Cyclic guanosine monophosphate-enhanced sequestration of Ca2+ by sarcoplasmic reticulum in vascular smooth muscle.

Abstract

The purpose of this study was to investigate the effects of the intracellular messenger cyclic GMP (cGMP) on sequestration of cytosolic calcium (Ca 1 Stimulation of particulate and soluble guanylate cyclase elevates cytosolic cGMP during the relaxation produced both by endogenous vasodilators (endothelium-derived relaxing factor 2 -3 and atrial natriuretic factor 4 ) and by the nitric oxide-producing drugs (nitroglycerine, nitroprusside). 5 The relaxation occurring with cGMP results from a lowering of the cytosolic concentration of calcium ions (Ca 2+ ). 6 ' 7 This is thought to result predominantly from stimulation of the plasmalemmal Ca 2+ -extrusion ATPase. 8 - 9 An additional means of reducing cytosolic Ca 2+ in vascular smooth muscle is the sequestration of Ca 2+ into an intracellular store, the sarcoplasmic reticulum (SR).10 Although stimulation of SR Ca 2+ uptake is recognized for cyclic AMP-dependent relaxation of vascular smooth muscle, 8 a similar effect for cGMP has yet to be demonstrated. This results partly from the difficulty in experimentally isolating the effects of cGMP on Ca 2+ transport at the SR from those at the plasmalemma. However, the recently described technique of chemical skinning of the plasmalemma by saponin has enabled the investigation of the function of the SR in vascular smooth muscle." Saponin forms micellar complexes Received September 9, 1987; accepted December 11, 1987. with cholesterol, a major component of the plasmalemma. This renders the plasmalemma permeable, while not affecting the membranes of the intracellular organelles, which have a lower cholesterol content. 12We have used this technique to investigate the role of cGMP on SR Ca 2+ transport in primary cultures of rat aortic smooth muscle. We have investigated the effect of cGMP on Ca 2+ uptake by the SR and also on the release of Ca 2+ by the SR in response to inositol 1,4,5-trisphosphate (IP 3 ) and caffeine.

Characteristics of the NANC post‐stimulus (‘rebound’) contraction of the urinary bladder neck muscle in sheep

“…The dependence on the duration of stimulation suggests that a cumulative process was involved. It is interesting to speculate that this might have represented loading of an internal Ca2 + store, since cyclic GMP is known to stimulate a sarcoplasmic reticulum Ca2+ pump (Twort & van Breemen, 1988;Raeymakers et al, 1988). Thus a speculative mechanism relating the above pieces of experimental evidence would be: release of NO causes production of cyclic GMP which then causes Ca2+ sequestration in the sarcoplasmic reticulum; on cessation of stimulation, the cyclic GMP is removed by phosphodiesterases and the sequestered Ca2+ is released into the cytoplasm; this causes the rapid phase of the post-stimulus contraction which may later be supplemented to a lesser extent by Ca2" influx.…”

Modulation of blood flow and tissue perfusion by endothelium‐derived relaxing factor

“…In maximally contracted arteries the dominant mechanism of relaxation appears to be uncoupling of stress development from myosin phosphorylation, rather than alterations in [Ca2"]i or the [Ca2+]i sensitivity of myosin phosphorylation, whereas in submaximally constricted tissues, and therefore presumably under physiological conditions, relaxation is also mediated by decreases in [Ca2+]i (Morgan & Morgan, 1984;McDaniel, Chen, Singer, Murphy & Rembold, 1992). The mechanisms participating in this decrease in [Ca2"] include: (1) stimulation of a plasmalemmal Ca2"-extrusion ATPase (Popescu, Panoiu, Hinescu & Nutu, 1985) and Na'-Ca2" exchange (Furukawa, Ohshima, Tawada-Iwata & Shigekawa, 1991), (2) depression of agonist-stimulated phosphoinositide turnover through reduced G protein activation and uncoupling of activated G protein to phospholipase C (Rapoport, 1986;Lang & Lewis, 1989;Hirata, Kohse, Chang, Ikebe & Murad, 1990), (3) increased sequestration of cytosolic Ca2+ in sarcoplasmic reticulum secondary to phosphorylation of phospholamban and activation of the Ca2+-ATPase pump (Twort & van Breemen, 1988;Lincoln & Cornwell, 1991), (4) attenuated Ca2" influx through both receptor-and voltage-operated Ca2" channels which are inhibited by cGMP-dependent protein kinase (Collins, Griffith, Henderson & Lewis, 1986;Blayney, Gapper & Newby, 1991;Ishikawa, Hume & Keef, 1993), and (5) membrane hyperpolarization, which closes voltage-operated Ca2" channels (Nelson, Patlak, Worley & Standen, 1990;Tare, Parkington, Coleman, Neild & Dusting, 1990) and reduces IP3 formation and its subsequent mobilization of Ca2" from internal stores (Itoh, Seki, Suzuki, Ito, Kajikuri & Kuriyama, 1992).…”

Nitric oxide–cyclic GMP pathway with some emphasis on cavernosal contractility

“…In addition, PKG increases activity of plasma and sarcolemmal (mediated via the regulatory protein, phospholamban) cation-ATPase pumps encouraging sequestration of calcium into stores and out of the cell. 86,87 nNOS and eNOS are activated by calcium entry into the cell, binding to calmodulin associated with the enzymes. 88 Whereas physiologic penile erection lasts several minutes, the calcium-dependent activation of nNOS or eNOS is quite transient.…”