Bobby D. Nossaman

Dexmedetomidine: a review of clinical applications.

Purpose of review The present review serves as an overview update in the diverse uses of the sedative dexmedetomidine. Recent findings Dexmedetomidine is a selective α2 adrenoreceptor agonist that has been described as a useful, safe adjunct in many clinical applications. This paper reviews current clinical uses, mechanism of action, and side effects of dexmedetomidine. The current uses reviewed include sedation in the ICU (adult and pediatric), neurosurgery, pediatric procedural sedation, awake fiber-optic intubation, cardiac surgery, and bariatric surgery. Summary Dexmedetomidine is a useful medication with many clinical applications. The medication has shown efficacy in decreasing the need for opioids, benzodiazepines, propofol, and other sedative medications. Short-term sedation has been shown to be safe in studies, although hypotension and bradycardia are the most significant side effects. Dexmedetomidine has been used effectively for sedation during pediatric procedures and in the ICU. In order to reduce sympathetic tone during cardiac surgery, a low-dose dexmedetomidine infusion has been utilized. The bariatric surgery population has also been studied with dexmedetomidine because of its adequate sedation and less prevalent respiratory depression when compared with opioid administration. Dexmedetomidine is emerging as an effective therapeutic agent in the management of a wide range of clinical conditions with an efficacious, safe profile.

Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins.

J Clin Hypertens (Greenwich). 2012;14:198–205. ©2012 Wiley Periodicals, Inc.

L-Name modulates responses to adrenomedullin in the hindquarters vascular bed of the rat

Responses to synthetic human adrenomedullin (ADM), a novel hypotensive peptide recently discovered in human pheochromocytoma cells, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the hindquarters vascular bed of the rat. Under conditions of controlled hindquarters blood flow, intraarterial injections of ADM (0.01-0.3 nmol) and of CGRP (0.03-0.3 nmol) caused dose-related decreases in hindquarters perfusion pressure and decreases in systemic arterial pressure. Following administration of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME), hindquarters vasodilator and systemic depressor responses to ADM were significantly decreased, whereas L-NAME did not significantly decrease the vasodilator response to CGRP in either the hindquarters or systemic vascular beds. Following administration of the cyclooxygenase inhibitor, meclofenamate, vasodilator responses to ADM and to CGRP were not significantly decreased. When the relative vasodilator activity of the two peptides was compared on a nmol basis, responses to ADM were similar to responses with CGRP in the hindquarters vascular bed, whereas ADM was 30-100 fold less potent than CGRP in decreasing systemic arterial pressure. The present data demonstrate that ADM has significant vasodilator activity in the hindquarters vascular bed of the rat, that hindquarters vasodilator and systemic vasodepressor responses to ADM, but not to CGRP, are dependent upon the release of nitric oxide from the endothelium.

Nitrates and Nitrites in the Treatment of Ischemic Cardiac Disease

The organic nitrite, amyl of nitrite, was initially used as a therapeutic agent in the treatment of angina pectoris, but was replaced over a decade later by the organic nitrate, nitroglycerin (NTG), due to the ease of administration and longer duration of action. The administration of organic nitrate esters, such as NTG, continues to be used in the treatment of angina pectoris and heart failure since the birth of modern pharmacology. Their clinical effectiveness is due to vasodilator activity in large veins and arteries through an as yet unidentified method of delivering nitric oxide (NO), or a NO–like compound. The major drawback is the development of tolerance with NTG, and the duration and route of administration with amyl of nitrite. Although the nitrites are no longer used in the treatment of hypertension or ischemic heart disease, the nitrite anion has recently been discovered to possess novel pharmacologic actions, such as modulating hypoxic vasodilation, and providing cytoprotection in ischemia-reperfusion injury. Although the actions of these 2 similar chemical classes (nitrites and organic nitrates) have often been considered to be alike, we still do not understand their mechanism of action. Finally, the nitrite anion, either from sodium nitrite or an intermediate NTG form, may act as a storage form for NO and provide support for investigating the use of these agents in the treatment of ischemic cardiovascular states. We review what is presently known about the use of nitrates and nitrites including the historical, current, and potential uses of these agents, and their mechanisms of action.

Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat.

Recent studies show that pulmonary vasodilator responses to nitrite are enhanced by hypoxia. However, the mechanism by which nitrite is converted to vasoactive nitric oxide (NO) is uncertain. In the present study, intravenous injections of sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure were enhanced when tone in the pulmonary vascular bed was increased with U-46619. Under elevated tone conditions, decreases in pulmonary and systemic arterial pressures in response to nitrite were attenuated by allopurinol in a dose that did not alter responses to the NO donors, sodium nitroprusside and diethylamine/NO, suggesting that xanthine oxidoreductase is the major enzyme-reducing nitrite to NO. Ventilation with a 10% O(2) gas mixture increased pulmonary arterial pressure, and the response to hypoxia was enhanced by N(G)-nitro-l-arginine methyl ester and not altered by allopurinol. This suggests that NO formed by the endothelium and not from the reduction of plasma nitrite modulates the hypoxic pulmonary vasoconstrictor response. Although intravenous injections of sodium nitrite reversed pulmonary hypertensive responses to U-46619, hypoxia, and N(G)-nitro-l-arginine methyl ester, the pulmonary vasodilator response to nitrite was not altered by ventilation with 10% O(2) when baseline pulmonary arterial pressure was increased to similar values in animals breathing room air or the hypoxic gas. These data provide evidence that xanthine oxidoreductase is the major enzyme-reducing nitrite to vasoactive NO, and that this mechanism is not modified by hypoxia.

