Guinea-pig Aorta Research Articles

Effects of hypoxia on the contractions and lactate release induced by high-K +, ouabain and epinephrine in guinea-pig aorta

1. The 60 mM K +, 152 mM K +, Na-deficient medium and oubain-induced contractions of aorta were not so affected by severe hypoxia. 2. The 60 mM K +, 152 mM K +, Na +-deficient medium-induced responses were greatly reduced by deprivation of external Ca 2+ in normoxia. 3. As the concentration of epinephrine increased, the remaining tensions which were expressed as a percentage of the original tensions became progressively greater in hypoxic condition. 4. The percentage of resistant components of the norepinephrine-induced contraction by the lower concentration was further reduced in Ca 2+-free medium by severe hypoxic condition. 5. The tensions under normoxia and lactate release under severe hypoxia induced by 60 mM K + or 2.5 × 10 −6 M epinephrine were of the same extent. 6. In conclusion, the inhibition of aortic response to epinephrine with severe hypoxia could not solely be explained by depression of the oxygen supply into the oxidative metabolism. Severe hypoxia did not affect Ca 2+ influx through voltage-operated Ca 2+ channels, but reduced both receptor-operated Ca 2+ influx and intracellular Ca 2+ release in the aorta.

P-153 - Effects of cyanide (NaCN) on fura-2 fluorescence and tension responses to norepinephrine (NE) and potassium (K+) in the guinea-pig aorta.

P-153 - Effects of cyanide (NaCN) on fura-2 fluorescence and tension responses to norepinephrine (NE) and potassium (K+) in the guinea-pig aorta.

Pharmacological profile of the novel .ALPHA.-adrenoceptor antagonist KT-611(naftopidil).

The pharmacological profile of a new alpha-adrenoceptor antagonist, KT-611 (naftopidil), was studied in vitro. In the dog mesenteric and carotid arteries and in the rabbit, guinea pig and rat thoracic aortae, KT-611 competitively inhibited alpha 1-adrenoceptor-mediated contractions induced by noradrenaline with pA2 values ranging from 6.73 to 8.15. KT-611 also inhibited the postjunctional alpha 2-adrenoceptor-mediated contractions in the dog saphenous vein (pA2 = 6.77) or dog basilar artery. However, the responses mediated through prejunctional alpha 2-adrenoceptors (rat vas deferens), beta-adrenoceptors (rat atria), muscarinic receptors (guinea pig ileum) and 5-HT2 receptors (dog mesenteric artery) were little affected by KT-611. KT-611 also inhibited the sympathetic adrenergic contraction evoked by electrical transmural stimulation in the dog mesenteric artery, and the inhibition was not relieved upon repetitive washing for 1 hour with the drug-free solution. 3H-prazosin and 3H-clonidine binding to the rat cortex membranes was inhibited by KT-611 with pKi values of 7.69 and 5.75, respectively. These results suggest that KT-611 is an alpha 1-adrenoceptor antagonist with a weak antagonistic activity to postjunctional alpha 2-adrenoceptors.

Pharmacological Profile of the Novel α-Adrenoceptor Antagonist KT-611 (Naftopidil)

The pharmacological profile of a new alpha-adrenoceptor antagonist, KT-611 (naftopidil), was studied in vitro. In the dog mesenteric and carotid arteries and in the rabbit, guinea pig and rat thoracic aortae, KT-611 competitively inhibited α1-adrenoceptor-mediated contractions induced by noradrenaline with pA2 values ranging from 6.73 to 8.15. KT-611 also inhibited the postjunctional α2-adrenoceptor-mediated contractions in the dog saphenous vein (pA2 = 6.77) or dog basilar artery. However, the responses mediated through prejunctional α2-adrcnoccptors (rat vas deferens), β-adrenoceptors (rat atria), muscarinic receptors (guinea pig ileum) and 5-HT2 receptors (dog mesenteric artery) were little affected by KT-611. KT-611 also inhibited the sympathetic adrenergic contraction evoked by electrical transmural stimulation in the dog mesenteric artery, and the inhibition was not relieved upon repetitive washing for 1 hour with the drug-free solution. 3H-prazosin and 3H-clonidine binding to the rat cortex membranes was inhibited by KT-611 with pKi values of 7.69 and 5.75, respectively. These results suggest that KT-611 is an α1-adrenoceptor antagonist with a weak antagonistic activity to postjunctional α2-adrenoceptors.

