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Anesth Analg 2001;93:177-182
© 2001 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effects of Alpha-Human Atrial Natriuretic Peptide and Milrinone on Pial Vessels During Blood-Brain Barrier Disruption in Rabbits

Hiroki Iida, MD, Mami Iida, MD*, Motoyasu Takenaka, MD, Akiyoshi Oda, MD, Masayoshi Uchida, MD, Hisayoshi Fujiwara, MD*, and Shuji Dohi, MD

Department of Anesthesiology and Critical Care Medicine, and *Second Department of Internal Medicine, Gifu University School of Medicine, Gifu City, Gifu, Japan

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu-City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The effects of {alpha}-human atrial natriuretic peptide (HANP) and milrinone on cerebral pial vessels, especially during blood-brain barrier (BBB) disruption, are not clear. We studied topical HANP (10-14, 10-12, and 10-10 M) or milrinone (10-7, 10-5, and 10-3 M), and IV HANP (0.1, 0.2, and 1.0 µg · kg-1 · min-1) or milrinone (0.5, 5.0, and 20.0 µg · kg-1 · min-1) with or without hyperosmolar BBB disruption, using a rabbit cranial window preparation. At 10-12 and 10-10 M topical HANP produced significant arteriolar (16%, 20%, respectively), but no venular dilation. Topical milrinone (10-3 M) produced significant arteriolar and venular dilation (21%, 8%, respectively). IV HANP produced no arteriolar or venular changes at any dose except during BBB disruption, when it caused a significant arteriolar (16%, 16%, and 17%, respectively), but no venular dilation. In contrast, IV milrinone caused small but significant arteriolar and venular dilation without BBB disruption (arterioles, 6%, 7% and 8%, respectively; venules, 6% at 20.0 µg · kg-1 · min-1). During BBB disruption, these responses to milrinone were similar. Although HANP and milrinone each have a direct vasodilator effect on arterioles, their systemic administration at clinical doses could induce different effects. BBB disruptive conditions could increase the response of pial vessels to systemically administered HANP.

Implications: Although {alpha}-human atrial natriuretic peptide (HANP) and milrinone each havea direct vasodilator effect on cerebral pial arterioles, their systemicadministration at clinical doses could have different effects andblood-brain-barrier disruptive conditions could alter the response of pialvessels to HANP, but not to milrinone.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Many drugs used for improving cardiovascular disorders can have an effect on blood vessels of the central nervous system (1–3). {alpha}-Human atrial natriuretic peptide (HANP), recently introduced into clinical practice for patients with heart failure, also has vasodilating and diuretic effects (4) and is used during and after cardiopulmonary bypass (CPB) (5) and in intensive care. Milrinone, a new positive inotropic drug, also has a vasodilator action and has been used in critical conditions, including cardiac surgery and severe heart failure (6).

A vasodilator drug can have quantitatively different effects on different vessels, and thus may have different effects on the functions of different organs. For example, nitroglycerin is often used to dilate coronary arteries; however, it also causes cerebrospinal fluid pressure to increase and cerebral perfusion pressure to decrease, and thus could cause cerebral ischemia by aggravating or exaggerating intracranial hypertension (1). The cerebral microcirculation is important in critically ill patients because of the need to prevent untoward ischemic events. There are no data to indicate whether HANP and milrinone affect cerebral microvessels, which may cause a disruption of the blood-brain-barrier (BBB), an issue of special importance in patients with brain damage.

We designed the present study using a closed cranial window technique to explore the effects of HANP and milrinone on cerebral microcirculation in normal rabbits and in rabbits in which BBB function had been disrupted pharmacologically.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Experimental Animals
We studied 50 male Japanese white rabbits weighing 2.0 to 2.2 kg. Experimental protocols were approved by our institution’s animal care committee and the care and handling of the animals were in accord with National Institutes of Health guidelines.

Each rabbit was anesthetized (pentobarbital sodium, 20 mg/kg body weight, IV) and mechanically ventilated through a tracheostomy tube via a ventilator using room air supplemented with oxygen. Tidal volume and respiratory rate were adjusted to maintain PaCO2 between 35 to 40 mm Hg throughout the experiment. Supplemental pentobarbital sodium was infused IV at 2–4 mg · kg-1 · h-1.

