E-Ring Isoprostanes Elevate [Ca2+]i In Pulmonary Vascular Endothelial Cells, Leading To Release Of Nitric Oxide And Vascular Smooth Muscle Relaxation

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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PKG substrates involved in vascular smooth muscle relaxation by cyclic GMP

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)33780-1 ◽

1997 ◽

Vol 73 ◽

pp. 2

Author(s):

Shoichi Imai

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Cyclic Gmp ◽

Muscle Relaxation ◽

Smooth Muscle Relaxation ◽

Vascular Smooth Muscle Relaxation

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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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