Showing papers by "Ulf Ekelund published in 1998"

Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice.

Abstract: Nitric oxide (NO) synthesized within mammalian sinoatrial cells has been shown to participate in cholinergic control of heart rate (HR). However, it is not known whether NO synthesized within neurons plays a role in HR regulation. HR dynamics were measured in 24 wild-type (WT) mice and 24 mice in which the gene for neuronal NO synthase (nNOS) was absent (nNOS-/- mice). Mean HR and HR variability were compared in subsets of these animals at baseline, after parasympathetic blockade with atropine (0.5 mg/kg i.p.), after beta-adrenergic blockade with propranolol (1 mg/kg i.p.), and after combined autonomic blockade. Other animals underwent pressor challenge with phenylephrine (3 mg/kg i.p.) after beta-adrenergic blockade to test for a baroreflex-mediated cardioinhibitory response. The latter experiments were then repeated after inactivation of inhibitory G proteins with pertussis toxin (PTX) (30 microgram/kg i.p.). At baseline, nNOS-/- mice had higher mean HR (711+/-8 vs. 650+/-8 bpm, P = 0.0004) and lower HR variance (424+/-70 vs. 1,112+/-174 bpm2, P = 0.001) compared with WT mice. In nNOS-/- mice, atropine administration led to a much smaller change in mean HR (-2+/-9 vs. 49+/-5 bpm, P = 0.0008) and in HR variance (64+/-24 vs. -903+/-295 bpm2, P = 0.02) than in WT mice. In contrast, propranolol administration and combined autonomic blockade led to similar changes in mean HR between the two groups. After beta-adrenergic blockade, phenylephrine injection elicited a fall in mean HR and rise in HR variance in WT mice that was partially attenuated after treatment with PTX. The response to pressor challenge in nNOS-/- mice before PTX administration was similar to that in WT mice. However, PTX-treated nNOS-/- mice had a dramatically attenuated response to phenylephrine. These findings suggest that the absence of nNOS activity leads to reduced baseline parasympathetic tone, but does not prevent baroreflex-mediated cardioinhibition unless inhibitory G proteins are also inactivated. Thus, neuronally derived NO and cardiac inhibitory G protein activity serve as parallel pathways to mediate autonomic slowing of heart rate in the mouse.

Alpha 2-adrenoceptor activation may trigger the increased production of endothelium-derived nitric oxide in skeletal muscle during acute haemorrhage

Abstract: Our previous studies indicated that acute haemorrhage leads to a pronounced increase in the release of endothelium-derived nitric oxide (EDNO) graded in relation to the magnitude of the blood loss. The EDNO-induced vasodilatation, confined selectively to the arterial 'feeder' vessels, attenuates the concomitant reflex adrenergic constriction and thereby prevents deleterious reduction of blood flow. The present study aimed at investigating whether the reflex release of blood-borne catecholamines might trigger this EDNO release via activation of endothelial alpha 2-adrenoceptors. The study was performed on the sympathectomized vascular bed of cat skeletal muscle with a technique permitting quantitative recordings of resistance (tone) in consecutive vascular sections. Selection alpha 2-adrenoceptor blockade with idazoxan applied at steady state vasoconstriction after a 35% blood loss evoked an initial generalized dilator response (attributable to inhibition of post-synaptic smooth muscle alpha 2-adrenoceptors), followed by a constrictor response selectively in the arterial feeder vessels, the latter compatible with the hypothesis of reduced EDNO release by alpha 2-adrenoceptor blockade. More direct evidence for the hypothesis was obtained from studies of the vascular response to EDNO blockade (L-NAME) after haemorrhage in the presence and absence of alpha 2-adrenoceptor blockade. The constrictor response to EDNO blockade, which is a measure of the pre-existing EDNO dilator influence (EDNO production), was significantly smaller (P < 0.01) in the presence than absence of alpha 2-adrenoceptor blockade. The results indicate that blood-borne catecholamines, via activation of endothelial alpha 2-adrenoceptors, trigger the increase in the EDNO release in acute haemorrhage, implying a functionally important negative feedback in the integrated control of vascular tone in bleeding.