Direct Relaxant Effect of Peganum Harmala Seed Extract on Smooth Muscles of Rabbit and Guinea Pig

AbstractThe Effects Of An Aqueous Extract Of Peganum Harmala Seeds On The Smooth Muscles Of Rabbit and Guinea Pig Were Tested In Vitro Using Isolated Segments Of Intestine, Trachea and Aorta. The Extract Inhibited The Spontaneous Movement Of The Rabbit Jejunum and Guinea Pig Ileum and The Contractions Of Rabbit Jejunum and Guinea Pig Ileum Induced By 10−4M Acetylcholine Stimulation. The Extract Also Inhibited The Contractions Of Rabbit Tracheal Smooth Muscle Induced By 10−4M Acetylcholine Stimulation and The Contractions Of Guinea Pig Tracheal Smooth Muscle Induced By 10−4M Histamine Stimulation. Furthermore, The Extract Inhibited The Contractions Of Rabbit and Guinea Pig Aortae Induced By 10−4M Norepinephrine Stimulation. These Inhibitions Were Concentration-Dependent and Reversible. These Data Suggest That This Seed Extract Has Antispasmodic, Anticholinergic, Antihistaminic and Antiadrenergic Effects.

Ontogeny of adenosine response in guinea pig heart and aorta

Effects of maturation on the responses of isolated perfused hearts and aortic rings to adenosine were examined. Dose-response relationships for adenosine were obtained in aortic rings and hearts isolated from immature (5 days) and mature (1-2 mo) guinea pigs. Immature and mature hearts were perfused at constant flows of 9.9 +/- 0.3 and 9.5 +/- 0.4 ml.min-1.g-1, respectively, and displayed basal resistances of 4.8 +/- 0.1 and 6.7 +/- 0.2 mmHg.ml-1.min.g. Immature hearts were more sensitive to exogenous adenosine, displaying a significantly lower 50% effective concentration (EC50, 2.5 x 10(-8) M) than mature hearts (1.1 x 10(-7) M, P less than 0.05). Adenosine induced dilation at a lower threshold dose in immature hearts (3 x 10(-9) M, 6.0 +/- 0.3% relaxation) than in mature hearts (10(-8) M, 3.1 +/- 1.3% relaxation). The time required to elicit 50% of the observed dilation was similar in immature and mature hearts, yet the time required for basal tone to recover by 50% was approximately 100% greater in immature hearts (P less than 0.05). Immature aortic rings, stretched to their optimal resting tensions and contracted with EC85 doses of prostaglandin F2 alpha, displayed a significantly lower EC50 (7.7 x 10(-5) M) than mature rings (1.1 x 10(-4) M, P less than 0.05). The maximum percent response to adenosine was greater in immature vessels (64 +/- 1 vs. 54 +/- 0.4%, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The coexistence of adenosine A 1 and A 2 receptors in guinea-pig aorta

The effects of adenosine, 5'-(N-ethyl)carboxamidoadenosine (NECA), 2-chloroadenosine (2-CA), No-cyclohexyladenosine (CHA) and N6(R-2-phenylisopropyl)-adenosine (R-PIA) on the tone of phenylephrine-constricted guinea-pig isolated aorta have been examined. For aortic relaxation the analogues exhibited the following rank order of potency: NECA > adenosine > 2-CA > R-PIA > CHA. This is consistent with previous reports that relaxation of this tissue is mediated by the adenosine A 2 receptor. An unexpected finding was that R-PIA, 2-CA and CHA all induced contractions at concentrations lower than were required for relaxation, giving a biphasic dose-response curve. Neither NECA nor adenosine contracted the aorta. This is consistent with activation of vascular A 1 receptors. An A 1-selective concentration of the antagonist l,3-dipropyl-8-cyclopentyl xanthine abolished the contraction elicited by R-PIA in the guinea-pig aorta. This further suggests that the contraction is mediated by a 1 receptors.