The femoral artery was cannulated for measurement of arterial blood pressure and to provide blood samples for determination of arterial blood gas tensions, pH, glucose, and serum electrolytes. The femoral vein was cannulated for administration of fluids and drugs. In 24 rabbits, the right external carotid artery was cannulated, with the catheter tip being positioned within the external carotid artery. This allowed drugs administered by this route to pass from the common carotid artery into the internal carotid artery and then to open the BBB. Body temperature was maintained between 38.0°C and 40.0°C by means of a heating blanket.

A closed cranial window was used for observation of the pial microcirculation, with the head fixed in the sphinx position. The scalp was retracted, a 10 mm-diameter hole was made in the bone over the right parietal cortex, and the dura and the arachnoid membrane were opened. A polypropylene ring with a glass coverslip was placed over the hole and secured with dental acrylic. The space under the window was filled with artificial cerebrospinal fluid (aCSF) having the following composition: Na+, 151 mEq/L; K+, 4 mEq/L; Ca2+, 3 mEq/L; Mg2+, 1.3 mEq/L; Cl-, 110 mEq/L; HCO3- 25 mEq/L; urea, 40 mg/dL; and glucose, 67 mg/dL; pH was adjusted to 7.48. The solution was freshly prepared each day and bubbled with 5% CO2 in air at 38°C for 15 min just before use. Four catheters were inserted into the ring. One was attached to a reservoir bottle containing aCSF to maintain a constant pressure within the window, the second was used to monitor pressure within the window, the third was for administration of experimental drugs and aCSF, and the fourth was for draining the fluid. Temperature within the window was monitored and was maintained at 38.0°C–40.0°C.

The pial views obtained in these experiments were stored on videotape (with a time record) for later playback and analysis. The inner diameters of three pial arterioles and three pial venules, which could be differentiated with beating and color, were measured using a videomicrometer (Model VM-20; Olympus, Tokyo, Japan) on a television monitor attached to a microscope (Model SZH-10; Olympus). The percentage changes recorded for individual arteriolar and venular segments were averaged for each rabbit, and this average value was used in the statistical analysis. Mean arterial blood pressure (MAP) and heart rate (HR) were continuously monitored.

Experimental Protocols
In Protocol 1, we investigated the direct effects of HANP and milrinone after topical application into the cranial window (each in six rabbits). Synthetic HANP (Suntory Inc., Tokyo, Japan) (10-14, 10-12, and 10-10 mol/L) and milrinone (Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan) (10-7, 10-5, and 10-3 mol/L) were freshly dissolved in aCSF for the current study. After 30 min of stabilization, pial arteriolar and venular diameters, MAP, HR, body temperature, arterial blood gas tensions, pH, and serum electrolytes were measured before and after topical application of the three different concentrations of HANP or milrinone into the cranial window in each rabbit, the three concentrations being tested sequentially. Each solution was infused into the window at a rate of 0.5 mL/min for 5 min (the space under the window was <0.5 mL). The measurements were then made. To reestablish the baseline vessel size, the window was continuously flushed with aCSF at a rate of 0.5 mL/min for 30 min after each measurement. Thirty minutes after the administration of the last solution, the pial vascular diameters had returned to baseline values.

In Protocol 2, we tested whether systemic administration of HANP or milrinone would cause the same effects as those seen on topical application. After 30 min of stabilization, the pial arteriolar and venular diameters were measured before and after 30 min IV infusion of 0.9% saline (baseline). Then, pial arteriolar and venular diameters, MAP, HR, body temperature, arterial blood gas tensions, pH, and serum electrolytes were measured before and after IV infusion of HANP or milrinone (each at three doses, tested sequentially) in six rabbits each. The three different doses (0.1 [clinical dose], 0.2 [clinical large dose limit], and 1 µg · kg-1 · min-1 for HANP; 0.5 [clinical dose], 5 [clinical priming dose], and 20 µg · kg-1 · min-1 for milrinone) were infused for 30 min each.

