Endothelial calcium-activated potassium channels as therapeutic targets to enhance availability of nitric oxide

The vascular endothelium plays a critical role in vascular health by controlling arterial diameter, regulating local cell growth, and protecting blood vessels from the deleterious consequences of platelet aggregation and activation of inflammatory responses. Circulating chemical mediators and physical forces act directly on the endothelium to release diffusible relaxing factors, such as nitric oxide (NO), and to elicit hyperpolarization of the endothelial cell membrane potential, which can spread to the surrounding smooth muscle cells via gap junctions. Endothelial hyperpolarization, mediated by activation of calcium-activated potassium (KCa) channels, has generally been regarded as a distinct pathway for smooth muscle relaxation. However, recent evidence supports a role for endothelial KCa channels in production of endothelium-derived NO, and indicates that pharmacological activation of these channels can enhance NO-mediated responses. In this review we summarize the current data on the functional role of endothelial KCa channels in regulating NO-mediated changes in arterial diameter and NO production, and explore the tempting possibility that these channels may represent a novel avenue for therapeutic intervention in conditions associated with reduced NO availability such as hypertension, hypercholesterolemia, smoking, and diabetes mellitus.

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A theoretical model of nitric oxide transport in arterioles: frequency- vs. amplitude-dependent control of cGMP formation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00525.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. H1043-H1056 ◽

Cited By ~ 51

Author(s):

Nikolaos M. Tsoukias ◽

Mahendra Kavdia ◽

Aleksander S. Popel

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Smooth Muscle ◽

Soluble Guanylate Cyclase ◽

Muscle Tone ◽

Muscle Relaxation ◽

Smooth Muscle Relaxation ◽

No Production ◽

Cgmp Formation

Nitric oxide (NO) plays many important physiological roles, including the regulation of vascular smooth muscle tone. In response to hemodynamic or agonist stimuli, endothelial cells produce NO, which can diffuse to smooth muscle where it activates soluble guanylate cyclase (sGC), leading to cGMP formation and smooth muscle relaxation. The close proximity of red blood cells suggests, however, that a significant amount of NO released will be scavenged by blood, and thus the issue of bioavailability of endothelium-derived NO to smooth muscle has been investigated experimentally and theoretically. We formulated a mathematical model for NO transport in an arteriole to test the hypothesis that transient, burst-like NO production can facilitate efficient NO delivery to smooth muscle and reduce NO scavenging by blood. The model simulations predict that 1) the endothelium can maintain a physiologically significant amount of NO in smooth muscle despite the presence of NO scavengers such as hemoglobin and myoglobin; 2) under certain conditions, transient NO release presents a more efficient way for activating sGC and it can increase cGMP formation severalfold; and 3) frequency-rather than amplitude-dependent control of cGMP formation is possible. This suggests that it is the frequency of NO bursts and perhaps the frequency of Ca2+ oscillations in endothelial cells that may limit cGMP formation and regulate vascular tone. The proposed hypothesis suggests a new functional role for Ca2+ oscillations in endothelial cells. Further experimentation is needed to test whether and under what conditions in silico predictions occur in vivo.

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Inducible and neuronal nitric oxide synthase involvement in lipopolysaccharide-induced sphincteric dysfunction

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.1.g32 ◽

2001 ◽

Vol 280 (1) ◽

pp. G32-G42 ◽

Cited By ~ 43

Author(s):

Ya-Ping Fan ◽

Sushanta Chakder ◽

Feng Gao ◽

Satish Rattan

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Muscle Relaxation ◽

Smooth Muscle Relaxation ◽

No Production ◽

Muscarinic Agonist ◽

Basal Tone ◽

Before And After ◽

Oxide Synthase ◽

Nanc Relaxation

We examined the effect of endotoxin lipopolysaccharide (LPS) on the basal tone and on the effects of different stimuli and agonists and transcriptional and translational expression of nitric oxide (NO) synthase (NOS) isozymes in the lower esophageal sphincter (LES), pyloric sphincter (PS), and internal anal sphincter (IAS). NO release was also examined before and after LPS. LPS caused a dose-dependent fall in the basal tone and augmentation of the relaxation caused by nonadrenergic, noncholinergic (NANC) nerve stimulation in the LES and IAS. In the PS, LPS had no significant effect on the basal tone and caused an attenuation of the NANC relaxation and an augmentation of the contractile response of muscarinic agonist. Interestingly, the smooth muscle relaxation by atrial natriuretic factor was suppressed in the LES and IAS but not in the PS. These changes in the sphincteric function following LPS may be associated with increase in the inducible NOS (iNOS) expression since they were blocked by iNOS inhibitorl-canavanine. Augmentation of NANC relaxation in the LES and IAS smooth muscle by LPS may be due to the increased activity of neuronal NOS and NO production.