Uterine artery estrogen receptors in the nonpregnant and pregnant guinea pig

Uterine artery, heart, and aorta or carotid specimens of nonpregnant, midpregnant, and term pregnant guinea pigs were examined for estrogen receptors by immnocytochemical methods. Estrogen receptors were found in the nuclei of cells in the endothelial, muscle, and adventitia layers of the uterine artery wall. The concentration of estrogen receptors was slightly higher in nonpregnant and term pregnant animals than in midpregnancy. No estrogen receptors were found in the heart, aorta, or carotid specimens of all animals. These results confirm the uterine artery as a target organ of estrogen action that would eventually lead to arterial functional adaptation in different biologic periods. (Am J Obstet Gynecol 1990;163: 1685-8.)

Differential Relaxant Responses to Pinacidil of Smooth Muscle Preparations Contracted by a High Concentration of Potassium in Isoosmolar and Hyperosmolar Solutions

Contractions were produced in guinea-pig trachealis, aorta and pulmonary artery by depolarization with 124 mM K+ using two commonly applied techniques. Addition of KCl to the organ bath solution making it hyperosmolar induced slowly developing contractions, which were only weakly inhibited by pinacidil. Hyperosmolar mannitol-induced contractions showed similar characteristics. In contrast, contractions elicited by isoosmolar K+ Krebs solution developed more rapidly and could be completely suppressed by pinacidil (10(-6)-10(-3) M) in a concentration-dependent manner. The findings explain previously published discrepant results on the relaxant response to pinacidil of smooth muscle preparations contracted by high concentrations of K+, and indicate other mechanisms of action for pinacidil in addition to K+ channel opening, in the concentration range 10(-6)-10(-3) M.

Effects of an aqueous extract of Ferula ovina on rabbit and guinea pig smooth muscle

The effects of an aqueous extract of Ferula ovina were tested in vitro using isolated segments of rabbit and guinea pig intestine, trachea and aorta. The extract inhibited the spontaneous movements of rabbit jejunum and guinea pig ileum and the contractions induced by acetylcholine. The aqueous extract also inhibited the contractions of rabbit trachealis muscle induced by acetylcholine and the contractions of guinea pig trachealis muscle induced by histamine. These inhibitions were dose-dependent and reversible. However, the aqueous extract did not inhibit the contractions of rabbit and guinea pig aortic rings induced by norepinephrine. These data suggest that this plant has non-specific anticholinergic and antihistaminic antispasmodic effects.

Endothelium-dependent and -independent relaxations to adenosine in guinea pig aorta

Effects of endothelial removal and hypoxia on responses to adenosine, 5'-(N-ethylcarboxamido)-adenosine (NECA), 2-chloroadenosine, N6-cyclohexyladenosine (CHA), sodium nitroprusside, and acetylcholine were examined in guinea pig aortic rings. Rings contracted with 2 microM prostaglandin F2 alpha (PGF2 alpha) relaxed in a dose-dependent manner in response to all drugs. The order of potency of adenosine compounds was NECA greater than 2-chloroadenosine greater than adenosine greater than CHA. Endothelial rubbing potentiated the PGF2 alpha response by 11 +/- 3%, eliminated the acetylcholine (ACh) response, but had no effect on nitroprusside and CHA responses. Responses to adenosine, NECA, and 2-chloroadenosine were significantly depressed by rubbing (P less than 0.05). Oxyhemoglobin (5 microM) and metyrapone (0.1 mM) reduced ACh responses in intact rings but had no effect on the adenosine and nitroprusside responses. Indomethacin treatment (10 microM) did not alter ACh, nitroprusside, or adenosine responses in intact rings. Hypoxia (10% O2) potentiated maximal responses to adenosine (+26 +/- 3%) and nitroprusside (+28 +/- 4%) in intact and rubbed rings and reduced the maximal response to ACh in intact rings (-28 +/- 3%). It is concluded that 1) adenosine mediates relaxation in guinea pig aorta by endothelial-dependent and -independent mechanisms, 2) receptors involved in both endothelial-dependent and -independent relaxations are characteristic of the A2 adenosine subtype, 3) the endothelial response appears unrelated to EDRF or prostanoid release, and 4) the adenosine response is significantly potentiated by hypoxia.

