Jay S. Grider

Mechanism of atrial natriuretic peptide release with increased inspiratory resistance

Elevated plasma atrial natriuretic peptide (ANP) levels and concomitant increases in renal sodium and water excretion are often encountered in respiratory diseases associated with increased airway resistance such as obstructive sleep apnea. The present study utilized an anesthetized rat model to determine the principal mechanism(s) responsible for stimulation of ANP release in this clinical syndrome. A 10-minute increase in external resistive loading, which reduced peak tracheal pressure to -15 to -17 mm Hg produced a significant increase in both central venous pressure and right atrial transmural pressure. This maneuver subsequently resulted in significant transient increases in glomerular filtration rate; urine flow; urinary Na+, K+, and Cl- excretion; and urinary cyclic guanosine monophosphate (cGMP) excretion, which was taken as an index of increased circulating levels of ANP. Similar changes in renal function and cGMP excretion occurred when arterial PO2 was lowered to a degree equivalent to that seen with increased resistive loading. Lowering arterial PO2 also significantly increased mean central venous pressure and right atrial transmural pressure. Conversely, the resistive loading-induced changes in renal function and cGMP excretion did not occur when the reduction in arterial PO2 was prevented by breathing a high O2 gas mixture during the resistive loading. Additionally, O2 supplementation prevented the increases in both mean central venous pressure and right atrial transmural pressure caused by increased resistive loading. These data indicate that the elevated ANP release that results from an acute increase in external resistive loading is not caused by a decrease in intrathoracic pressure but rather suggest that the elevated ANP release is primarily caused by an increased right atrial transmural pressure resulting from hypoxia-induced pulmonary vasoconstriction.

P450 arachidonate metabolites mediate bradykinin-dependent inhibition of NaCl transport in the rat thick ascending limb.

Recent studies from this laboratory demonstrated that bradykinin transiently elevates intracellular Ca2+ and inhibits Cl-reabsorption in the in vitro microperfused medullary thick ascending limb (mTAL) of the rat. The present study was designed to identify the intracellular signaling mechanism(s) that mediate this response. Preincubation with the intracellular calcium chelator BAPTA (10(-5) M) completely eliminated the bradykinin-dependent increase in intracellular Ca2+ and the suppression of Cl- transport. Preincubation with the cGMP-dependent protein kinase inhibitor H-89 (10(-5) M) had no effect on the transport response to bradykinin. In contrast, 17-octadecynoic acid (17-ODYA; 10(-5) M), a suicide-substrate inhibitor of renal cytochrome P450 omega-hydroxylase, completely blocked the transport response to bradykinin, while the cyclooxygenase inhibitor sodium meclofenamate (10(-5) M) had no effect. Finally, addition of the cytochrome P450 omega-hydroxylase metabolite 20-hydroxyeicosatetraenoic acid (20-HETE; 10(-8) M) to the bathing medium significantly inhibited Cl- transport in the mTAL (delta -39 +/- 6.0%; p < 0.05), while the epoxygenase metabolite 5,6-epoxyeicosatrienoic acid (5,6-EET; 10(-8) M) had no effect. These data suggest that the bradykinin-dependent inhibition of Cl- transport in the mTAL of the rat is mediated by cytochrome P450 dependent metabolite(s) of arachidonic acid.

A Randomized, Double-Blind Trial Comparing Continuous Thoracic Epidural Bupivacaine With and Without Opioid in Contrast to a Continuous Paravertebral Infusion of Bupivacaine for Post-thoracotomy Pain

OBJECTIVE To compare the results of continuous epidural bupivacaine analgesia with and without hydromorphone to continuous paravertebral analgesia with bupivcaine in patients with post-thoracotomy pain. DESIGN A prospective, randomized, double-blinded trial. SETTING A teaching hospital. PARTICIPANTS Patients at a tertiary care teaching hospital undergoing throracotomy for lung cancer. INTERVENTIONS Subjects were assigned randomly to receive a continuous thoracic epidural or paravertebral infusion. Patients in the epidural group were randomized to receive either bupivacaine alone or in combination with hydromorphone. Visual analog scores as well as incentive spirometery results were obtained before and after thoracotomy. METHODS AND MAIN RESULTS Seventy-five consecutive patients presenting for thoracotomy were enrolled in this institutional review board-approved study. On the morning of surgery, subjects were randomized to either an epidural group receiving bupvicaine with and without hydromorphone or a paravertebral catheter-infused bupvicaine. Postoperative visual analog scores and incentive spirometry data were measured in the postanesthesia care unit, the evening of the first operative day, and daily thereafter until postoperative day 4. Analgesia on all postoperative days was superior in the thoracic epidural group receiving bupivacaine plus hydromorphone. Analgesia was similar in the epidural and continuous paravertebral groups receiving bupivacaine alone. No significant improvement was noted by combining the continuous infusion of bupivacaine via the paravertebral and epidural routes. Incentive spirometry goals were best achieved in the epidural bupivacaine and hydromorphone group and equal in the group receiving bupivacaine alone either via epidural or continuous paravertebral infusion. CONCLUSIONS The current study provided data that fill gaps in the current literature in 3 important areas. First, this study found that thoracic epidural analgesia (TEA) with bupivacaine and a hydrophilic opioid, hydromorphone, may provide enhanced analgesia over TEA or continuous paravertebral infusion (CPI) with bupivacaine alone. Second, in the bupivacaine-alone group, the increased basal rates required to achieve analgesia resulted in hypotension more frequently than in the bupivacaine/hydromorphone combination group, underscoring the benefit of the synergistic activity. Finally, in agreement with previous retrospective studies, the current data suggest that CPI of local anesthetic appears to provide acceptable analgesia for post-thoracotomy pain.

