James C. Schadt

Attenuated baroreflex control of sympathetic nerve activity after cardiovascular deconditioning in rats

The effect of cardiovascular deconditioning on baroreflex control of the sympathetic nervous system was evaluated after 14 days of hindlimb unloading (HU) or the control condition. Rats were chronically instrumented with catheters and sympathetic nerve recording electrodes for measurement of mean arterial pressure (MAP) and heart rate (HR) and recording of lumbar (LSNA) or renal (RSNA) sympathetic nerve activity. Experiments were conducted 24 h after surgery, with the animals in a normal posture. Baroreflex function was assessed using a logistic function that related HR and LSNA or RSNA to MAP during infusion of phenylephrine and nitroprusside. Baroreflex influence on HR was not affected by HU. Maximum baroreflex-elicited LSNA was significantly reduced in HU rats (204 ± 11.9 vs. 342 ± 30.6% baseline LSNA), as was maximum reflex gain (-4.0 ± 0.6 vs. -7.8 ± 1.3 %LSNA/mmHg). Maximum baroreflex-elicited RSNA (259 ± 10.8 vs. 453 ± 28.0% baseline RSNA), minimum baroreflex-elicited RSNA (-2 ± 2.8 vs. 13 ± 4.5% baseline RSNA), and maximum gain (-5.8 ± 0.5 vs. -13.6 ± 3.1 %RSNA/mmHg) were significantly decreased in HU rats. Results demonstrate that baroreflex modulation of sympathetic nervous system activity is attenuated after cardiovascular deconditioning in rodents. Data suggest that alterations in the arterial baroreflex may contribute to orthostatic intolerance after a period of bedrest or spaceflight in humans.

Routine, direct measurement of aortic pressure in the conscious rabbit

A method for preparation and application of an indwelling catheter for measurement of aortic pressure in conscious rabbits is described. The catheter is generally reliable for periods longer than one month and requires little interference with the normal circulation. The system utilizes coiled polyethylene tubing which has a tapered tip covered with silicone rubber tubing and, at its exterior end, a Velcro matrix for skin healing. The catheter tip is pulled into the abdominal aorta with a trocar, directed caudally. The exterior end is run subcutaneously to the nape of the neck. In 19 rabbits prepared by this method, mean pressure was determined to be 68 +/- 2 mm Hg and pulse pressure was 29 +/- 1 mm Hg two weeks after implantation. The catheters remained patent in 17 rabbits at the time of sacrifice, 12 to 120 days later. In an in vitro sweep-frequency test, maximal resonance of the catheter system was found to lie between 12-14 Hz, at which point the measured pressure amplitude exceeded control by 12.5%.

Involvement of both adrenergic and cholinergic receptors in the cardiovascular effects of naloxone during hemorrhagic hypotension in the conscious rabbit

Opiate receptor blockade with naloxone reverses the hypotension associated with severe hemorrhage in a variety of animal models. In the present study, we examined the mechanisms of naloxones actions in conscious rabbits made hypotensive by hemorrhage. This was accomplished through pharmacological blockade of the efferent limbs of the sympathetic or parasympathetic nervous systems prior to naloxone injection. In addition, we examined the effects of naltrexone in the same model. Naloxone treatment in hypotensive-hypovolemic, conscious rabbits results in an increase in mean arterial blood pressure (BP) and a decrease in heart rate (HR). The bradycardia appears to be due to a reduction in beta-adrenergic and an increase in muscarinic-cholinergic activity. The pressor effect is apparently due to increased alpha-adrenergic receptor activation, and is accompanied by an increase in cardiac output, stroke volume, and total peripheral resistance. Naltrexone did not significantly affect BP but it did reduce HR. The results from the present study suggest that naloxones effects are mediated by an integrated response of the sympathetic and parasympathetic nervous systems. The actions of naloxone may be mediated through antagonism of endogenous opiates.

