Contraction Of Guinea-pig Aorta Research Articles

Effect of ropivacaine on endothelium-dependent phenylephrine-induced contraction in guinea pig aorta

Previous studies have shown that ropivacaine has biphasic vascular effects, causing vasoconstriction at low concentrations and vasorelaxation at high concentrations. This study was designed to examine the role of the endothelium during accidental intravascular absorption of ropivacaine, and to elucidate the mechanisms responsible. Isolated guinea pig aortic rings were suspended for isometric tension recording. The effects of ropivacaine on endothelium-intact and endothelium-denuded aortic rings were assessed. Endothelium-intact aortic rings were pre-contracted with phenylephrine before being exposed to ropivacaine and acetylcholine, in order to generate and compare concentration-response curves. In the absence and presence of yohimbine, propranolol, atropine, indometacin, N(G)-nitro-l-arginine methyl ester (l-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or methylene blue, the contractile response induced by ropivacaine was assessed on endothelium-intact aortic rings pre-contracted with phenylephrine. Ropivacaine (3 x 10(-4) to 10(-2) mol/l) produced vasoconstriction in endothelium-denuded aortic rings, whereas no such response was observed in aortic rings with intact endothelium. In phenylephrine pre-contracted intact aortic rings, ropivacaine induced a greater degree of vasorelaxation than did acetylcholine. Yohimbine, propranolol and atropine all failed to affect the relaxation responses induced by ropivacaine. However, pre-treatment with indometacin (cyclo-oxygenase inhibitor), l-NAME (nitric oxide synthase inhibitor), methylene blue (soluble guanylyl cyclase inhibitor) or ODQ (soluble guanylyl cyclase inhibitor), significantly decreased the ropivacaine-induced relaxation of endothelium-intact aortic rings (3 x 10(-4) to 10(-2) mol/l). Ropivacaine elicits an endothelium-dependent vasorelaxation in phenylephrine pre-contracted aortic rings via the nitric oxide-cyclic guanosine 3',5'-monophosphate pathway and the prostaglandin system.

Tyrosine phosphorylation increases Ca 2+ sensitivity of vascular smooth muscle contraction

In order to elucidate the role of tyrosine phosphorylation in vasoconstriction, we investigated the effects of inhibitors of tyrosine kinase (genistein, 30 μM) and phosphatase (sodium o-vanadate, 5 μM) on the contraction of aorta isolated from guinea pig. Genistein significantly inhibited norepinephrine-induced contraction, but it did not affect that induced by KCl. Thus, tyrosine phosphorylation may not be involved in the contractile response to KCl alone. The aortic contraction elicited by KCl was significantly augmented by sodium o-vanadate, which increased both the maximum force and pD 2 values of KCl contraction. In the presence of verapamil, KCl-induced contraction was abolished even after pretreatment with sodium o-vanadate. Sodium o-vanadate also augmented Ca 2+-induced contraction in the aortic strips depolarized with KCl, increasing both its maximum force and pD 2 values. Neither basal 45Ca 2+ uptake nor verapamil-sensitive 45Ca 2+ uptake induced by KCl were affected by pretreatment with sodium o-vanadate. These results suggest that tyrosine phosphorylation is involved in the contraction of guinea-pig aorta not through transplasmalemmal Ca 2+ entry but through increased Ca 2+ sensitivity of the intracellular contractile pathway.

P–385 - Effects of OP-41483, a prostacyclin analogue, on cytoplasmic Ca2+ level and muscle contraction in guinea pig aorta.

P–385 - Effects of OP-41483, a prostacyclin analogue, on cytoplasmic Ca2+ level and muscle contraction in guinea pig aorta.

