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D B Hoover 《Peptides》1989,10(2):343-347
The pharmacological effects of guinea pig vasoactive intestinal peptide (VIP) were studied in isolated perfused guinea pig hearts. Bolus injections of VIP produced a dose-dependent tachycardia that was not affected by atenolol. A decrease in amplitude of ventricular contractions occurred in response to all doses of VIP. This response was preceded by a small increase in amplitude in 3 of 6 hearts at the highest dose. VIP produced a decrease in perfusion pressure which was prominent after coronary tone was elevated with [Arg8]-vasopressin. The present findings support speculation that VIP may have a role in the regulation of heart rate and coronary blood flow.  相似文献   

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Three calcium (Ca) antagonists and dipyridamole were examined in the isolated perfused guinea pig heart at perfusate Ca concentrations of 1.25 and 3.75 mM. The Ca antagonists: FR 7534, nifedipine and D600 produced similar dose-dependent decreases in left ventricular dp/dt and myocardial oxygen consumption (MV?O2) at both Ca concentrations. However, dose response curves were shifted significantly to the right by increased perfusate Ca requiring six to ten times more Ca antagonist to produce equivalent effects. Dipyridamole produced only slight negative inotropic effects which appeared to be less dependent on external Ca concentration. All four agents significantly increased coronary blood flow at 1.25 mM Ca but not at 3.75 mM Ca. The Ca antagonists decreased heart rate at 3.75 mM Ca whereas dipyridamole had strong negative chronotropic effects at both perfusate Ca concentrations. These experiments provide evidence that FR 7534 acts as a Ca antagonist. In addition, Ca antagonists of different structure had similar effects on the isolated heart distinct from those of dipyridamole.  相似文献   

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Ca2+ binding to fragmented sarcolemma isolated from canine heart was measured by an ultracentrifugation technique. Two classes of binding site with dissociation constants of 2.0 · 10?5 and 1.2 · 10?3 M were identified. The capacities of the high- and low-affinity sites were 15 and 452 nmol/mg, respectively. These sites were not affected by treatment with neuraminidase. The effects of various cations and drugs on Ca2+ binding were studied. All cations tested inhibited Ca2+ binding with the following order of potency: trivalent > divalent > monovalent cations. The order of potency for the monovalent ions was: Na+ > K+ > Li+ ? Cs+ and for the divalent and trivalent ions: La3+ ? Mn2+ > Sr2+ ? Ba2+ > Mg2+. 1 · 10?3 M caffeine and 1 · 10?8 M ouabain increased the capacity of the low-affinity sites to 1531 and 837 nmol/mg, respectively. 1 · 10?7 M verapamil, acidosis (pH 6.4), 1?10?5 M Mn2+ and 1 · 10?4 M ouabain depressed the capacity of the low-affinity sites to a range of 154–291 nmol/mg. The dissociation constants of the high- and low-affinity sites and the capacity of the high-affinity sites were not affected by these agents.  相似文献   

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David D. Ku 《Life sciences》1982,30(3):277-284
The effects of chronic reserpine pretreatment (0.1 mg/kg/day, 7–9 days) on myocardial sodium pump activity, the binding of 3H-ouabain to Na+, K+-ATPase, and the positive inotropic effect of ouabain were studied in guinea pig hearts. Ouabain-sensitive 86Rb uptake, an estimate of sodium pump activity, was significantly decreased (33.0%) in papillary muscles of chronic reserpine-pretreated guinea pigs as compared to the saline-treated controls. Kinetic analyses of the interaction of 3H-ouabain with Na+, K+-ATPase indicated that chronic reserpine pretreatment resulted in a significant decrease (24.3%) in the maximum 3H-ouabain binding site concentration when the results were expressed as pmoles per mg protein. The maximum 3H-ouabain binding sites or the number of Na+, K+-ATPase units, however, were not significantly different between the two groups when they were expressed as pmoles per mg DNA. The affinity or the dissociation rate constant (Kd) of 3H-ouabain binding was not altered after chronic reserpine pretreatment. In isolated, electrically-driven left atrial preparations, the basal contractile force was slightly higher in the reserpine-pretreated animals; the subsequent development of the positive inotropic effect and the concentration of ouabain needed to produce half-maximal inotropic response, however, were not different from the controls. Thus, it is concluded that chronic reserpine pretreatment is accompanied by a significant reduction in myocardial sodium pump activity; however, the number of sodium pump sites per cell was unchanged. The sensitivity of the reserpine-pretreated myocardium to the inotropic action of ouabain as well as its affinity for 3H-ouabain binding in vitro are also unchanged.  相似文献   

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Isolated left and right guinea pig atria were used as a bioassay for the detection of an endogenous cardioactive substance in bovine serum. Serum, buffer exchanged to Krebs–Henseleit solution, produced positive inotropic and chronotropic effects on the isolated guinea pig atria. The cardiotonic effects were unaffected by the combined presence of propranolol and methysergide (both 10–6M) and were also dissimilar in time course from other known cardiotons such as catecholamines and cardiac glycosides. Following ultrafiltration (using XM100A Amicon membranes), activity was found solely in the retentate fractions and was therefore probably due to a large molecular weight (>100 kDa) substance or a small molecule bound to a large protein. The cardioactive factor (CF) in the whole serum was heat labile, sensitive to acidification, exposure to potassium bromide and equilibration to physiological buffers of a low ionic strength. Isolation by conventional protein purification techniques was unsuccessful due to the labile nature of the active molecule(s) when exposed to non-physiological experimental conditions. Physical and biochemical properties of the CF which may help avoid inactivation are discussed for future experiments aimed at elucidating the nature and identity of the cardiotonic principle. (Mol Cell Biochem 261: 201–207, 2004)  相似文献   