In Protocol 3, we tested whether BBB disruption changes the effects induced by systemically administered HANP and milrinone. After 30 min of stabilization, the pial arteriolar and venular diameters were measured before and after 30 min IV infusion of 0.9% saline (baseline). To open the BBB, a solution of 25% mannitol (filtered and warmed to body temperature) was infused through the catheter in the external carotid artery for 30 s at a rate of 0.25 mL · kg-1 · s. Then, an infusion of 0.1 µg · kg-1 · min-1 HANP was started in six rabbits. Mannitol was infused at a rate well below that previously shown to cause a hypertensive opening of the BBB (7), but sufficient to produce an optimum disruption of the BBB without serious immediate or delayed neurotoxicity (8). The same procedures were performed at two more (0.2 and 1.0 µg · kg-1 · min-1) doses with 30 min intervals. Measurements were made as in Protocol 2. The effects of milrinone were examined in the same way (except that the doses were 0.5, 5.0, and 20 µg · kg-1 · min-1). For the control study, instead of HANP or milrinone, 0.9% saline was infused systemically in six rabbits. All drug solutions were freshly prepared on the day of the experiment.

In an additional experiment, just after (n = 4) and 30 min after (n = 4) 25% mannitol infusion to the carotid artery, 2 mL/kg of a 2% Evans blue solution was infused systemically. Thirty minutes after the Evans blue injection, the animals were killed, and the brain was rapidly removed for evaluating Evans blue extravasation. Evans blue, which is tightly bound to albumin, will not stain cerebral tissue having intact BBB when injected IV.

Data Analysis
All data relating to the concentration- and dose-dependent effects of HANP and milrinone were tested by a one-way analysis of variance for repeated measurements followed by Scheffé’s test for post hoc comparisons. The group effects of HANP or milrinone on pial vessel diameters during BBB opening were compared with those of HANP or milrinone without BBB opening, or with those seen in the control groups (saline with BBB opening) by a two-way analysis of variance, and the differences at a given dose were tested by an unpaired Student’s t-test. Significance was set at P < 0.05. All values are presented as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
MAP, HR, arterial blood gas tensions, pH, serum electrolytes, and body temperature did not change significantly at any topically applied dose of HANP and milrinone. During IV infusion of HANP at doses of 0.2 and 1.0 µg · kg-1 · min-1 without BBB opening and at dose of 1.0 µg · kg-1 · min-1 with BBB opening, MAP decreased significantly (Table 1). There was no marked change in HR, arterial gases, pH, or electrolytes after IV infusion of HANP. During the IV infusion of milrinone at 20 µg · kg-1 · min-1 without BBB disruption, MAP decreased significantly, and HR increased significantly when milrinone was infused at this dose with BBB disruption (Table 1). None of the other physiological variables changed during IV administration of milrinone.


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  		Table 1. Hemodynamic Measurements During IV Administration of {alpha}-Human Atrial Natriuretic Peptide (HANP) or Milrinone With or Without Blood-Brain-Barrier (BBB) Opening, or Control With BBB Opening
 
Baseline diameters (45–153 µm) showed no significant differences between experiments or between arterioles and venules.

Topical application of HANP produced a significant pial arteriolar dilation at concentrations of 10-12 and 10-10 M (Fig. 1a). The maximal dilation was approximately 20% for the pial arterioles at a concentration of 10-10 M. Pial venules were found to be unresponsive to even the largest concentration of HANP. Topical application of milrinone produced a significant pial arteriolar and venular dilation at a concentration of 10-3 M, but 10-5 M produced no significant changes (Fig. 1b). The maximal dilation with milrinone is around 21% for the pial arterioles and around 8% for the venules at concentration of 10-3 M.



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  		Figure 1. (a) Dose-related effects of topically applied {alpha}-human atrial natriuretic peptide (HANP) on the diameter of pial vessels in rabbits. Each bar indicates percentage change in diameter (mean ± SD) from the baseline value. * P < 0.05 compared with 10-14 M HANP. (b) Dose-related effects of topically applied milrinone on the diameter of pial vessels in rabbits. Each bar indicates percentage change in diameter (mean ± SD) from the baseline value. * P < 0.05 compared with 10-7 M milrinone. # P < 0.05 compared with 10-5 M milrinone.