Differential sensitivity to ATP-sensitive potassium channel openers of norepinephrine-induced contraction of guinea pig and rat aorta

Vasorelaxant effects of ATP-sensitive potassium (K ATP) channel openers were examined on the tonic phase of vascular contraction induced by norepinephrine (NE) in guinea pig and rat aorta. K ATP channel openers, NIP-121 and cromakalim, produced glibenclamide-sensitive and concentration-dependent relaxations in guinea pig and rat aorta preconstricted with NE. However, the vascular relaxations induced by both K ATP channel openers were less pronounced in guinea pig aorta than in rat aorta. d - cis-Diltiazem, at the concentration up to 10 −5 M, did not appreciably inhibit the NE-induced contraction of guinea pig aorta, whereas the compound almost completely inhibited the NE-induced contraction of rat aorta at the same concentration. By contrast, sodium nitroprusside relaxed the NE-induced contractions in both guinea pig and rat aorta with similar potencies. These findings suggest that vasorelaxant effects of K ATP channel openers on the NE-induced sustained contraction in guinea pig aorta is not attributable to the subsequent inhibition of Ca 2+ influx through L-type voltage-gated Ca 2+ channels. Lower sensitivity of guinea pig aortic smooth muscle to K ATP channel openers is most likely due to the low dependence of NE-induced contraction on the Ca 2+ influx in this vascular smooth muscle.

Imidazol-1-yl and pyridin-3-yl derivatives of 4-phenyl-1,4-dihydropyridines combining Ca2+ antagonism and thromboxane A2 synthase inhibition

A series of derivatives of 4-phenyl-1,4-dihydropyridine bearing imidazol-1-yl or pyridin-3-yl moieties on the phenyl ring were synthesized with the aim of combining Ca2+ antagonism and thromboxane A2 (TxA2) synthase inhibition in the same molecule. Some of these compounds showed significant combined Ca2+ antagonism and TxA2 synthase inhibition in vitro, while others showed only one single activity. Structural requirements for significant single or combined activities are discussed. Theoretical conformational analysis, by molecular mechanics and semiempirical AM1 calculations, was performed for 1,4-dihydro-2,6-dimethyl-4-[3-(1H-imidazol-1-yl)phenyl]- 3,5-pyridinedicarboxylic acid, diethyl ester (FCE 24265) and two close congeners. FCE 24265, which inhibited TxB2 production in rat whole blood with IC50 = 1.7 x 10(-7) M and antagonized K+ induced contraction in guinea pig aorta with IC50 = 6.0 x 10(-8) M, was selected for further pharmacological evaluation. Our results show that this compound is less potent than nifedipine both in vitro and in vivo yet presents a favorable profile in vivo, lowering blood pressure without inducing reflex tachycardia. Moreover, its additional potent and selective TxA2 synthase inhibitory activity makes this compound an interesting pharmacologic tool in pathologies where both enhanced TxA2 synthesis and cellular Ca2+ overload are involved.

THE MECHANISM OF CONTRACTILE ACTION OF PALYTOXIN ON VASCULAR SMOOTH MUSCLE OF GUINEA-PIG AORTA

The mode of action of palytoxin (PTX) on the contractile responses and ion movements in guinea-pig aorta was investigated. PTX (10−8 M) induced a contraction with a latency period of 0.5–1 min, and it reached maximum after about 20 min. This contraction was not affected by phentolamine (10−6 M). The contraction induced by PTX was rapidly abolished by removal of external Ca. Readdition of Ca restored the contraction. Verapamil, which markedly antagonized the contraction induced by some depolarizing agents (K, Ba and tetraethylammonium), decreased the rate of rise of the PTX-induced contraction, but did not affect the sustained tension level. Removal of external Na markedly inhibited the contraction induced by PTX (10−10-10−8 M), while it had no effect on the contraction induced by histamine (10−7-10−5 M). PTX rapidly decreased tissue K content with a similar time course to that of the increase in tension. Ouabain (10−4 M) also caused contraction and decreased tissue K content in the muscle, but the rate of these changes was much slower than the PTX-induced ones. PTX increased cellular 45Ca content in normal solution, but not in Na deficient solution. These results suggest that the PTX-induced contraction in guinea-pig aorta is due to an increase in membrane Na permeability.

The mechanism of contractile action of palytoxin on vascular smooth muscle of guinea-pig aorta.