Adrenoceptor-Blocking Activity and Cardiohemodynamic Effects of Carvedilol in Animals

The beta-blocking activities of a new beta-adrenoceptor blocking drug, carvedilol, evaluated in isolated atria and trachea of the guinea pig were 2.0 (beta 1) and 3.2 times (beta 2), respectively, as potent as those of propranolol. Carvedilol exhibited the alpha-blocking activities in the aorta of guinea pigs and rats. Carvedilol was 2 and 50 times less potent in guinea pigs and rats, respectively, than prazosin as an alpha-blocker. Thus, the alpha-blocking activities were twice as potent as the beta-blocking activity in the rat and one-fifth that of the beta-blocking activity in the guinea pig. In anesthetized open-chest dogs, the beta-blocking activity of carvedilol was 1.5 times more potent than that of propranolol and had 3.8 times the alpha-blocking activity. Thus, carvedilol is a nonselective beta-blocking drug with a potent alpha-blocking activity. Carvedilol and propranolol showed dose-dependent and significant decreases in the blood pressure, total cardiac output, left ventricular pressure, dp/dt, heart rate, coronary flow, and oxygen consumption in anesthetized open-chest dogs. Carvedilol decreased the total peripheral resistance significantly (the decrease was not proportional to the decreases in the blood pressure at high doses), while propranolol increased it significantly and dose-dependently. These results indicate the importance of alpha-adrenoceptor blocking activity in the decrease in blood pressure produced by carvedilol.

Correlation between radioligand binding- and functional data indicate that the predominant α 1-adrenoceptor in rat aorta is of the α 1A-subtype and in guinea-pig aorta and rat spleen of the α 1B-subtype

Correlation between radioligand binding- and functional data indicate that the predominant α 1-adrenoceptor in rat aorta is of the α 1A-subtype and in guinea-pig aorta and rat spleen of the α 1B-subtype

Additional evidence for differences in alpha 1-adrenoceptors between rat and guinea-pig aorta

Additional evidence for differences in alpha 1-adrenoceptors between rat and guinea-pig aorta

Developmental Changes in Sodium Nitroprusside and Atrial Natriuretic Factor Mediated Relaxation in the Guinea Pig Aorta

Sodium nitroprusside (SNP), a nonreceptor mediated stimulant of soluble guanylate cyclase, and atrial natriuretic factor, a receptor-dependent stimulator of particulate guanylate cyclase, mediate relaxation responses by increasing intracellular cGMP. This in vitro study was designed to compare the ontogeny of relaxation responses to SNP and atrial natriuretic factor in the guinea pig thoracic aorta. Aortic rings from fetuses at 55-60 d gestation (term = 68 d), 1- to 3-d-old newborn, and 12-wk-old adult Hartley guinea pigs were mounted in an organ bath, bathed in Kreb's solution, and connected to a force-displacement transducer to measure isometric tension. Relaxation responses to SNP and atriopeptin III were studied with the vessels at optimal resting tension and after preconstriction with an EC85 concentration of norepinephrine. SNP-mediated relaxation showed a significant increase in sensitivity with development among the three age groups (p less than 0.05). Methylene blue, an inhibitor of soluble guanylate cyclase, produced no inhibition of relaxation to SNP in fetal aortae, significantly decreased responses along the straight portion of the concentration-response curve in newborn aortae (p less than 0.05), and significantly shifted the concentration-response curve to the right (p less than 0.05) in adult aortae; but did not prevent vessels from relaxing almost 100% in any age group. However, atriopeptin III-mediated responses were similar in the three age groups and were unaffected by methylene blue. These results suggest that 1) sensitivity to SNP increases with age from fetal through adult life; 2) relaxation mediated by atriopeptin III is similar during development; 3) methylene blue does not affect SNP mediated relaxation in fetuses but progressively decreases sensitivity to SNP in newborns and adults; and 4) methylene blue does not affect atriopeptin III-mediated relaxation in any age group.

