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In human placenta, endothelin (ET) could derive from maternal, fetal, and/or endogenous sources. Therefore, localization of ET-1 was investigated by immunohistochemistry in human term placenta and in cultured trophoblasts. In sections of placenta, ET-1 immunoreactivity (ET-1 IR) was specifically detected in the endothelium of the vessels and in the syncytiotrophoblasts of the villi. ET-1 IR was also detected in the decidual cells and in the extravillous cytotrophoblasts of the basal plate. The extravillous cytotrophoblasts of the chorionic plate and of the placental septa also exhibited strong ET-1 IR. For trophoblast culture, cytotrophoblastic cells were obtained from placental villi by trypsin-DNAse dispersion, further purified on a Percoll gradient, and enriched by employing a monoclonal anti-HLA class I antibody. After different periods of culture of purified cytotrophoblastic cells (1-5 days), ET-1 IR was observed in 95% of cells: cytotrophoblastic cells, trophoblast aggregates, and syncytiotrophoblasts. The presence of ET-1,2 immunoreactivity (ET-1,2 IR) in the culture media was demonstrated by radioimmunoassay. A uniform daily production of the peptide was observed over at least 5 days (approximately 50 fmol/10(6) cells/24 h). Furthermore, trophoblastic cells that had been cultured for 5 days contained significant amounts of ET-1,2 IR (24 fmol/10(6) cells). These results suggest a trophoblastic origin for ET-1 and support the hypothesis of a paracrine and autocrine action of the peptide in the physiology of the trophoblast and placenta.

The objective of this study was to determine whether ATP-dependent potassium channel activation is involved in the mechanism by which nicorandil reduces postischemic contractile dysfunction produced by a brief period of ischemia (myocardial stunning). Barbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. Saline or nicorandil (100 micrograms/kg + 25 micrograms/kg/min) were infused 15 min before and throughout occlusion with or without addition of the KATP channel antagonist, glibenclamide 0.3 mg/kg as an intravenous (i.v.) bolus. Regional myocardial blood flow was measured by radioactive microspheres, and left ventricular (LV) segment function was measured by sonomicrometry. There were no significant differences between the groups in area-at-risk size or collateral blood flow. In contrast, nicorandil significantly reduced mean aortic blood pressure (BP) and the rate-pressure product (RPP) which persisted throughout the occlusion period. In addition, nicorandil markedly accelerated recovery of segment shortening in the ischemic/reperfused region as compared with control dogs. Pretreatment of dogs with glibenclamide blocked none of the hemodynamic effects of nicorandil, but it did prevent improvement in reperfusion segment function. The small dose of glibenclamide used had no effect on hemodynamics or the degree of stunning. Thus, these results suggest that nicorandil attenuates stunning in anesthetized dogs by a direct cardioprotective effect as a result of KATP channel activation in ischemic myocardium.

The present article presents an overview of the pharmacologic profile of the benzopyran derivative RP 58866, a racemic mixture, and of RP 62719 (terikalant), its active enantiomer. In normal cardiac tissues studied in vitro, both drugs dose-dependently prolonged the atrial and ventricular action potential but affected neither the upstroke of the action potential nor the diastolic potential. Patch-clamp experiments demonstrated that the prolongation of the action potential induced by the drugs is due to a specific blockade of the inward rectifier K+ current. In vivo, intravenous administration to anesthetized dogs of low doses of RP 62719 consistently induced bradycardia and prolonged the atrial, nodal, and ventricular refractory periods, but did not affect the conduction velocity. Because of these properties, RP 58866 and RP 62719 exert potent antiarrhythmic and antifibrillatory actions both at the atrial and ventricular levels in various experimental models of arrhythmia. Our results demonstrate that RP 58866 and RP 62719 are K(+)-channel blockers acting as pure class III antiarrhythmic drugs.

