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(Stroke. 1996;27:134-139.)
© 1996 American Heart Association, Inc.

Articles

Ischemia Reduces CGRP-Induced Cerebral Vascular Dilation in Piglets

Thomas M. Louis, PhD; Wei Meng, MD; Ferenc Bari, PhD; Robert A. Errico, MD David W. Busija, PhD

From the Department of Anatomy and Cell Biology, East Carolina University, Medical School, Greenville (T.M.L.), and the Departments of Physiology and Pharmacology (W.M., D.W.B.) and Pediatrics (R.A.E.), Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC; and the Department of Physiology, Albert Szent-Györgyi Medical University, Szeged, Hungary (F.B.).

Correspondence to Thomas M. Louis, PhD, Department of Anatomy and Cell Biology, East Carolina University, Medical School, Greenville, NC 27858.

	Abstract

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Background and Purpose Effects of anoxic stress on cerebrovascular responses to calcitonin gene–related peptide (CGRP) have not been examined previously. We determined the effects of total global ischemia on cerebral arteriolar responses to CGRP in newborn pigs.

Methods Piglets were anesthetized and ventilated with a respirator. Pial arteriolar diameter was determined using a closed cranial window and intravital microscopy. Baseline arteriolar diameters ranged from 80 to 100 µm. Arteriolar responses to 10^-9 and 10^-8 mmol/L CGRP applied topically were determined before and 1, 2, and 4 hours after a 10-minute period of total global ischemia. Ischemia was caused by increasing intracranial pressure.

Results Before ischemia, CGRP dilated arterioles by 14±2% (n=6) and 24±3% (n=7) at 10^-9 and 10^-8 mmol/L, respectively. However, after ischemia, arteriolar responses to 10^-9 mmol/L CGRP were reduced at 1 hour to 4±1%, at 2 hours to 3±2%, and at 4 hours to 5±4% (P<.05 for all comparisons). Similarly, arteriolar responses to 10^-8 mmol/L CGRP were reduced to 5±2% at 1 hour, 5±2% at 2 hours, and 10±6% at 4 hours (P<.05 for all comparisons). In time control animals, arteriolar responses to CGRP did not change over time. In other animals, we examined effects of pretreatment with indomethacin (5 mg/kg IV) on ischemia-induced decreases in arteriolar responses to CGRP. Indomethacin administration did not preserve arteriolar dilation to CGRP at 1 hour after ischemia, but responses were normal at 2 hours.

Conclusions Total global ischemia leads to prolonged attenuated dilator responses of cerebral arterioles to CGRP. In addition, indomethacin treatment alters effects of ischemia on CGRP-induced dilation.

Key Words: cerebral arteries • indomethacin • oxygen radical • prostaglandins • vasodilation • pigs

	Introduction

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Calcitonin gene–related peptide (CGRP) is a potent dilator of cerebral resistance vessels,^{1 2 3} and it has access to cerebral blood vessels primarily from perivascular nerves originating from the trigeminal ganglia.^{4 5} The mode of arteriolar dilation in response to CGRP largely involves activation of ATP-sensitive K⁺ channels,⁶ although nitric oxide (NO)–dependent mechanisms also have been proposed.⁷ CGRP has been implicated in cerebrovascular responses to physiological and pathological stimuli. For example, CGRP promotes cerebrovascular dilation during cortical spreading depression⁸ or arterial hypotension.⁹ Furthermore, CGRP from the trigeminal nerve probably provides dilator influences to cerebral arterioles during seizures,¹⁰ arterial hypertension,¹¹ and ischemia.¹²

Because CGRP is one of the most potent cerebral vasodilators in humans¹³ as well as animals,^{1 2 3 6} this peptide has become a potential candidate for use as a therapeutic agent. Recently, pretreatment with intravenous CGRP before insult has been shown to limit the extent of brain damage after focal cerebral ischemia.¹⁴ Although exact mechanisms are unclear, it seems likely that protective actions of CGRP involve cerebral vasodilation. For CGRP to be useful clinically against cerebral ischemia, it must be effective if given after the onset of ischemia or other pathological conditions such as subarachnoid hemorrhage.¹⁵ However, cerebral vascular responses to exogenous CGRP after ischemia have not been examined. Cerebral vascular responsiveness may be altered, since anoxic stress has been shown to downregulate ATP-sensitive K⁺ channels¹⁶ and eliminate or attenuate NO-dependent responses.^{17 18}