Ca<sup>2+</sup> Influx Insensitive to Organic Ca<sup>2+</sup> Entry Blockers Contributes to Noradrenaline-Induced Contractions of the Isolated Guinea Pig Aorta

We determined the contribution of intracellular Ca2+ to the noradrenaline (NA, 3 X 10(-5) mmol/l)-induced contraction of the isolated guinea pig aorta. Since only about 55% of the NA-induced contraction could be attributed to intracellular Ca2+ release, we assumed that a Ca2+ influx component contributes to the NA-induced contraction. This influx component proved resistant to the organic calcium entry blockers (CEBs) nifedipine, diltiazem, flunarizine and gallopamil which, in contrast, antagonized K(+)-induced Ca2+ influx completely. Conversely, the NA-induced Ca2+ influx component could be antagonized by the inorganic cations La3+, Cd2+, Mn2+, Ni2+ and Co2+. 45Ca2+ uptake experiments also revealed that both KCl and NA induce Ca2+ influx of which only the latter one is resistant to nifedipine. It was concluded that in the guinea pig aorta NA activates a receptor-operated channel through which Ca2+ can be translocated from the extracellular space to the cytosol to contribute directly to contraction.

P-095 - Fura-2 fluorescence and tension responses to caffeine in the guinea pig aorta

P-095 - Fura-2 fluorescence and tension responses to caffeine in the guinea pig aorta

Characterization of the prostanoid receptor profile of enprostil and isomers in smooth muscle and platelets in vitro

1. Enprostil is composed, in approximately equal proportions, of 4 allenic isomers which are prostanoids structurally related to prostaglandin E2 (PGE2). The isomers are denoted as RS-86505-007, RS-86812-007 which are in the 'natural' R and S configuration (with respect to PGE2) and RS-86505-008 and RS-86812-008 which are in the 'unnatural' R and S configuration. In the present study we have characterized their activity at prostanoid receptors, in vitro. 2. Enprostil acted as a highly potent (-log EC50 = 8.30 +/- 0.08; mean +/- s.e.mean, n = 6) EP3 receptor agonist in the guinea-pig vas deferens, although no activity was observed at guinea-pig tracheal EP2 receptors at concentrations up to and including 10 microM. Attempts to study the action of enprostil at EP1 receptors were complicated by a general increase in the spontaneous activity of the guinea-pig isolated ileum. This response was stereospecific (i.e. observed, with the 'natural' R and S isomers only) and was not mediated through EP1, FP or TP receptors. 3. Enprostil also exhibited a potent agonist effect at FP and TP receptors in the rat colon and guinea-pig aorta (-log EC50 values = 7.34 +/- 0.11 and 6.54 +/- 0.07, mean +/- s.e. mean, n = 4-8 respectively). No activity at concentrations up to and including 10 microM was observed at DP or IP receptors in the guinea-pig platelet mediating inhibition of ADP-induced aggregation. 4. A similar profile was observed with the 'natural' R and S allenic isomers of enprostil (RS-86505- 007 and RS-86812-007, respectively); RS-86505-007 was between 4 and 10 fold more potent than the racemic enprostil. The 'unnatural' allenic R and S isomers of enprostil were much less potent than enprostil, with the latter being virtually inactive. 5. Enprostil and the 'natural' R and S isomers, therefore, were EP3, FP and TP agonists, being most potent at the EP3 receptor. The preferred configurations for these receptors appears to be the R, and to a lesser extent the S, form of the natural allenic isomer. The effect of enprostil at EP1 receptors was not characterized in view of the presence of excitatory EP3 receptors in the guineapig ileum. These data were in accordance with the pharmacological activity of enprostil, including inhibition of gastric acid secretion (possibly EP3) and diaorrhea (possibly TP).

