonium) had no effect on the tyramine TPVR response in either strain. DeltaTPVR to hexamethonium, prazosin, and L-NAME were greater in SHR than WKY, and hexamethonium reduced DeltaTPVR to L-NAME in SHR only.


CONCLUSIONS
The alpha1-adrenoceptor TPVR response to endogenous noradrenaline release was increased in SHR. This was not due to reduced bioavailable NO; on the contrary, NO counteraction was greatly increased, derived from endothelial NOS, with an additional role of neuronal NOS not seen in WKY. An influence of oxidative stress on these responses was not detected in either strain. In addition, a central eNOS sympathoinhibitory component appeared to influence baseline TPVR in SHR.
Berg
Torill
T
Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1103, Blindern, 0317 Oslo, Norway. torill.berg@basalmed.uio.no
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D005730:Ganglionic Blockers / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D018738:Hexamethonium / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014439:Tyramine / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects*
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D005730:Ganglionic Blockers; D007191:Indazoles; D009569:Nitric Oxide; D018738:Hexamethonium; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine; D014439:Tyramine; D011224:Prazosin