oxadiazoles and Hypotension

Angiotensin receptor blockers (ARBs) are widely used to treat hypertension, but severe refractory hypotension during general anesthesia is a well-known complication associated with the continuation of ARBs during the perioperative period. It has therefore been recommended that ARBs be withheld for 24 hours before induction of general anesthesia. However, impaired renal function affects the pharmacokinetics of each ARB differently. The half-life of azilsartan is prolonged in accordance with the degree of renal impairment. Herein, we describe a patient with chronic kidney disease grade 3B who experienced severe refractory hypotension after induction of general anesthesia requiring administration of dopamine following inadequate responses to ephedrine and phenylephrine despite a 24-hour azilsartan washout period. When the same patient underwent general anesthesia for a subsequent surgery, azilsartan was withheld for 48 hours before induction, resulting in mild intraoperative hypotension that responded adequately to phenylephrine. Severe refractory hypotension during general anesthesia cannot always be avoided by holding azilsartan for 24 hours in patients with significant renal impairment. Therefore, a longer washout period may be preferable for patients regularly taking azilsartan who also have concurrent substantial renal impairment.

Topics: Anesthesia, General; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Blood Pressure; Humans; Hypotension; Oxadiazoles

The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 μg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5-HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5-HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergotamine; Hypotension; Oxadiazoles; Piperazines; Piperidones; Rats; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds

5-Carboxamidotryptamine (5-CT; 0.003-310 microg/kg, i.v.) produced dose-dependent hypotensive responses which were blocked in a complex manner by the 5-HT(7) receptor antagonist, (R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl] pyrrolidine (SB-269970; 1 mg/kg, i.v.), in anesthetized vagosympathectomized rats. Interestingly, the 5-HT(1B/1D) receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1-biphenyl]-4-carboxamide hydrochloride monohydrate GR-127935 (1 mg/kg, i.v.), also inhibited 5-CT-induced hypotension but the effect was clearly noncompetitive. Finally, the combination of GR-127935+SB-269970 (1 mg/kg, i.v., each) produced a further decreased of 5-CT-induced responses as compared to the effect of individual treatments. These data suggest that, in addition to 5-HT(7) receptors, 5-HT(1B/1D) receptors may also mediate hypotension in rats.

Topics: Anesthesia; Animals; Blood Pressure; Hypotension; Male; Oxadiazoles; Phenols; Piperazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides

Increasing evidence has demonstrated that nitric oxide (NO) is involved in central cardiovascular regulation. In this study, we directly measured extracellular NO levels, in real-time, in the nucleus tractus solitarius (NTS) of anesthetized cats using Nafion/Porphyrine/o-Phenylenediamine-coated NO sensors. We found that local application of L-arginine (L-Arg) induced NO overflow in NTS and hypotension. These responses were potentiated in the vagotomized animals. Pretreatment with NO synthase (NOS)/guanylate cyclase inhibitor methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or NO scavenger hemoglobin attenuated L-Arg-induced hypotension, suggesting that exogenous supplement of NO suppressed cardiac functions through the NOS/cyclic guanosine monophosphate mechanism. The role of endogenous NO was examined after local application of N(G)-nitro-L-arginine methyl ester (L-NAME). We found that L-NAME suppressed endogenous NO levels in NTS and elicited hypertension and tachycardia. Taken together, our data suggest that NO is tonically released in the NTS to inhibit blood pressure.

Topics: Animals; Arginine; Biosensing Techniques; Blood Pressure; Bradycardia; Cats; Computer Systems; Electrochemistry; Enzyme Inhibitors; Extracellular Space; Female; Guanosine Monophosphate; Guanylate Cyclase; Hemoglobins; Hypertension; Hypotension; Male; Methylene Blue; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Pressoreceptors; Quinoxalines; Reflex; Sensitivity and Specificity; Solitary Nucleus; Tachycardia; Vagotomy

1. This study examined the role of K(+) channels in vascular hyporeactivity of rats with endotoxic shock ex vivo. 2. At the end of the in vivo experiments, thoracic aortas were removed from endotoxaemic and control rats. After removal of the endothelium, aortic segments were mounted in myographs for recording of isometric tension and smooth muscle membrane potential. 3. Membrane potentials recorded from endotoxaemic rats were hyperpolarized compared to those of the controls. This hyperpolarization was partially reversed by tetraethylammonium, charybdotoxin or glibenclamide, but not significantly affected by apamin. The hyperpolarization was also partially attenuated by N(omega)-nitro-L-arginine methyl ester (L-NAME) or 1H:-[1,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ). 4. In phenylephrine-contracted aortic rings, both agonists of K(+) channels, NS1619 and pinacidil, induced greater relaxations and re-polarizations in the preparations obtained from endotoxaemic rats. The NS1619-induced relaxation and re-polarization in arteries from endotoxaemic rats were partially inhibited by tetraethylammonium and completely inhibited by charybdotoxin, L-NAME or ODQ, but not significantly affected by apamin. Similarly, the greater relaxation and re-polarization induced by pinacidil in arteries from endotoxaemic rats were also inhibited by glibenclamide, L-NAME or ODQ. However, these inhibitors had no significant effect on relaxations and re-polarizations induced by NS1619 and pinacidil in arteries from controls. 5. This study provides the electrophysiological and functional evidence showing an abnormal activation of K(+) channels in vascular smooth muscle in animals with endotoxic shock. Our observations suggest that overproduction of nitric oxide causes an activation of large conductance Ca(2+)-activated K(+) channels and ATP-sensitive K(+) channels which contributes to endotoxin-mediated vascular hyporeactivity.

Topics: Animals; Aorta; Apamin; Benzimidazoles; Charybdotoxin; Drug Interactions; Enzyme Inhibitors; Glyburide; Hypoglycemic Agents; Hypotension; Lipopolysaccharides; Male; Membrane Potentials; Muscle Relaxation; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Oxadiazoles; Pinacidil; Potassium Channels; Quinoxalines; Rats; Rats, Inbred WKY; Shock, Septic; Tetraethylammonium; Vasodilation; Vasodilator Agents

Balloon catheter damage of the rat carotid artery endothelium results in an extensive and reproducible neointimal lesion composed of smooth muscle cells and connective matrix. The authors have examined two calcium channel blockers, PN 200-110 and PY 108-068, for their ability to inhibit neointimal lesion development in the rat carotid model. When given subcutaneously (1.0 mg/kg day) both compounds produced rapidly acting and long-lasting hypotension, reducing blood pressure 25-29%. At this dose given daily, PN 200-110 reduced lesion cross-sectional area by 44%, compared with only 25% seen by PY 108-068, which suggests that the antiatherosclerotic effect may not be related to lowering of blood pressure. Furthermore, PN 200-110 did not reduce the extent of platelet deposition (compared with controls) occurring at the denuded vessel surface 1 hour or 24 hours after balloon catheterization, which indicates that the inhibition of lesion development may not reflect an antiplatelet mechanism. The observed inhibition by PN 200-110 may relate to mitogen responses of the smooth muscle cell in the vessel wall (migration and proliferation) involved in lesion progression after endothelial damage.

Topics: Angioplasty, Balloon; Animals; Arteriosclerosis; Blood Platelets; Blood Pressure; Carotid Arteries; Hypotension; Isradipine; Male; Muscle, Smooth, Vascular; Nifedipine; Oxadiazoles; Rats; Rats, Inbred Strains