Electrophysiologic characteristics of single myocytes isolated from hypertrophied guinea-pig hearts

To determine whether the electrical changes associated with cardiac hypertrophy are due to alterations in the membrane properties of individual hypertrophied cells, we recorded action potentials in single myocytes isolated from normal and hypertrophied hearts. Cardiac hypertrophy was produced by a gradual pressure overload created by placing a band around the ascending aorta in young guinea-pigs (200–250g). Almost half the animals that developed left ventricular (LHV) hypertrophy also developed evidence of cardiac dysfunction. Action potentials were recorded with standard microelectrodes in single ventricular myocytes isolated by enzymatic dispersion of the heart. The action potential duration at 1 Hz was significantly longer in hypertrophied cells than in control cells. The degree of action potential prolongation in isolated cells did not correlate with the degree of hypertrophy but did correlate with the degree of myocardial disease, the duration being longer in hypertrophied myocytes from dyspneic than in those from non-dyspneic animals. The resting potential was significantly lower in hypertrophied myocytes from dyspneic animals than in hypertrophied cells from non-dyspneic animals or control cells stimulated at 5 Hz. The relationship between the frequency of stimulation (0.33, 1, and 5 Hz) and action potential duration was steeper in hypertrophied than normal myocytes. The mean membrane capacitance ( c m) of hypertrophied myocytes increased by 31% over the control value. Thus, isolated hypertrophied myocytes retain the prolonged duration of the action potential and the exaggerated dependence of duration on rate observed in intact hypertrophied muscle. The increased duration of the action potential in hypertrophied cells cannot be readily attributed to the observed increase in c m. Our results indicate that the membrane changes responsible for the altered electrical properties of hypertrophied myocardium are due to an effect of hypertrophy on individual myocytes and that the prolonged duration of the action potential is probably due to changes in active currents flowing during repolarization.

MECHANISMS FOR THE STIMULATION OF PROSTANOID SYNTHESIS BY CYCLOSPORINE AND BACTERIAL LIPOPOLYSACCHARIDE

Both cyclosporine and bacterial lipopolysaccharide enhance prostanoid synthesis and regulate the immune response. This study was designed to establish whether these agents affect prostanoid synthesis by common or different mechanisms. CsA and LPS stimulate prostanoid synthesis both in human monocytes and smooth muscle cells from guinea pig aorta. Only LPS stimulates synthesis in the presence of exogenous arachidonic acid. Dexamethasone totally blocks CsA but only partially inhibits LPS. CsA and LPS both enhance the release of labeled metabolites from cells labeled with arachidonic acid, but indomethacin only blocks the effect of LPS. CsA and the releasing agent calcium ionophore (A23187) both increase PGE2 and PGI2 synthesis without changing their relative concentrations, cause the release of free arachidonic acid, and lead to the formation of new metabolites that are not products of cyclooxygenase activity. Preincubation with either CsA or A23187 and a subsequent wash deplete the arachidonic acid pool available for prostanoid synthesis. Thus, A23187 and CsA have very similar effects on arachidonic acid metabolism. In contrast, LPS increases PGE2 and PGI2 synthesis and alters their relative concentrations, diminishes the relative concentration of free arachidonic acid, and enhances the formation of new metabolites that are products of cyclooxygenase activity. These differences are explained by mechanisms in which CsA promotes prostanoid synthesis through arachidonic acid release, and LPS promotes prostanoid synthesis through increased cyclooxygenase activity.