Abstract
K+-channels of the Kv7/KCNQ-family hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells (VSMC). Kv7 may therefore play a role in blood pressure (BP) homeostasis, and prevent a high total peripheral vascular resistance (TPR), a hallmark of hypertensive disease. The present study analyzed if Kv7 channels influence catecholamine release and TPR in normotensive (WKY) and spontaneously hypertensive rats (SHR), and if they may contribute to the antihypertensive protection seen in young, female SHR. Tyramine-stimulated norepinephrine release evokes an adrenergic cardiovascular response, and also allows modulation of release to be reflected in the overflow to plasma. The experiment itself activated some secretion of epinephrine. The results show: (1) XE-991 (Kv7.1-7.4-inhibitor), but not chromanol 293B (Kv7.1-inhibitor), increased tyramine-stimulated norepinephrine overflow and epinephrine secretion in both sexes in SHR, but not WKY. (2) Surprisingly, the Kv7-openers retigabine (Kv7.2-7.5) and ICA-27243 (Kv7.2-7.3-preferring) increased catecholamine release in female SHR. (3) The rise in TPR following tyramine-stimulated norepinephrine release was increased by XE-991 but not chromanol in the female WKY only. (4) Retigabine and ICA-27243 reduced the TPR-response to tyramine in the female SHR only. These results suggested: (1) Up-regulation of Kv7.2-7.3 function in sympathetic neurons and chromaffin cells hampered catecholamine release in SHR of both sexes. (2) The increase catecholamine release observed after channel openers in the female SHR may possibly involve reduced transmission in cholinergic neurons which hamper catecholamine release. These two mechanisms may serve to counter-act the hyperadrenergic state in SHR. (3) Kv7.4, most likely in the vasculature, opposed the tension-response to norepinephrine in the female WKY. (4) Vascular Kv7.4-7.5 could be stimulated and then opposed norepinephrine-induced vasoconstriction in the female SHR. (5) Vascular Kv7 channels did not counter-act norepinephrine induced vasoconstriction in male rats, possibly due to different Kv7 channel regulation. Kv7 channels may represent a novel target for antihypertensive therapy.
Highlights
Sympathetic nerve hyperactivity plays an important role in the pathology of hypertension, and can be detected years before the clinical occurrence of a high blood pressure (BP) (Julius, 1992)
The tyramine-induced norepinephrine overflow was greater in spontaneously hypertensive rats (SHR) than in WKY in both sexes (P ≤ 0.002), and higher in the females than in the males in both strains (P = 0.014)
The Kv7.1 inhibitor chromanol induced a minor reduction in the plasma catecholamine levels in the female WKY but otherwise had no effect
Summary
Sympathetic nerve hyperactivity plays an important role in the pathology of hypertension, and can be detected years before the clinical occurrence of a high blood pressure (BP) (Julius, 1992). Transmitter release from sympathetic nerve terminals and contraction of vascular smooth muscle cells (VSMC) are both activated by a rise in the intracellular concentration of Ca2+ ([Ca2+]i) In nerve terminals, this occurs during depolarization, which opens voltage-sensitive Ca2+ channels (CaV), allowing the entry of Ca2+ (Figure 1). The Kv7.1–7.4 inhibitor XE-991 surprisingly increased norepinephrine and epinephrine release in SHR, activated by depolarization induced by a non-Kv7 Kv blocker (3,4-diaminopyridine) (Berg, 2016b). This observation suggested an up-regulated role of Kv7 channels in hampering the release of catecholamines in SHR. The role of Kv7 channels in TPR and BP control may be studied preferably during norepinephrine-induced VSMC constriction
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