Role of K(ATP)(+) channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine.

The role of ATP-sensitive K(+) (K(ATP)(+)) channels in vasomotor tone regulation during metabolic stimulation is incompletely understood. Consequently, we studied the contribution of K(ATP)(+) channels to vasomotor tone regulation in the systemic, pulmonary, and coronary vascular bed in nine treadmill-exercising swine. Exercise up to 85% of maximum heart rate increased body O(2) consumption fourfold, accommodated by a doubling of both cardiac output and body O(2) extraction. Mean aortic pressure was unchanged, implying that systemic vascular conductance (SVC) also doubled, whereas pulmonary artery pressure increased almost in parallel with cardiac output, so that pulmonary vascular conductance (PVC) increased only 25 +/- 9% (both P < 0.05). Myocardial O(2) consumption tripled during exercise, which was paralleled by an equivalent increase in O(2) supply so that coronary venous PO(2) was maintained. Selective K(ATP)(+) channel blockade with glibenclamide (3 mg/kg iv), decreased SVC by 29 +/- 4% at rest and by 10 +/- 2% at 5 km/h (both P < 0.05), whereas PVC was unchanged. Glibenclamide decreased coronary vascular conductance and hence myocardial O(2) delivery, necessitating an increase in O(2) extraction from 76 +/- 2% to 86 +/- 2% at rest and from 79 +/- 2% to 83 +/- 1% at 5 km/h. Consequently, coronary venous PO(2) decreased from 25 +/- 1 to 17 +/- 1 mmHg at rest and from 23 +/- 1 to 20 +/- 1 mmHg at 5 km/h (all values are P < 0.05). In conclusion, K(ATP)(+) channels dilate the systemic and coronary, but not the pulmonary, resistance vessels at rest and during exercise in swine. However, opening of K(ATP)(+) channels is not mandatory for the exercise-induced systemic and coronary vasodilation.

5-Amino-4-imidazolecarboxamide riboside raises adenosine in perfused hypoxic rat heart.

The effects of 5-amino-4-imidazolecarboxamide riboside (rAICA) on coronary adenosine efflux were examined in blood-free perfused working rat heart preparations subjected to mild (70% O2) and severe hypoxia (45% O2). Under these hypoxic conditions, no significant increase of coronary adenosine effluxes was observed in the presence of 300 microM rAICA alone. However, rAICA-induced augmentation of coronary adenosine efflux during hypoxia was revealed in the presence of an adenosine deaminase inhibitor, erythro-(2-hydroxy-3-nonyl)adenine hydrochloride, indicating that the failure to note the increase in coronary adenosine efflux was due to a rapid deamination of adenosine to inosine. A depression in heart rate during mild and severe hypoxia was significantly exacerbated by rAICA. These effects on heart rate were mediated by adenosine, since they were effectively blocked by 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine, a selective adenosine A1-receptor antagonist. These results suggest that rAICA elevates adenosine efflux during hypoxia.

2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands.

The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.

CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity.

CGS 21680C (2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamido adenosine) a 2-substituted analog of the riboside uronamide, 5'-N-ethylcarboxamido adenosine and the related analog CGS 21577 (2-phenethylamino-5'-N-ethylcarboxamido adenosine), have high in vitro affinity for brain striatal adenosine A2 receptors (IC50 values = 22 and 13 nM, respectively). Both compounds were considerably less active at A1 receptors with CGS 21577 and CGS 21680C having respective IC50 values of 0.76 and 3.1 microM. The former compound was thus 59-fold selective for A2 receptors whereas CGS 21680C was 140-fold selective. In contrast, the reference A2 selective ligand, CV 1808 (2-phenylaminoadenosine), showed only 8-fold selectivity as an A2 ligand, having an IC50 of 115 nM in the [3H]-5'N-ethylcarboxamide adenosine assay and an IC50 of 910 nM at the N6-[3H] cyclohexyladenosine site. Further examination of CGS 21680C showed that the compound was without effect on binding to 17 other putative neurotransmitter/neuromodulator sites indicating its selectivity as an adenosine receptor ligand. In an isolated perfused working rat heart model, CGS 21680C effectively increased coronary flow with an ED25 value of 1.8 nM. The corresponding value for CGS 21577 was 3 nM whereas that for CV 1808 was 110 nM. The EC25 for eliciting bradycardia for all three compounds was greater than 1000 nM. The effects of all three compounds could be reversed by treatment with the xanthine adenosine antagonist, xanthine amine congener.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between binding affinities for brain A1 and A2 receptors of adenosine agonists and antagonists and their effects on heart rate and coronary vascular tone.