Comparison of responses to adrenomedullin and calcitonin gene-related peptide in the pulmonary vascular bed of the cat

Pulmonary vascular responses to the newly discovered hypotensive peptide, adrenomedullin, were compared with responses to the structurally related peptides, calcitonin gene-related peptide (CGRP) and amylin, in the intact-chest cat. Under conditions of controlled blood flow, when tone in the pulmonary vascular bed had been raised to a high steady level, intralobar injections of adrenomedullin (0.03-1 nmol), CGRP (0.1-3 nmol), and amylin (0.1 and 0.3 nmol) caused dose-related decreases in lobar arterial pressure without changing left atrial pressure. In terms of relative vasodilator activity in the pulmonary vascular bed, the dose of the peptide that decreased lobar arterial pressure 7.5 mm Hg (ED7.5 mm Hg) was significantly lower for adrenomedullin than for CGRP. The duration of the pulmonary vasodilator responses to CGRP was longer than for adrenomedullin, and both peptides decreased systemic arterial pressure when injected into the perfused lobar artery in the higher doses studied. The present data demonstrate that synthetic human adrenomedullin and CGRP have potent but relatively short-lasting vasodilator activity in the pulmonary vascular bed. These data show also that amylin, a structurally related pancreatic peptide, also has significant pulmonary vasodilator activity.

Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat

Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% O(2)-90% N(2) gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in l-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase.

Anti-Inflammatory Mesenchymal Stem Cells (MSC2) Attenuate Symptoms of Painful Diabetic Peripheral Neuropathy

Mesenchymal stem cells (MSCs) are very attractive candidates in cell‐based strategies that target inflammatory diseases. Preclinical animal studies and many clinical trials have demonstrated that human MSCs can be safely administered and that they modify the inflammatory process in the targeted injured tissue. Our laboratory developed a novel method that optimizes the anti‐inflammatory effects of MSCs. We termed the cells prepared by this method MSC2. In this study, we determined the effects of MSC2‐based therapies on an inflammation‐linked painful diabetic peripheral neuropathy (pDPN) mouse model. Streptozotocin‐induced diabetic mice were treated with conventionally prepared MSCs, MSC2, or vehicle at three specific time points. Prior to each treatment, responses to radiant heat (Hargreaves) and mechanical stimuli (von Frey) were measured. Blood serum from each animal was collected at the end of the study to compare levels of inflammatory markers between the treatment groups. We observed that MSC2‐treated mice had significant improvement in behavioral assays compared with the vehicle and MSC groups, and moreover these responses did not differ from the observations seen in the healthy wild‐type control group. Mice treated with conventional MSCs showed significant improvement in the radiant heat assay, but not in the von Frey test. Additionally, mice treated with MSC2 had decreased serum levels in many proinflammatory cytokines compared with the values measured in the MSC‐ or vehicle‐treated groups. These findings indicate that MSC2‐based therapy is a new anti‐inflammatory treatment to consider in the management of pDPN.

Stimulators and Activators of Soluble Guanylate Cyclase: Review and Potential Therapeutic Indications

The heme-protein soluble guanylyl cyclase (sGC) is the intracellular receptor for nitric oxide (NO). sGC is a heterodimeric enzyme with α and β subunits and contains a heme moiety essential for binding of NO and activation of the enzyme. Stimulation of sGC mediates physiologic responses including smooth muscle relaxation, inhibition of inflammation, and thrombosis. In pathophysiologic states, NO formation and bioavailability can be impaired by oxidative stress and that tolerance to NO donors develops with continuous use. Two classes of compounds have been developed that can directly activate sGC and increase cGMP formation in pathophysiologic conditions when NO formation and bioavailability are impaired or when NO tolerance has developed. In this report, we review current information on the pharmacology of heme-dependent stimulators and heme-independent activators of sGC in animal and in early clinical studies and the potential role these compounds may have in the management of cardiovascular disease.

Advances in perioperative pain management: use of medications with dual analgesic mechanisms, tramadol & tapentadol.

Recovery from ambulatory surgical procedures can be limited by postoperative pain. Inadequate analgesia may delay or prevent patient discharge and can result in readmission. More frequently, postoperative pain produces discomfort and interrupts sleep, contributing to postoperative fatigue. The development of effective analgesic regimens for the management of postoperative pain is a priority especially in patients with impaired cardiorespiratory, hepatic, or renal function. Tramadol and tapentadol hydrochloride are novel in that their analgesic actions occur at multiple sites. Both agents are reported to be mu-opioid receptor agonists and monoamine-reuptake inhibitors. In contrast to pure opioid agonists, both drugs are believed to have lower risks of respiratory depression, tolerance, and dependence. The Food and Drug Administration has approved both drugs for the treatment of moderate-to-severe acute pain in adults. This article provides an evidence-based account of the role of tramadol and tapentadol in modern clinical practice.