Respiratory and cardiovascular effects of buprenorphine in conscious rabbits

OBJECTIVE To quantify the respiratory and cardiovascular effects of intravenous or subcutaneous buprenorphine in conscious rabbits. STUDY DESIGN Prospective experimental trial. ANIMALS Eight healthy, young adult New Zealand white rabbits (four female). METHODS Rabbits were instrumented with intraabdominal arterial and venous catheters and diaphragmatic electromyographic electrodes 2 weeks before experiments. Arterial blood pressure, arterial blood gases, heart rate and respiratory rate were monitored during experiments. Buprenorphine (0.06 mg) was administered either intravenously or subcutaneously to conscious rabbits. Respiratory and cardiovascular parameters were compared to baseline at 10 and 22 minutes after intravenous buprenorphine administration, and at 30, 60, and 90 minutes after subcutaneous buprenorphine administration. RESULTS Buprenorphine administration, at a dose of approximately 0.02 mg kg(-1), did not change blood pressure or heart rate. However, respiratory rate decreased from 252 +/- 26 to 39 +/- 26 breaths minute(-1) (mean +/- SD), and from 306 +/- 38 to 90 +/- 38 breaths minute(-1) following intravenous and subcutaneous administration of buprenorphine, respectively. Subsequent to intravenous and subcutaneous buprenorphine, arterial oxygen tension decreased from 88 +/- 4 to 72 +/- 4 mmHg (11.7 +/- 0.5 to 9.6 +/- 0.5 kPa) and from 87 +/- 3 to 77 +/- 3 mmHg (11.6 +/- 0.4 to 10.3 +/- 0.4 kPa), respectively. Buprenorphine, by either route of administration, increased arterial carbon dioxide tension from 36 to 41 mmHg (4.8-5.5 kPa) and increased the alveolar-arterial oxygen gradient from 15 to > or =20 mmHg (2 to > or =2.7 kPa). CONCLUSIONS AND CLINICAL RELEVANCE Buprenorphine administration decreased respiratory rate and produced mild hypoxemia in conscious rabbits. While these changes were well tolerated by healthy animals, caution should be exercised when administering buprenorphine to rabbits predisposed to respiratory depression.

Sympathetic and hemodynamic adjustments to hemorrhage: A possible role for endogenous opioid peptides

The traditional view of the decrease in blood pressure during blood loss is that it is a passive phenomenon. Blood pressure falls due to the inability of the compensatory mechanisms to keep pace with blood loss. However, recent evidence indicates that this transition from normotension to hypotension may involve an active decrease in compensation by the sympathetic nervous system. In the conscious, chronically prepared rabbit, blood pressure is maintained early in hemorrhage primarily by sympathetically mediated compensatory increases in vascular resistance and heart rate. When blood loss exceeds approximately 20% of total blood volume, hypotension develops abruptly due to a decrease in vascular resistance. This vasodilation is accompanied by decreased plasma norepinephrine (NE) levels and decreased sympathetic nerve activity. Therefore, the transition from normotension to hypotension during hemorrhage involves an active change, a decrease in vascular resistance, associated with a decrease in sympathetic nerve activity. Opioid receptor blockade with naloxone reverses acute hemorrhagic hypotension by increasing vascular resistance. The increase in resistance is accompanied by increased plasma NE and increased sympathetic nerve activity. Thus, the transition to hypotension during acute hemorrhage may be an active event brought on by a decrease in sympathetic outflow. Naloxones reversal of the hypotension is consistent with the central involvement of endogenous opioid peptides in this phenomenon and thus in the pathogenesis of hypotension during blood loss.

Effect of buprenorphine on the cardiovascular and respiratory response to visceral pain in conscious rabbits.