The activities of a series of A1 and A2 adenosine receptor agonists and antagonists were determined using radioligand binding techniques in rat brain tissues. The potencies of these agonists on heart rate and coronary vascular tone were also assessed in the perfused working rat heart preparation. The order of potency of these agonists in producing negative chronotropic effects was similar to the rank order for their A1 receptor binding activities [6-N-cyclohexyladenosine (CHA) = 6-N-(R-phenylisopropyl)-adenosine greater than 5'-N-ethylcarboxamideadenosine (NECA) = 2-chloroadenosine greater than 2-phenylaminoadenosine] with a correlation coefficient of 0.97. Their order of potency in reducing coronary vascular tone followed the same rank order as their A2 receptor binding activities with a correlation coefficient of 0.97 (NECA greater than 2-chloroadenosine = 6-N-(R-phenylisopropyl)-adenosine = 2-phenylaminoadenosine greater than CHA). In addition, the antagonists 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]ox]phenyl-1,3- dipropylxanthine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl) xanthine (PACPX) and 8-phenyltheophylline (8-PT) blocked the negative chronotropic effect of CHA and the vasodilatory effect of NECA in a concentration-dependent manner. The same order of potency of the antagonists was noted in blocking CHA-induced bradycardia and A1 receptor binding activities (XAC = PACPX greater than 8-PT). A similar correlation was observed for their effects in blocking NECA-induced vasodilation and A2 receptor binding activity (XAC greater than PACPX greater than 8-PT).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of acetaldehyde and xanthine oxidase in ethanol-induced oxidative stress.

Single doses of ethanol (5 g/kg, intragastric) produce oxidative stress in the liver as well as in the heart. The metabolism of acetaldehyde through xanthine oxidase appears to play an important role in the production of oxidative stress in the heart, but it has only a contributory role in the liver. It is suggested that, as oxidative stress through lipid peroxidation may produce organ pathology, the metabolic pathway of acetaldehyde through xanthine oxidase may be one of the mechanisms which mediate cardiac pathology in alcoholism.

Inhibition of thromboxane biosynthesis in splanchnic ischemia shock.

Administration of dazoxiben (5 mg/kg, i.v.), which effectively suppressed plasma thromboxane concentrations, decreased the number of dogs that deteriorated into shock following a temporary (3-hr) splanchnic artery occlusion (SAO). Dazoxiben pretreatment also moderated the rise of plasma prostacyclin, but it augmented circulating prostaglandin E2 following the release of SAO. These alterations in arachidonic acid metabolism were accompanied by a moderation in the rise of plasma beta-glucuronidase activity, suggesting a moderation of tissue damage in the ischemic splanchnic region, and mitigation of the progressive hemodynamic deterioration caused by the SAO. The possible existence of causal relationships between the plasma eicosanoid concentrations, extent of damage in the ischemic splanchnic region, hemodynamic deterioration, and ultimate production of circulatory failure in dogs subjected to SAO are discussed.

Platelet serotonin uptake during myocardial ischemia.

Platelets are believed to play a role in the pathologic sequelae of acute myocardial ischemia. Several of the compounds generated and released by activated platelets during cardiac ischemia may contribute to the production of cellular necrosis (free oxygen radicals), coronary vasoconstriction (thromboxane, serotonin, catecholamines), and perpetuation of the platelet aggregatory reaction (thromboxane, serotonin, adenosine diphosphate). In the present study, it was demonstrated that platelet serotonin uptake function is markedly depressed following the induction of myocardial ischemia in cats. The possible mechanism through which the depression occurs and the resulting pathologic sequelae are discussed. The results of the present study illustrate another mechanism by which platelets can potentially mediate the severity and perpetuation of cellular events during acute myocardial ischemic insult.

Phenothiazine protection in calcium overload-induced heart failure: a possible role for calmodulin.

