benzofurans and Hypotension

Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats.. Anesthetized rats were infused iv with the tested compounds and selective α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment.. Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only.. Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones.

Topics: Animals; Benzofurans; Blood Pressure; Heart Rate; Hypotension; Idazoxan; Imidazoles; Imidazolidines; Imidazoline Receptors; Imidazolines; Indazoles; Male; Rats; Receptors, Adrenergic, alpha-2

Clonidine (a mixed alpha2-adrenoceptor and imidazoline I1 receptor agonist)-evoked hypotension was associated with dissimilar reductions in c-jun gene expression in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS) in normotensive rats. In the present study, we investigated the relative contribution of the alpha2-adrenoceptor vs. the imidazoline I1 receptor to the reduction in c-jun gene expression in these two brainstem areas. In conscious spontaneously hypertensive rats (SHRs), equihypotensive doses of three centrally acting hypotensive drugs with different selectivity for the two receptors were administered intracisternally (4 microl) to limit their actions to the brain. As a control, a similar hypotensive response was elicited by i.v. hydralazine. Clonidine (0.5 microg), or alpha-methylnorepinephrine (alpha-MNE, 4 microg), a highly selective alpha2-adrenoceptor agonist, similarly reduced c-jun mRNA expression in the NTS and rostral ventrolateral medulla. In contrast, a similar hypotensive response (-37+/-3.5 mm Hg) caused by the selective imidazoline I1 receptor agonist rilmenidine (25 microg) was associated with reduction in c-jun mRNA expression in the rostral ventrolateral medulla, but not in the NTS. Further, intra-rostral ventrolateral medulla rilmenidine (40 nmol) reduced c-Jun protein expression in rostral ventrolateral medulla and blood pressure and both responses were antagonized by selective imidazoline I1 receptor (efaroxan, 4 nmol), but not alpha2-adrenoceptor (SK&F 86466, 10 nmol) blockade. These results suggest: (1) the c-jun containing neurons in the brainstem are involved in the centrally mediated hypotension elicited by centrally acting antihypertensive agents, and (2) the alpha2-adrenoceptor modulates c-jun gene expression in the NTS and rostral ventrolateral medulla implicated in centrally mediated hypotension, and (3) the imidazoline I1 receptor mediated inhibition of c-jun gene expression in the rostral ventrolateral medulla, but not in the NTS, contributes to the centrally mediated hypotension by the second generation drugs.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzazepines; Benzofurans; Blood Pressure; Brain Stem; Cerebrospinal Fluid; Clonidine; Consciousness; Gene Expression; Heart Rate; Hydralazine; Hypotension; Imidazoles; Imidazoline Receptors; Immunohistochemistry; Male; Medulla Oblongata; Neurons; Nordefrin; Oxazoles; Proto-Oncogene Proteins c-jun; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Receptors, Drug; Rilmenidine; RNA, Messenger; Time Factors; Vasoconstrictor Agents; Vasodilator Agents

We tested the hypothesis that the I1 receptor mediates the reduction in rostral ventrolateral medulla (RVLM) neuronal norepinephrine (NE; index of sympathetic activity) that leads to hypotension independent of other brainstem areas or the alpha2-adrenergic receptor. To this end, we developed a model that permitted measurement of real-time changes in neuronal NE in the RVLM or nucleus tractus solitarius (NTS) along with blood pressure and heart rate in the conscious SHR in response to localized microinjections of selective I1 (rilmenidine) or alpha2-adrenergic (alpha-methylnorepinephrine; alpha-MNE) agonist versus the mixed I1/alpha2 agonist clonidine. To further support the hypothesis, we investigated the effects of localized selective alpha2- (SK&F86466) or I1 (efaroxan) blockade on the reductions in neuronal NE and blood pressure elicited by intra-RVLM rilmenidine. In the latter experiment, changes in RVLM neuronal c-Fos (another marker of sympathetic neural activity) were also investigated. Intra-RVLM rilmenidine (40 nmol) or clonidine (1 nmol) similarly reduced RVLM NE and blood pressure; these responses were approximately 2-fold greater than those elicited by the pure alpha2-adrenergic agonist alpha-MNE (10 nmol). By contrast, intra-NTS rilmenidine or clonidine had no effect on NTS NE or blood pressure versus significant reductions in both parameters by alpha-MNE. Intra-RVLM rilmenidine decreased c-Fos expression, and these responses were abolished by efaroxan but not by SK&F 86466. These findings suggest: (1) in the RVLM, I1-receptor signaling suppresses cardiovascular neuron activity, which leads to lowering of blood pressure; (2) although the alpha2-adrenergic receptor in the RVLM serves a similar role, it does not exert a tonic neuronal inhibitory effect and is not essential, as a downstream signaling entity, for the I1-evoked neurobiological effects in the brainstem. The potential confounding effects of anesthetics on the I1 and/or alpha2 receptor-mediated neuronal and cardiovascular responses were circumvented in the present study.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Area Postrema; Benzazepines; Benzofurans; Blood Pressure; Clonidine; Consciousness; Heart Rate; Hypotension; Imidazoles; Interleukin-1; Male; Motor Activity; Neurons; Nordefrin; Norepinephrine; Oxazoles; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Rilmenidine; Solitary Nucleus