The mode of action of palytoxin (PTX) on the contractile responses and ion movements in guinea-pig aorta was investigated. PTX (10(-8) M) induced a contraction with a latency period of 0.5-1 min, and it reached maximum after about 20 min. This contraction was not affected by phentolamine (10(-6) M). The contraction induced by PTX was rapidly abolished by removal of external Ca. Readdition of Ca restored the contraction. Verapamil, which markedly antagonized the contraction induced by some depolarizing agents (K, Ba and tetraethylammonium), decreased the rate of rise of the PTX-induced contraction, but did not affect the sustained tension level. Removal of external Na markedly inhibited the contraction induced by PTX (10(-10) - 10(-8) M), while it had no effect on the contraction induced by histamine (10(-7) - 10(-5) M). PTX rapidly decreased tissue K content with a similar time course to that of the increase in tension. Ouabain (10(-4) M) also caused contraction and decreased tissue K content in the muscle, but the rate of these changes was much slower than the PTX-induced ones. PTX increased cellular 45Ca content in normal solution, but not in Na deficient solution. These results suggest that the PTX-induced contraction in guinea-pig aorta is due to an increase in membrane Na permeability.

The mode of contractile action of palytoxin in isolated vascular smooth muscle of guinea-pig aorta

The mode of action of palytoxin (Palythoa tuberculosa) on the contractile responses and ion movements in guinea-pig aorta was investigate^. Experiments were conducted in the presence of phentolamine (10 M). PTX (10 M) induced a contraction with a latency period of about 1 min, and it reached maximum after about 20 min. The contraction induced by PTX was rapidly abloished by a removal nf external Ca. Readdition of Ca restored the contraction. Verapamil, which markedly antagonized the contraction induced by high-K depolarization, decreased the rate of rise of the PTX-induced contraction, but did not inhibit the sustained tension level. Removal of external Na markedly inhibited the contraction induced by PTX, while it had no effect on the contrction induced by histamine. PTX rapidly decreased tissue K content with a similar time course as that for the increase in tension. Ouabain (10-4 M) also decreased tissue K content in the muscle, but the rate of these changes was much solwer than the PTX-induced ones. PTX increased cellular Ca content (measured by a modified ‘La method’) in normal solution but not in Na deficient solution. These results suggest that the PTX-induced contraction in guinea-pig aorta is due to an increase in membrane Na permeability.

Raised Intracellular Sodium Consequent to Sodium-Potassium-Dependent ATPase Inhibition Does Not Cause Myogenic Contractions of 150 μm Arteries from Rat and Guinea Pig

1. We have examined effects of inhibition of Na+,K+-dependent ATPase in large and small arterial ring preparations from rats and guinea pigs. 2. Ouabain (1 mmol/l) caused myogenic contraction of rat aorta and tail artery, but had no long-lasting effect on 150 μm mesenteric and 150 μm femoral resistance vessels over a 3 h period. Much lower concentrations of ouabain (1 μmol/l) caused contraction of guinea pig aorta, but had no effect on the mesenteric and femoral resistance vessels. 3. In the mesenteric resistance vessels, ouabain (1 mmol/l, rat vessels; 1 μmol/l, guinea pig vessels) caused the intracellular sodium content to rise over 2 h from approx. 13 mmol/l to approx. 60 mmol/l, and in the rat mesenteric resistance vessels this was associated with membrane depolarization from approx. −54 mV to approx. −30 mV after 3 h. 4. The results suggest that whereas Na+,K+-ATPase inhibition and consequent raised intracellular sodium may cause contraction of large vessels, this does not seem to be the case for small vessels. It therefore seems that further investigation is required before it is accepted that raised intracellular sodium is in itself a factor of importance in the etiology of hypertension.

Effects of ouabain and potassium-free solution on the contraction of isolated blood vessels

Ouabain and K-free solution affected the tension development of isolated vessels as follows. In rabbit aorta, ouabain induced a transient contraction followed by a delayed sustained contraction whereas K-free solution was almost ineffective; both ouabain and K-free solution produced a sustained contraction in guinea pig aorta; rat aorta rarely responded to ouabain but developed a contraction in K-free solution. Phentolamine inhibited the transient contraction produced by ouabain in rabbit aorta. In rabbit aorta, , ouabain produced a concentration-dependent potentiation of norepinephrine contraction. In denervated rabbit aorta, however, the potentiation only occurred in the presence of 5 × 10 −7 to 5 × 10 −6 M ouabain. K-free solution inhibited the norepinephrine contraction in denervated rabbit aorta. Ouabain potentiated the norepinephrine contraction in guinea pig aorta but not in rat aorta. It is concluded that ouabain and K-free solution affect contraction both indirectly via the release of endogenous catecholamines and directly by acting on vascular smooth muscle, and that there are species differences in the sensitivity to ouabain.