The effect of several phenothiazines on the extent of cellular damage resulting from the calcium paradox was examined. Hearts treated with trifluoperazine, a potent calmodulin inhibitor, exhibited less cellular damage than untreated myocardium as reflected by light microscopy, high-energy phosphate content and the loss of protein and creatine phosphokinase into the perfusate. A dose response of this effect revealed a maximal response at about 1 microM trifluoperazine, a concentration which lies well within the range generally attributed to calmodulin inhibition. Several other lines of evidence were also obtained suggesting a possible role for calmodulin in calcium-overload induced necrosis. First, the phenothiazines had little influence on membrane changes believed responsible for altered calcium permeability. Second, trifluoperazine was without major effect unless included in the reperfusion buffer, indicating that the drug is only effective during the phase associated with calcium overload. Finally, less protection was afforded hearts exposed to phenothiazines such as chlorpromazine and promethazine, which are weaker inhibitors of calmodulin, than those treated with the potent inhibitor trifluoperazine. While other interpretations are possible, these studies are consistent with a role for calmodulin in calcium overload-induced heart failure.

Improved lactate extraction in dogs with coronary artery ligation following administration of a thromboxane synthetase inhibitor.

Increased thromboxane A2 formation has been implicated in the pathophysiology of acute myocardial ischemia. The present study was designed to investigate the action of imidazole, a thromboxane synthetase inhibitor, during acute myocardial ischemia induced in anesthetized dogs. Regional ischemia was produced by ligation of the left anterior descending coronary artery (LAD), which caused a decrease in myocardial lactate extraction across the ischemic area, decreases in myocardial high energy phosphate contents and an increase in myocardial lactate in the center of the ischemic region. Intravenous administration of imidazole prior to LAD ligation attenuated the decrease in myocardial lactate extraction, but did not alter the depression in high energy phosphates or the rise in myocardial lactate content in the center of the ischemic myocardium. The results of this study support the suggested protective action of imidazole during an ischemic insult; perhaps by maintaining the metabolic status of the moderately ischemic border zone.

A possible role of xanthine oxidase in producing oxidative stress in the heart of chronically ethanol treated rats.

Examination of hearts and livers of rats fed ethanol for 25-30 weeks showed significant increases in catalase and glutathione peroxidase activity. Further examination revealed that the xanthine dehydrogenase/oxidase activity ratio in both tissues were decreased, suggesting that an interconversion of the dehydrogenase into oxidase might have occurred. Such an interconversion would be expected to enhance the formation of superoxide anions during acetaldehyde metabolism by xanthine oxidase. Since a role of oxidative or free radical damage in the etiology of ethanol-induced liver pathology is becoming increasingly apparent, the observation that the biochemical changes in the heart and liver are comparable suggests that oxidative damage is involved in alcoholic pathology of the heart as well as liver.

Effect of nitroglycerine on coronary circulation and cardiac metabolism.

Nitroglycerine administered intravenously to dogs under chloralose anesthesia elicits a biphasic effect. During the first phase, it causes an increase in heart rate, a decrease in mean arterial bloodpressure and a rise in cardiac output, coronary blood flow and myocardial oxygen consumption. During the second phase, the heart rate remains elevated and the arterial bloodpressure remains below control, but cardiac output, coronary blood flow and myocardial oxygen consumption decrease to or below control values. During both phases, the myocardial oxygen arteriovenous difference is decreased below its control value because of a rise in the oxygen content of the coronary sinus blood. It is concluded that nitroglycerine first increases the myocardial oxygen consumption less than the coronary blood flow, then may decrease the oxygen consumption more than the coronary flow.

Effect of aminophylline on coronary circulation and cardiac metabolism.

Doses of aminophylline commensurate with human doses, administered intravenously to dogs under chloralose anesthesia cause an increase in heart rate, a decrease in mean systemic arterial blood pressure, a rise in cardiac output, coronary blood flow and myocardial oxygen consumption and an increase in the oxygen content of the coronary sinus blood which resulted in a decrease in the coronary oxygen arteriovenous difference as the oxygen content of the arterial blood remained essentially unchanged. This increase in coronary blood flow in the presence of a decrease in arterial blood pressure is obviously due to a decrease in the resistance of the coronary bed, which is probably due, at least partially, to dilatation of the coronary bed. Furthermore, since aminophylline decreases the coronary oxygen arteriovenous difference although it raises the myocardial oxygen consumption, it is concluded that aminophylline increases the coronary blood flow more than the myocardial oxygen consumption.