 
IV infusion of HANP produced no pial arteriolar changes at any dose (0.1, 0.2, or 1.0 µg · kg-1 · min-1) (Fig. 2a). The pial venular diameters were unchanged by any concentration of IV HANP (Fig. 2b). During hyperosmolar BBB disruption, IV HANP (0.1, 0.2, and 1.0 µg · kg-1 · min-1) caused a significant pial arteriolar, but not venular dilation (compared to baseline, to IV HANP without BBB disruption, or to 0.9% saline infusion with BBB disruption). The pial arteriolar and venular diameters were unchanged during 0.9% saline with BBB disruption (Fig. 2).



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  		Figure 2. Dose-related effects of IV alpha-human atrial natriuretic peptide (HANP) on the diameter of pial arterioles (a) and venules (b) in rabbits with or without blood-brain barrier (BBB) opening. Each bar indicates percentage change in diameter (mean ± SD). * P < 0.05 compared with baseline (percentage change in diameter during IV infusion of 0.9% saline without BBB opening). {dagger} P < 0.05 between indicated values. NS = not significant.

 
As shown in Figure 3, IV infusion of milrinone in the absence of BBB disruption produced small but significant dose-dependent pial arteriolar and venular dilations. During hyperosmolar BBB disruption, these pial arteriolar and venular dilations were not enhanced.



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  		Figure 3. Dose-related effects of IV milrinone on the diameter of pial arterioles (a) and venules (b) in rabbits with or without blood-brain barrier (BBB) opening. Each bar indicates percentage change in diameter (mean ± SD). * P < 0.05 compared with baseline (percentage change in diameter during IV infusion of 0.9% saline without BBB opening). NS = not significant.

 
When Evans blue was injected just after mannitol, its staining occurred on the mannitol-perfused side of the brain with all four rabbits. However, when it was injected 30 min after mannitol injection, obvious staining on the brain was not observed.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The major findings of the present study are that topical HANP induces vasodilation in pial arterioles, but not in pial venules. Systemic administration of HANP does not produce a significant change in pial vessels unless the BBB is disrupted, when it causes vasodilation in pial arterioles, but not in pial venules. Although systemic administration of HANP may not induce cerebral vasodilation under normal conditions, under pathological conditions in which the BBB is damaged, systemic HANP could cause a significant cerebral vasodilation. In contrast, milrinone induced a small but significant vasodilation in pial arterioles and venules under normal conditions, whether administered topically or IV, and hyperosmolar BBB disruption did not increase the pial vascular responses to IV milrinone.

Mammalian cardiac atrial myocytes possess secretory granules that contain a peptide, originally termed atrial natriuretic factor, with potent diuretic and natriuretic activity. An amino acid sequence has been synthesized, as HANP, for clinical use in heart-failure patients because it has both vasodilator and diuretic effects (4). Ishihara et al. (9) demonstrated that HANP, when given intraarterially or IV in dogs, dilated the renal artery more selectively than the vertebral, femoral, common carotid, and coronary arteries. They also found that in isolated canine arterial strips, HANP selectively relaxed K+-contracted renal arterial strips more than basilar, coronary, or femoral artery strips. Cyclic 3',5'-guanosine monophosphate has been proposed as the intracellular mediator of some atrial natriuretic peptide actions. Cyclic 3',5'-guanosine monophosphate accumulation and cyclic 3',5'-guanosine monophosphate-dependent protein kinase activation to atrial natriuretic peptide precede vascular relaxation (10). The effect of HANP on the cerebral microcirculation has not been defined. Its high molecular weight and water solubility suggest that HANP will not pass through the BBB under physiological conditions. Indeed, in the present study systemic administration of HANP did not induce any effects on pial arterioles under physiological conditions. Administration of HANP is a useful way of improving cardiac performance in patients during and after CPB (5). Although CPB itself may preserve the BBB (11), it is possible for the BBB to be disrupted or damaged when the host’s inflammatory mediators are activated—an event that can adversely affect capillary permeability (12,13). In addition, gaseous microemboli, which commonly occur during CPB (14), could alter the integrity of the BBB (15). In the present study, systemic HANP induced cerebral arteriolar dilation during hyperosmolar BBB disruption. Thus, systemic administration of HANP may affect the cerebral microcirculation under any circumstance in which the BBB is disrupted such as during and after CPB and after cardiopulmonary resuscitation (16,17).