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Isolated left and right guinea pig atria were used as a bioassay for the detection of an endogenous cardioactive substance in bovine serum. Serum, buffer exchanged to Krebs-Henseleit solution, produced positive inotropic and chronotropic effects on the isolated guinea pig atria. The cardiotonic effects were unaffected by the combined presence of propranolol and methysergide (both 10(-6)M) and were also dissimilar in time course from other known cardiotons such as catecholamines and cardiac glycosides. Following ultrafiltration (using XM100A Amicon membranes), activity was found solely in the retentate fractions and was therefore probably due to a large molecular weight (> 100 kDa) substance or a small molecule bound to a large protein. The cardioactive factor (CF) in the whole serum was heat labile, sensitive to acidification, exposure to potassium bromide and equilibration to physiological buffers of a low ionic strength. Isolation by conventional protein purification techniques was unsuccessful due to the labile nature of the active molecule(s) when exposed to non-physiological experimental conditions. Physical and biochemical properties of the CF which may help avoid inactivation are discussed for future experiments aimed at elucidating the nature and identity of the cardiotonic principle.  相似文献   

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The existence of substance P immunoreactive nerves in the trachea of guinea pig is known. In this study, capsaicin induced a long-lasting and marked contraction in the guinea pig trachea and nicotine-induced contraction was partially reduced in the capsaicin-treated muscle. Furthermore, the contractile response to nicotine (10(-5) M) in the presence of atropine (10(-7) M) was abolished by a substance P antagonist, [D-Arg1, D-Pro2, D-Trp7,9 Leu11]substance P (10(-5) M). These findings suggest that noncholinergic contractile response to nicotine may be due to the release of material(s) resembling substance P in the isolated tracheal smooth muscle preparation of guinea pig.  相似文献   

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Under high Ca2+ load conditions, Ca2+ concentrations in the extra-mitochondrial and mitochondrial compartments do not display reciprocal dynamics. This is due to a paradoxical increase in the mitochondrial Ca2+ buffering power as the Ca2+ load increases. Here we develop and characterize a mechanism of the mitochondrial Ca2+ sequestration system using an experimental data set from isolated guinea pig cardiac mitochondria. The proposed mechanism elucidates this phenomenon and others in a mathematical framework and is integrated into a previously corroborated model of oxidative phosphorylation including the Na+/Ca2+ cycle. The integrated model reproduces the Ca2+ dynamics observed in both compartments of the isolated mitochondria respiring on pyruvate after a bolus of CaCl2 followed by ruthenium red and a bolus of NaCl. The model reveals why changes in mitochondrial Ca2+ concentration of Ca2+ loaded mitochondria appear significantly mitigated relative to the corresponding extra-mitochondrial Ca2+ concentration changes after Ca2+ efflux is initiated. The integrated model was corroborated by simulating the set-point phenomenon. The computational results support the conclusion that the Ca2+ sequestration system is composed of at least two classes of Ca2+ buffers. The first class represents prototypical Ca2+ buffering, and the second class encompasses the complex binding events associated with the formation of amorphous calcium phosphate. With the Ca2+ sequestration system in mitochondria more precisely defined, computer simulations can aid in the development of innovative therapeutics aimed at addressing the myriad of complications that arise due to mitochondrial Ca2+ overload.  相似文献   

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Neurotensin (NT) infusions into isolated, perfused, spontaneously beating hearts of guinea pigs evoked a concentration-dependent, positive chronotropic effect which was preceded in some hearts by transient bradycardia. The tachycardia caused by NT was not affected by propranolol, cimetidine, indomethacin, a mixture of methysergide and morphine or by atria removal. The incidence and amplitude of bradycardia caused by NT were increased by neostigmine but reduced by atropine. Neostigmine and atropine also tended to decrease and increase respectively, the tachycardia caused by NT. These results suggest that the positive chronotropic effect of NT in guinea pig isolated heart results from a direct effect on the specialized conduction system of the heart while its negative chronotropic effect is likely to reflect the activation by NT of cardiac vagal cholinergic neurons.  相似文献   

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Isolated guinea pig hearts were perfused, by the Langendorff technique, with 30, 15, 7.5, and 1.5 μM Zn2+ in Chenoweth solution. Contractile force, coronary flow, and heart rate were recorded by means of Narco IV Physiograph. Calcium inhibitor (Verapamil 1 μM) and anion inhibitor (DIDS: 0.1, 1, and 5 μM) were used subsequently in the perfusing solutions in order to distinguish some of the possible mechanisms that Zn2+ uses to exert its action on cardiac myocytes. Isomolar to zinc concentration of Pb (II) and Co (II) were used to elucidate whether zinc effects on heart are specific for this metal. All hearts were used to estimate their zinc and calcium content by means of AAS (Atomic Absorption Spectrometry). Our findings suggest that the higher the Zn2+ concentration, the more toxic effects on heart are expressed by rapid reversible contractile force reduction and reversible specific changes of heart rate and flow. Zinc 1.5 μM in the perfusing solution benefits heart performance, but not significantly. Furthermore, the metal exerts specific effects on guinea pig heart, and it is rather possible that these effects on cardiac myocytes are held through cell membrane receptors.  相似文献   

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