The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines

Pain treatment is best performed when a patient‐centric, safety‐based philosophy is used to determine an algorithmic process to guide care. Since 2007, the International Neuromodulation Society has organized a group of experts to evaluate evidence and create a Polyanalgesic Consensus Conference (PACC) to guide practice.

The Polyanalgesic Consensus Conference (PACC): Recommendations for Intrathecal Drug Delivery: Guidance for Improving Safety and Mitigating Risks

Intrathecal therapy is an important part of the pain treatment algorithm for chronic disease states. The use of this option is a viable treatment strategy, but it is inherent for pain physicians to understand risk assessment and mitigation. In this manuscript, we explore evidence and mitigating strategies to improve safety with intrathecal therapy.

Dopamine D1 receptor-dependent inhibition of NaCl transport in the rat thick ascending limb: mechanism of action.

Our previous in vitro microperfusion studies established that dopamine inhibits sodium chloride transport in the rat medullary thick ascending limb. The present study was designed to determine the intracellular signaling pathway mediating this response. The dopamine D1 receptor agonist fenoldopam (1 microM) inhibited sodium chloride transport in the thick ascending limb by 42+/-5%. The dopamine D1 receptor antagonist R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH-23390) completely blocked this effect of fenoldopam. Suppression of protein kinase A activity using either myristoylated protein kinase inhibitor (PKI) or N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89), as well as suppression of phospholipase C activity using 1-(6-((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U-73122), had no effect on fenoldopam-dependent inhibition of transport. In contrast, inhibition of phospholipase A2 activity using E-6-(Bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (HELSS) significantly attenuated the effect of fenoldopam by 74%. The cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA) and the protein kinase C inhibitor staurosporine both significantly attenuated the effects of fenoldopam by 67%. Exposure to 20-Hydroxy-(5Z, 8Z, 11Z, 14Z)-eicosatetraenoic acid (20-HETE) inhibited transport by 31+/-5%, and this effect was significantly attenuated by 66% in the presence of staurosporine. We propose a signaling pathway in which dopamine activates a calcium-independent phospholipase A2 in the medullary thick ascending limb. Released arachidonic acid is then metabolized to 20-HETE which subsequently increases protein kinase C activity that acts as a final transport effector.

Effect of luminal vasopressin on NaCl transport in the medullary thick ascending limb of the rat

The aim of the present study was to determine whether vasopressin affects NaCl reabsorption in the medullary thick ascending limb of the loop of Henle when administered selectively to the luminal membrane. At 5 x 10(-6) M and 10(-8) M, luminal [Arg8]vasopressin significantly inhibited Cl- transport in the in vitro microperfused rat medullary thick ascending limb by 46.4 +/- 5.9% (P < 0.01) and 32.4 +/- 2.0% (P < 0.05) respectively. The response to 10(-8) M luminal [Arg8]vasopressin was completely blocked by the vasopressin V1 receptor antagonist [beta-mercapto-beta,beta-cyclopenta-methylenepropionyl1, O-Me-Tyr2,Arg8]vasopressin (10(-6) M), and was mimicked by the vasopressin V1 receptor agonist [Phe1, Ile5, Orn8]vasopressin (10(-8) M; delta -35.0 +/- 4.5%; P < 0.05). Luminal administration of the vasopressin V2 receptor agonist [deamino-Cys1, D-Arg8]vasopressin (5 x 10(-6) M) had no effect on transport. These data suggest that luminal vasopressin can inhibit NaCl transport in the medullary thick ascending limb of the rat via vasopressin V1 receptors.

The Polyanalgesic Consensus Conference (PACC): Recommendations for Trialing of Intrathecal Drug Delivery Infusion Therapy

Intrathecal (IT) drug infusion is an appropriate and necessary tool in the algorithm to treat refractory cancer and noncancer pain. The decision‐making steps/methodology for selecting appropriate patients for implanted targeted drug delivery systems is controversial and complicated. Therefore, a consensus on best practices for determining appropriate use of IT drug infusion may involve testing/trialing this therapy before implantation.

Acute effects of gentamicin on thick ascending limb function in the rat

It is well established that the aminoglycoside antibiotics can adversely affect proximal tubule function. Predominantly indirect evidence suggests that aminoglycosides may also affect function of more distal nephron segments. The present study utilized whole kidney clearance, in vivo micropuncture and in vitro microperfusion to directly determine whether acute gentamicin treatment affects sodium chloride transport in the thick ascending limb of the loop of Henle. Gentamicin (25 mg/kg) significantly increased urine flow, as well as sodium, potassium and chloride excretion within 15 min of intravenous injection. Glomerular filtration rate and proximal tubule fluid reabsorption were not altered by acute gentamicin treatment. In contrast, both fractional and absolute loop chloride transport was significantly decreased. In the in vitro microperfused medullary thick ascending limb, luminal but not basolateral administration of gentamicin (1 mM) significantly decreased chloride reabsorption when compared to time controls. These data suggest that the increased urine and electrolyte excretion associated with acute gentamicin treatment is, at least in part, a consequence of decreased transport in the thick ascending limb of Henles loop.

Trialing and Maintenance Dosing Using a Low-Dose Intrathecal Opioid Method for Chronic Nonmalignant Pain: A Prospective 36-Month Study.

To evaluate low‐dose intrathecal opioid trialing and maintenance with regard to analgesia and psychometric functional capacity.