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Nitric Oxide: From Gastric Motility to Gastric Dysmotility

International Journal of Molecular Sciences ◽

10.3390/ijms22189990 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9990

Author(s):

Eglantina Idrizaj ◽

Chiara Traini ◽

Maria Giuliana Vannucchi ◽

Maria Caterina Baccari

Keyword(s):

Nitric Oxide ◽

Smooth Muscle ◽

Gastric Motility ◽

Muscle Relaxation ◽

Physiological Role ◽

Smooth Muscle Relaxation ◽

No Production ◽

Main Role ◽

Motor Responses

It is known that nitric oxide (NO) plays a key physiological role in the control of gastrointestinal (GI) motor phenomena. In this respect, NO is considered as the main non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter responsible for smooth muscle relaxation. Moreover, many substances (including hormones) have been reported to modulate NO production leading to changes in motor responses, further underlying the importance of this molecule in the control of GI motility. An impaired NO production/release has indeed been reported to be implicated in some GI dysmotility. In this article we wanted to focus on the influence of NO on gastric motility by summarizing knowledge regarding its role in both physiological and pathological conditions. The main role of NO on regulating gastric smooth muscle motor responses, with particular reference to NO synthases expression and signaling pathways, is discussed. A deeper knowledge of nitrergic mechanisms is important for a better understanding of their involvement in gastric pathophysiological conditions of hypo- or hyper-motility states and for future therapeutic approaches. A possible role of substances which, by interfering with NO production, could prove useful in managing such motor disorders has been advanced.

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Interactions between nitroglycerin and endothelium in vascular smooth muscle relaxation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1991.260.3.h698 ◽

1991 ◽

Vol 260 (3) ◽

pp. H698-H701 ◽

Cited By ~ 5

Author(s):

J. L. Dinerman ◽

D. L. Lawson ◽

J. L. Mehta

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Muscle Relaxation ◽

Smooth Muscle Relaxation ◽

No Production ◽

Cyclic Monophosphate ◽

The Mean ◽

Smooth Muscle Relaxant ◽

Vascular Smooth Muscle Relaxation

To evaluate the role of endothelium in nitroglycerin (NTG)-mediated vascular relaxation, epinephrine-contracted rat thoracic aortic segments with and without intact endothelium were exposed to NTG (10(-10) to 10(-5) M). Aortic segments with intact (endo+, n = 15) and denuded endothelium (endo-, n = 9) exhibited typical NTG-induced relaxation. However, the mean effective concentration of NTG was lower for endo- than for endo+ segments (P less than 0.001). To determine if this phenomenon related to nitric oxide (NO) generation by endothelium, six endo+ segments were treated with NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO production. These endo+ segments exhibited greater (P less than 0.001) relaxation in response to NTG than the untreated endo+ segments. Oxyhemoglobin, an inhibitor of guanylate cyclase activation, greatly diminished NTG-mediated relaxation of all aortic segments. To determine if the enhanced NTG-mediated relaxation of endo- segments was unique to the guanosine 3',5'-cyclic monophosphate-dependent vasodilator NTG, other endo+ and endo- segments were exposed to adenosine 3',5'-cyclic monophosphate-dependent vasodilator papaverine (10(-8) to 10(-4) M), and no difference in EC50 was noted between endo+ and endo- segments. Thus endothelium attenuates NTG-mediated vasorelaxation, and this attenuation is abolished by inhibition of endothelial NO production with L-NMMA. These observations indicate that endothelium is a dynamic modulator of vascular smooth muscle relaxant effects of NTG. This modulation appears to result from a competitive interaction between endothelial NO and NTG.

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