Autonomic dysfunctions play important roles in
hypertension,
heart failure and
arrhythmia, often with a detrimental and fatal effect. The present study analyzed if these dysfunctions involved M-channels (members of the Kv7/KNCQ family) in spontaneously hypertensive rats (SHR). Cardiac output and heart rate (HR) were recorded by a flow probe on the ascending aorta in anesthetized SHR and normotensive rats (WKY), and blood pressure (BP) by a femoral artery
catheter. Total peripheral vascular resistance (TPR) was calculated.
XE-991 (Kv7.1-7.4-inhibitor) reduced resting HR in WKY but only after
reserpine in SHR.
XE-991 increased TPR and BP baseline in both strains.
Retigabine (Kv7.2-7.5-opener) reduced HR, TPR and BP, also after
reserpine. Depolarization induced by
3,4-diaminopyridine (3,4-DAP), a voltage-sensitive K+ channel (Kv) inhibitor, activated release of both
acetylcholine and
norepinephrine, thus activating an initial,
cholinergic bradycardia in SHR, followed by sustained,
norepinephrine-dependant
tachycardia in both strains.
XE-991 augmented the initial 3,4-DAP-induced
bradycardia and eliminated the late
tachycardia in SHR, but not in WKY. The increased
bradycardia was eliminated by
hexamethonium and
methoctramine (M2muscarinic receptor antagonist) but not
reserpine.
Retigabine eliminated the increased
bradycardia observed in reserpinized SHR.
XE-991 also increased 3,4-DAP-stimulated
catecholamine release, but not after
hexamethonium or
reserpine.
CONCLUSIONS: M-currents hampered parasympathetic ganglion excitation and, through that, vagal control of HR, in SHR but not WKY. M-currents also opposed
catecholamine release in SHR but not in WKY. M-currents represented a vasodilatory component in resting TPR-control, with no strain-related difference detected. Excessive M-currents may represent the underlying cause of autonomic dysfunctions in
hypertension.