1. In the present study, we aimed to determine the involvement of brain thromboxane A2 (TXA2) in blood pressure decreases evoked by acute and/or graded haemorrhage in rats. 2. Sprague-Dawley rats were used throughout the study. Acute haemorrhage was achieved by withdrawing a total volume of 2.1 and 2.5 mL blood/100 g bodyweight over a period of 10 min. A microdialysis study was performed in a hypothalamic area to measure extracellular TXA2 levels. Graded haemorrhage was conducted successively by withdrawing carotid arterial blood (0.55 mL/100 g bodyweight) over a 10 s period four times (S1-S4) at 5 min intervals. Furegrelate (125, 250 and 500 microg), a TXA2 synthase inhibitor, was injected intracerebroventricularly (i.c.v.) 60 min before acute or graded haemorrhage was initiated. U-46619 (0.5, 1 and 2 microg, i.c.v.), a synthetic TXA2 analogue, was administered 5 min before acute haemorrhage (2.1 mL/100 g bodyweight). 3. Acute haemorrhage produced a severe and long-lasting decrease in blood pressure and had a tendency to increase heart rate. Both haemorrhage protocols (2.1 or 2.5 mL/100 g) generated similar approximate twofold increases in extracellular hypothalamic TXA2 levels. Intracerebroventricular furegrelate (250 microg) pretreatment completely blocked the TXA2 increases induced by acute haemorrhage. Furegrelate administration (100, 250 and 500 microg, i.c.v.) attenuated the fall in arterial pressure evoked by acute haemorrhage and caused significant increases in heart rate at all doses injected. 4. Graded haemorrhage progressively lowered arterial pressure and increased plasma vasopressin and adrenaline levels in the last period. Furegrelate-injected rats were greatly resistant to the hypotensive effect of haemorrhage for all degrees of blood removed. Plasma adrenaline and vasopressin levels were significantly elevated in furegrelate-pretreated rats compared with the saline-treated group during S2-S3 and S4, respectively. U-46619 administration caused small but statistically significant decreases in arterial pressure induced by haemorrhage. 4. The results show that acute hypotensive haemorrhage increases extracellular hypothalamic TXA2 levels. The increase in brain endogenous TXA2 levels involves a decrease in blood pressure evoked by haemorrhage because the blockade of TXA2 synthesis by furegrelate pretreatment attenuated the haemorrhagic hypotension. Increases in plasma adrenaline and vasopressin levels may mediate this effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epinephrine; Heart Rate; Hemorrhage; Hypotension; Hypothalamus; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vasoconstrictor Agents; Vasopressins

The beta-carboline, harmane (0.1 - 1.0 nmol) produces dose dependent hypotension when microinjected unilaterally into the rostral ventrolateral medulla (RVLM) of the anaesthetized rat. The potency of harmane on blood pressure is similar to that of the imidazoline, clonidine. The hypotensive effects of both clonidine and harmane are reversed by microinjection of the relatively I(1)-receptor selective antagonist efaroxan (20 nmol). These results are consistent with harmane acting at an I(1)-receptor in the RVLM. This is the first report of an endogenous ligand for I(1)-receptors that has central effects on blood pressure.