OBJECTIVE To evaluate the effect of buprenorphine administration on the cardiovascular and respiratory responses to noxious colorectal distension in conscious rabbits. STUDY DESIGN Prospective experimental trial. ANIMALS Fifteen healthy, young adult New Zealand white rabbits (eight female). METHODS Experiments were performed on conscious rabbits that were instrumented with intraabdominal arterial and venous catheters, and diaphragmatic and abdominal electromyographic electrodes. Colorectal distension was achieved by inflation of an acutely placed colorectal balloon catheter until mean arterial pressure increased 10-15 mmHg. Buprenorphine (0.06 mg) or saline was administered intravenously prior to, or during colorectal distension. Arterial blood pressure, heart rate, respiratory rate, abdominal electromyographic activity, and intra-balloon pressure were monitored. RESULTS In the absence of colorectal distension, buprenorphine increased arterial blood pressure and decreased respiratory rate but did not change heart rate. Colorectal distension increased arterial blood pressure and heart rate, and decreased respiratory rate. The increase in arterial blood pressure associated with colorectal distension was attenuated following preemptive buprenorphine, but was not changed by buprenorphine administered during distension. CONCLUSIONS AND CLINICAL RELEVANCE If cardiovascular changes reflect the intensity of noxious stimulation, then these results support the preemptive administration of buprenorphine for visceral analgesia.

A novel electrode design for chronic recording of electromyographic activity.

We describe a simple, self-retaining electromyography (EMG) electrode for use in chronic recording of EMG activity. The EMG electrode is helical in shape, resembling the screw-in fixation device on many cardiac pacing electrodes. Screw-like placement of the electrode secures it in the musculature without sutures. We have been using this electrode design to obtain months of quality diaphragmatic EMG recording in conscious rabbits. By changing the electrode wire size and coil dimensions, this design could be applied to chronic EMG recording in a variety of muscles and species.

Cold- and ethanol-induced hypothermia reduces cellular levels of mRNA-encoding Thyrotropin-Releasing Hormone (TRH) in neurons of the preoptic area.

Thyrotropin-releasing hormone (TRH)-containing neurons have been implicated in the central control of body temperature. TRH-containing neurons are located in brain areas known to influence body temperature, and TRH injected into these areas can produce changes in body temperature. While these lines of evidence support the view that central TRH is involved in thermoregulation, it has been difficult to confirm that TRH-containing neurons of the preoptic area are involved in this process. We used a different approach to test this hypothesis, based on recent evidence that changes in cellular levels of neuropeptide mRNA are linked to changes in neurosecretory processes. Hence, we predicted that if TRH neurons of the preoptic area are involved in body temperature regulation, cellular levels of TRH mRNA would be altered in animals in which body temperature had been experimentally altered. TRH mRNA levels were measured by in situ hybridization histochemistry in neurons of the preoptic area (POA) of animals that had been exposed to cold (5 degrees C) or that had been given a hypothermic dose of ethanol. Cellular levels of TRH mRNA were reduced by both treatments. However, cellular levels of the mRNA-encoding gastrin-releasing peptide were not affected by these treatments in neurons of the POA, indicating that hypothermia exerted selective effects on TRH neurons in this brain region. Considering that both cold exposure and ethanol administration increase blood pressure, that the POA contains neurons which are both thermosensitive and barosensitive, and that TRH has been implicated in the control of blood pressure, we manipulated arterial blood pressure pharmacologically without changing body temperature to determine whether TRH neurons were also responsive to cardiovascular changes. Infusions with either nitroprusside, a vasodilator, or phenylephrine, a vasoconstrictor, produced significant changes in arterial blood pressure and heart rate, but did not affect TRH mRNA in the POA. These findings demonstrate that TRH neurons of the POA are thermoresponsive, supporting the view that they play a role in the central control of body temperature.

A modification of the Harper-McGinty microdrive for use in chronically prepared rabbits

We describe a modification of the Harper-McGinty microdrive for use with extracellular, microwire recording in conscious, chronically prepared rabbits. Improvements over existing designs are in ease of assembly and mechanical stability. The microdrive is easily fabricated with hand tools and readily available parts. In addition, assembly of the microdrive utilizes epoxy, avoiding the difficult task of soldering stainless steel parts. Finally, the microdrive is mounted directly to the skull enhancing mechanical stability and eliminating the need to allow space for screw travel. Importantly, this microdrive has proven to be durable as well as functional in our preparation.