Faison et al. (18) demonstrated that HANP is markedly selective in its ability to relax isolated rabbit arteries and veins. The aorta, renal, and mesenteric arteries and the facial vein were the most sensitive with the more distal arteries and most veins being relatively less responsive. In the present study, HANP did not cause pial venular dilation, even when it was applied topically or systemically with hyperosmolar BBB opening. Because most blood volume is contained in the venous compartment, it is possible that HANP would produce only a small increase in intracranial pressure (ICP) as a result of its comparatively minor effects on venules, even when the BBB is damaged. This powerful vasorelaxant selectivity of HANP between pial arterioles and venules may help to protect the brain from experiencing an increase in ICP.

Milrinone is a powerful inotrope and vasodilator because it increases cyclic 3',5'-adenosine monophosphate levels through inhibition of type III cyclic 3',5'-adenosine monophosphate specific phosphodiesterase in both cardiac and vascular smooth muscle. Increased cyclic 3',5'-adenosine monophosphate levels may produce smooth muscle relaxation by several mechanisms, either through protein kinase A or through a direct effect on vascular Ca2+, Mg2+-adenosine triphosphatase, or Na+, K+-adenosine triphosphatase activity (19,20). A previous report indicated that amrinone, another bipyridine derivative, did not have any effects on cerebral blood flow (21). However, Toda et al. (22) demonstrated that amrinone relaxed the isolated dog basilar and middle cerebral arteries, and that this relaxation did not involve the muscarinic, ß-adrenergic, histaminergic, adenosine-related, or prostaglandin-related mechanisms. Other reports indicated that milrinone was more potent as a vasorelaxant than amrinone, and that delayed cerebral ischemia resulting from vasospasm can be prevented by milrinone (23,24). Drexler et al. (25), using the radioactive microsphere technique, found that milrinone exerted regional vasodilator effects in a conscious rat model, the most prominent being in the coronary and cerebral circulations at a dose of 3 µg · kg-1 · min-1, without any alteration in central hemodynamics. The results of these various reports are consistent with our present findings. The clinical doses of 0.5 and 5 µg · kg-1 · min-1 of milrinone used in this study caused a small but significant increase in pial arteriolar diameter under both normal and BBB disruptive conditions. Although the vasodilator effects on cerebral pial vessels observed in the present study may lead to ICP increases, administration of milrinone during BBB disruption is not likely to increase the risk of a severe increase in ICP.

The differences in vascular responses between HANP and milrinone that is administered IV may be explained by BBB permeability, which could be related to molecular weight (HANP, 3080; milrinone, 211). Evans blue injected just after the mannitol injection caused extravasation in the cerebral hemisphere ipsilateral to injection. However, when Evans blue was injected 30 minutes after mannitol injection no obvious extravasation was observed. These results indicated that mannitol injection into the carotid artery causes temporary BBB disruption lasting less than 30 minutes. Cosolo et al. (8) showed that methotrexate remained in the brain 30 min after it was injected if it was injected before or up to 10 minutes after mannitol. Therefore we assumed that infusion of HANP for 30 minutes, which was started just after mannitol infusion, would still exert vasodilatory effects on pial arterioles at 30 minutes after mannitol infusion. However, milrinone, which has a lower molecular weight than HANP, would be expected to induce a different effect on pial vessels at 30 minutes after mannitol infusion. Thus we cannot deny completely that the present results might be modified if we evaluated the diameters of pial vessels at earlier times after mannitol infusion.

In conclusion, although HANP and milrinone each have a direct vasodilator effect on pial arterioles, their systemic administration at clinical doses could have different effects on pial vessels, and BBB disruptive conditions could alter the response of pial vessels to HANP, but not to milrinone. This difference should be considered when choosing a drug for heart failure in critically ill patients, such as those undergoing CPB or cardiopulmonary resuscitation, in whom BBB dysfunction may be present.


   Acknowledgments
 
Supported, in part, by Grant-in Aid for Scientific Research No. 11671489 and No. 13671570 from the Ministry of Education, Science and Culture, Japan.


   Footnotes
 
Presented, in part, at the 18th Brain Symposium, June 15-19, 1997, Baltimore, Maryland, and IARS 74th Clinical and Scientific Congress, March 10-14, 2000, in Honolulu, Hawaii.


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 Materials and Methods
 Results
 Discussion
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Accepted for publication March 28, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press