In pentobarbital-anesthetized rats endothelin-1 (ET-1), endothelin-2 (ET-2), endothelin-3 (ET-3), and mouse ET-2 (mET-2), in contrast to human big ET-1 (h-big ET), administered as i.v. bolus injections (0.25 nmol/kg i.v.) produced rapidly appearing and short-lasting blood pressure decreases. This effect was markedly inhibited (80-100%) after an 8-min i.v. infusion (0.1 nmol/kg/min over 10 min) of any of the ET studied, but not by h-big ET, the precursor of ET-1. Similarly, in pithed rats given a 10 min i.v. infusion of an equipressor dose (0.1 nmol/kg/min) of ET-1 or h-big ET, the hypotensive effects of ET-1 were entirely blocked only in the group of animals pretreated with ET-1. In pithed rats, ET-1 (0.25 nmol/kg i.v.) and h-big ET (0.5 nmol/kg i.v.) produced equivalent maximal pressor responses and the same pattern of increase in systemic, hindquarter, and renal vascular resistance. However, ET-1 was three times more potent than h-big ET as a vasoconstrictor of the mesenteric bed. Also the pressor response to h-big ET, but not ET-1 (0.25 nmol/kg i.v.), was markedly inhibited by the metalloprotease inhibitor phosphoramidon (5 mg/kg i.v.). These results indicate that the hypotensive effects of ET isopeptides have a common mechanism because they elicit cross tachyphylaxis, although h-big ET did not inhibit the decrease in blood pressure produced by ET-1. A possible explanation for this finding is that h-big ET has intrinsic pressor activity but does not have affinity for receptors mediating the vasodepressor effects of ET isoforms. Alternatively, h-big ET is converted into ET-1 too slowly to yield biophase concentrations of ET-1 necessary for lowering blood pressure and developing tachyphylaxis to ET-isoform-induced hypotension. Finally, if the pressor effects of h-big ET are mediated by ET-1 formation, phosphoramidon can be considered as an inhibitor of the endothelin-converting enzyme.

Under control conditions a primary culture containing about 80-90% of granular juxtaglomerular (JG) cells prepared from rat kidneys continuously released renin into the culture medium at a rate of 17.9 +/- 1.4 ng angiotensin I/h per mg of cell proteins per 30 min (n = 14). Dopamine (1.0 microM), the DA-1 dopamine receptor agonist fenoldopam (0.5 microM), and isoproterenol (1.0 microM) increased renin secretion markedly (130-200%). Propranolol (0.1 microM) reduced the effects of isoproterenol significantly (80%), but not those of dopamine or fenoldopam. In contrast, SCH 23390 (0.01 microM), a DA-1 dopamine receptor antagonist, inhibited markedly only the renin release evoked by the latter two agonists, whereas S-sulpiride (10 microM), a DA-2 dopamine receptor antagonist, and phentolamine (10 microM), a nonselective alpha-adrenoceptor antagonist, did not modify the effects of either dopamine or fenoldopam. In rats, pithed to eliminate reflexogenic mechanisms regulating renin release, at the end of a 15 min i.v. infusion of fenoldopam (20 micrograms/kg per min) there was a significant increase in plasma renin activity. This effect was completely prevented by SCH 23390 (0.1 mg/kg i.v.) but not significantly changed by S-sulpiride (0.3 mg/kg i.v.) or phentolamine (3.0 mg/kg i.v.) plus propranolol (0.75 mg/kg i.v.). In conclusion, these results indicate that DA-1 dopamine receptors are present in rat kidney JG cells and that pharmacological stimulation of these receptors with dopamine or fenoldopam leads to renin secretion.

In pentobarbital-anesthetized rats prepared for hemodynamic measurements with Doppler flow probes, intravenous (i.v.) infusions of fenoldopam (2.5 - 160.0 micrograms/kg/min during 15 min) decreased mean carotid artery blood pressure, total peripheral, hindquarter, renal, and mesenteric vascular resistances and increased renal blood flow strongly. The hypotensive effects attained a maximum within the first 3 min of infusion but waned by greater than 30% at the end of fenoldopam administration. This tolerance was observed for calculated total peripheral and hindquarter vascular resistances and to a lesser extent for mesenteric resistance. However, it was absent on the renal vascular bed. Pretreatment with either enalapril, pepstatine, or bilateral nephrectomy significantly increased the hypotensive response to fenoldopam and attenuated the development of tolerance. In conscious spontaneously hypertensive rats (SHR), enalapril potentiated strongly the small blood pressure-lowering activity of fenoldopam. The fall in blood pressure produced by fenoldopam was specifically blocked by SCH 23390, an antagonist of DA-1 dopamine receptors. In normotensive vasopressin-supported pithed rats given phenoxybenzamine plus propranolol, fenoldopam, like SCH 23390, blocked the vasodepressor effects of i.v. bolus injection of dopamine and fenoldopam. In pithed rats, fenoldopam evoked a pressor response that was significantly reduced by enalapril, SCH 23390, or bilateral nephrectomy. In conclusion, fenoldopam exerts DA-1 agonist and antagonist effects. The latter property, together with the activation of the renin-angiotensin system, appears to be responsible for the development of tolerance to the fenoldopam evoked-hypotension. The lack of a tolerance at the level of the renal vascular bed is possibly due to the existence of a large population of DA-1 receptors in this region.

