Role of calcium in U 46619 and PGF2 alpha pulmonary vasoconstriction in rat lungs

Abstract

The role of calcium and calmodulin during U 46619 and PGF2 alpha-induced pulmonary vasoconstriction was studied in isolated rat lungs perfused with Krebs-Ringer bicarbonate (KRB) or calcium-free KRB. In lungs perfused with KRB, bolus injections of U 46619 (0.2 microgram) and PGF2 alpha (40.0 micrograms) resulted in a 48.0 +/- 4.0 and 23.9 +/- 2.5% increase in mean pulmonary artery pressure, respectively. During lung perfusion with KRB without calcium, the U 46619 response decreased to 31.1 +/- 7.5% whereas the PGF2 alpha response increased to 34.6 +/- 4.1%. Repeated challenges with PGF2 alpha in the KRB without calcium resulted in reduction of the response to 11.8 +/- 1.2%; the U 46619 response was unaltered. The intracellular calcium blocker, 8-(N,N-diethylamino)-octyl-3,4,5, trimethoxybenzoate HCL (TMB-8) significantly attenuated the pressor response to U 46619 at low doses and PGF2 alpha at high doses. The calmodulin inhibitor trifluoperazine (TFP 100 microM) attenuated the vasoconstrictor response to U 46619 by 54%, whereas the PGF2 alpha was unchanged. However, in the calcium-free KRB, TFP attenuated the pressor response to both U 46619 and PGF2 alpha. The U 46619 pressor response depends on intracellular and extracellular calcium to achieve calmodulin-dependent vasoconstriction. PGF2 alpha requires extracellular calcium to replenish depletable intracellular calcium pools and is independent of calmodulin activation.

The Effect of Thromboxane on Contraction of Canine Mesenteric and Lingual Arteries

“…Again, this effect was partially dependent on the presence of an intact endothelium, suggesting that a contractile agent released from the endothelium by U-46619 may facilitate the maintained contraction of the lingual artery to U-46619 or may act in a manner similar to that of U-46619. This is unique to the lingual artery and in contrast to the finding that 1-2 mmolfL EGTA relaxes contractions of other blood vessel types induced by U-44619 (Angerio et al, 1982;Dorn et al, 1987;Santoian et al, 1987Santoian et al, , 1989Greenberg et al, 1991) and U-44069, a stereo-isomer of U-46619 (Loutzenhiser and Van Breeman, 1981). Thus, the lingual artery differed from the pulmonary, renal, and mesenteric arter- ies and the aorta in its ability to contract in response to stimulation of calcium influx (KCl), as well as in its sensitivity to U-46619-induced contraction.…”

“…U-46619 causes vascular smooth muscle to contract by increasing calcium influx (Horrobin et al, 1978;Seeger et al, 1987;Santoian et al, 1987Santoian et al, , 1989. U-46619 may increase calcium influx by acting at specific TXA receptors on/or in the smooth muscle and platelets (Halushka et al, 1989;Takahara et al, 1990), or by acting as a calcium ionophore in which it forms a calcium-U-46619 complex (Gerrard et al, 1978;Brasseur and Ruysschaert, 1984).…”

“…U-46619 can also release intracellular calcium ion (Ca2+j) from binding sites within the sarcoplasmic reticulum (SR) or mitochondria (Greenberg, 1981;Brace et al, 1985;Dorn et al, 1987;Seeger et al, 1987;Santoian et al, 1987Santoian et al, , 1989. This latter mechanism has been shown, by the ability of dantrolene sodium and TMB-8 (which block the release of Ca2+), to inhibit the contractions of smooth muscle to U-46619 (Angerio et al, 1982;Brace et al, 1985;Santoian et al, 1987Santoian et al, , 1989.…”

“…This latter mechanism has been shown, by the ability of dantrolene sodium and TMB-8 (which block the release of Ca2+), to inhibit the contractions of smooth muscle to U-46619 (Angerio et al, 1982;Brace et al, 1985;Santoian et al, 1987Santoian et al, , 1989. Moreover, its ability to release Ca2 , may result from its stimulation of second messengers such as INSP3 and diacylglycerol (Mene et al, 1988;Nakahata et al, 1989;Sakuma et al, 1989), which then act on the SR and protein-kinase C (PKC) to release Ca2+i and stimulate contraction.…”

Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF2α or endothelin

“…could be reversed to a small extent by felodipine. Also, calcium influx has been shown to be important for PGF2g-induced vasoconstriction in perfused lungs from rats (Santoian et al, 1989). Tonic contractions to endothelin in various blood vessels have also been reported to involve protein kinase C activation, probably via diacyl glycerol production (Griendling et al, 1989;Sugiura et al, 1989;Steffan & Russell, 1990).…”