Topics: Adrenergic alpha-Agonists; Animals; Benzofurans; Blood Pressure; Clonidine; Harmine; Heart Rate; Hypotension; Imidazoles; Imidazoline Receptors; Male; Medulla Oblongata; Microinjections; Rats; Rats, Sprague-Dawley; Receptors, Drug

Eleven critically ill patients with life-threatening cardiac arrhythmias refractory to currently approved antiarrhythmic drugs were treated with intravenous amiodarone. Two patients had acute myocarditis, five had acute myocardial infarction, two had left ventricular failure secondary to ischemic heart disease, one had Wolff-Parkinson-White syndrome, and one manifested postoperative atrial fibrillation. Eight of the patients had severe cardiac failure and five had hypotension requiring intravenous dopamine. Five patients were treated for recurrent ventricular fibrillation, two for recurrent ventricular tachycardia, and four for recurrent atrial arrhythmias. Six patients had repeated cardioversions. The arrhythmias had lasted a mean of 88.3 hours resistant to a mean of 2.7 different intravenous antiarrhythmic drugs. The ventricular arrhythmias did not recur after commencing intravenous amiodarone, but some minor atrial arrhythmias occurred for 24 hours. One patient died of intractable left ventricular failure, chronic obstructive lung disease, and respiratory arrest during treatment. The dose of amiodarone was 150 mg over 5 minutes, followed by 600 mg/24 hr for 3 to 4 days; one patient on total parenteral nutrition required intravenous amiodarone for 20 days. Hypotension, cardiac failure, and bradyarrhythmias were not induced by this treatment. Intravenous amiodarone can be used safely in critically ill patients with impaired left ventricular function to control life-threatening refractory cardiac arrhythmias.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Blood Pressure; Dopamine; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Hypotension; Infusions, Parenteral; Male; Middle Aged; Myocardial Infarction; Myocarditis; Time Factors

Evidence from three types of experiments indicates that platelet activating factor (PAF)1 is an important mediator of endotoxin-induced hypotension in rats. a) Endotoxin infusion stimulates the time-dependent appearance of PAF in the blood. b) PAF infusion results immediately (less than 30 sec) in hypotension while endotoxin-induced hypotension takes 3-5 min to occur, allowing time for PAF production. c) Infusion of the specific PAF-receptor antagonist kadsurenone (2.2 mumole/kg bolus, 0.9 mumoles/min/kg continuous infusion), which inhibits PAF-induced hypotension by 67%, causes a 67% reversal of endotoxin-elicited hypotension. An additional finding of this study is that rats respond hypotensively to each of a series of low-dose PAF infusions but only to the first low-dose endotoxin infusion. These endotoxin-refractory rats do respond to subsequent PAF infusions.

Topics: Animals; Benzofurans; Benzopyrans; Endotoxins; Escherichia coli; Female; Hypotension; Kinetics; Lignans; Platelet Activating Factor; Platelet Membrane Glycoproteins; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, G-Protein-Coupled

Topics: Amiodarone; Benzazepines; Benzofurans; Diltiazem; Drug Interactions; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypotension; Middle Aged; Myocardial Contraction; Sinoatrial Node

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Female; Humans; Hypotension; Intraoperative Complications

Topics: Adolescent; Adult; Aged; Benzoates; Benzofurans; Coronary Disease; Coumarins; Dipyridamole; Female; Gallic Acid; Glycolates; Heart Diseases; Humans; Hypotension; Lung Diseases; Male; Middle Aged; Myocardial Infarction; Myocardium; Oxygen Consumption; Propylamines; Vasodilator Agents; Verapamil; Xanthines

Topics: Adolescent; Adult; Aged; Benzoates; Benzofurans; Blood Flow Velocity; Blood Pressure; Coronary Disease; Coronary Vessels; Coumarins; Dipyridamole; Female; Glycolates; Heart Rate; Humans; Hypertension; Hypotension; Isosorbide Dinitrate; Lung Diseases; Male; Middle Aged; Myocardial Infarction; Myocarditis; Regional Blood Flow; Vascular Resistance; Vasodilator Agents; Verapamil; Xanthines