In anesthetized dogs, a 15-min intravenous (i.v.) infusion of fenoldopam (2.0 micrograms/kg/min) produced a decrease in mean aortic blood pressure (MAP) and an increase in renal blood flow (RBF) and plasma renin activity (PRA). The hypotensive effect attained a maximum within 5 min and then waned by approximately 30% at the end of fenoldopam administration. The development of this "tolerance" phenomenon was prevented by enalapril or saralasin. The hypotension and the increase in PRA were not modified by either propranolol or chlorisondamine but were inhibited by SCH 23390, a DA1 antagonist. Fenoldopam (0.1 microgram/kg/min for 15 min) infused into the left renal artery (i.a.) in intact or ganglion-blocked dogs did not change MAP but increased PRA. This effect was antagonized by SCH 23390. In ganglion-blocked preparations in which an apparently maximal renal vasodilatation had been achieved by an i.a. acetylcholine, i.a. fenoldopam produced an increase in PRA which was again blocked by SCH 23390. In uninephrectomized dogs, blockade of alpha- and beta-adrenoceptors or inhibition of renal baroreceptor and macula densa mechanisms of renin release failed to prevent the fenoldopam-induced increase in PRA. In conclusion, the release of renin by fenoldopam is responsible for the development of tolerance to the hypotensive effects of fenoldopam. Furthermore, because the increase in PRA was blocked by SCH 23390 and occurred in the absence of either operational systemic or intrarenal regulatory mechanisms, we propose that it is mediated by stimulation of specific dopamine (DA1) receptors on the juxtaglomerular (JG) cells.

In conscious rabbits prepared for continuous arterial pressure measurements by means of a catheter placed into the main ear artery, intravenous administration of prazosin (5.0 micrograms/kg, i.v. over 20 min) produced a significant decrease in arterial pressure and cardioacceleration. This dose of prazosin inhibited by approximately 70% the pressor effects of phenylephrine. However, prazosin failed to produce significant functional modifications of either the bradycardia or the tachycardia which accompanied the changes in arterial pressure evoked, respectively, by intravenous bolus injections of angiotensin II or acetylcholine. It is concluded that prazosin in the dose studied does not appear to interfere with reflex heart rate responses to vasodepressor or vasopressor stimuli in conscious rabbits.

In conscious, spontaneously hypertensive rats (SHR) oral prazosin (0.03-3.0 mg/kg) resulted in dose-related reductions of systolic blood pressure measured with a tail cuff. In SHR whose tail artery blood pressure was continuously monitored the antihypertensive effect of prazosin (1.0 mg/kg, p.o.) was accompanied by a significant increase in heart rate. Several groups of SHR were pithed 2 hr after oral prazosin (1.0 mg/kg) or placebo. In this preparation the mean carotid blood pressure increases following i.v. injections of angiotensin II or 5-hydroxytryptamine and the positive chronotropic responses to i.v. norepinephrine or electrical stimulation of the spinal cord were similar in control and prazosin-pretreated animals. However, the dose-pressor response curves to i.v. norepinephrine or electrical stimulation of the spinal cord from prazosin-pretreated SHR lay to the right of the control curves. In addition, the slopes of the linear portion of these curves were flatter after prazosin and remained so even after i.v. propranolol was given alone or with cocaine. Prazosin-pretreated SHR responded to phenylephrine with a fall followed by a rise in carotid blood pressure. The depressor effect was abolished and the pressor phase enhanced by i.v. propranolol. The pressor responses to i.v. cirazoline or clonidine were significantly inhibited by prazosin. Finally, prazosin failed to significantly modify the negative chronotropic effects of clonidine observed in pithed SHR whose heart rate was raised by continuous electrical stimulation of the thoracic spinal cord. These results indicate that oral prazosin exerts pronounced antihypertensive effects in the SHR. This action apparently results from impairment of the sympathetic nervous system at the level of vascular postsynaptic alpha-adrenoceptors.