The purpose of this study was to investigate the effects of ischemia on dilator responses of cerebral arterioles to topically applied CGRP. We tested the hypothesis that the ability of CGRP to dilate cerebral arterioles would be reduced when CGRP is administered after ischemia. Furthermore, we investigated the role of cyclooxygenase-derived radicals in altered cerebral vascular responses to CGRP. Arteriolar dilation to CGRP has been shown to be eliminated by agents that generate oxygen radicals.¹⁹ The primary source of oxygen radicals in piglet cortex with ischemia-reperfusion is via the cyclooxygenase pathway, and superoxide anion production is blocked by indomethacin pretreatment.²⁰ By itself, indomethacin administration does not alter cerebrovascular responses to CGRP.¹

	Materials and Methods

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Surgical Preparation
Experiments were carried out on newborn (1 to 7 days) pigs of either sex weighing 1 to 2 kg. All procedures were approved by the institution's animal care and use committee. The piglets were anesthetized with sodium thiopental (30 mg/kg IP) and then -chloralose (75 mg/kg IV). -Chloralose was administered as needed to maintain a stable level of anesthesia. The piglets were intubated and artificially ventilated. A femoral artery and vein were cannulated with PE-90 tubing. Arterial blood samples were taken regularly from the femoral artery to measure blood gases and pH. Levels of arterial blood pressure, gases, and pH were maintained within the normal physiological range. Each piglet's head was fixed in a stereotaxic apparatus, the scalp was cut, and the connective tissue over the parietal bone was removed. A craniectomy (19 mm in diameter) was made in the parietal bone. The dura was cut and reflected over the skull. A stainless steel and glass cranial window with three ports was put into the opening, sealed with bone wax, and cemented with superglue followed by two layers of dental acrylic. The closed window was filled with artificial cerebrospinal fluid (aCSF) that was warmed to 37°C and equilibrated with 6% O₂ and 6.5% O₂ in N₂.

Cerebral Ischemia-Reperfusion Injury
Cerebral ischemia-reperfusion injury²⁰ was produced using a hollow brass bolt implanted in the right parietal cranium 20 mm rostral to the cranial window. Immediately after placement of the cranial window, we drilled a hole in the skull with an electric drill with a toothless bit. A circular (diameter, 3 mm) piece of skull was removed without damaging the dura. The bolt was secured with superglue and dental acrylic. The hollow bolt allowed infusion of aCSF into the cranium to increase intracranial pressure, producing ischemia. After implantation of the window and the bolt, aCSF was allowed to equilibrate with the periarachnoid fluid under the window for 20 minutes. To induce total cerebral ischemia, aCSF was infused to maintain intracranial pressure approximately 15 mm Hg above mean arterial pressure. Venous blood was withdrawn as necessary to maintain mean arterial pressure near normal. This procedure results in a complete reduction of blood flow through the cortex. At the end of the 10-minute ischemia period, the infusion tube was clamped, and the intracranial pressure was allowed to return to atmospheric pressure.

The arterioles on the cerebral surface were observed under a microscope (Wild M36) equipped with a television camera (Panasonic) and a monitor (Panasonic). The diameter of the blood column in the arteriole was measured perpendicularly on the monitor with a video microscaler (IV-550, For-A Co).

Experimental Design
At the beginning of each experiment, the cranial window was flushed with aCSF several times, and arteriolar responses to CGRP (10^-9 and 10^-8 mmol/L) were determined. Then, piglets were divided into either sham or ischemia groups. In the sham group, the bolt was implanted but intracranial pressure was not increased. In the ischemia group, intracranial pressure was increased for 10 minutes. During the ischemic period, there was no blood flow through the pial vessels. In sham or ischemic animals, arteriolar responses to CGRP were tested at 1, 2, and 4 hours.

To assess the role of ATP-sensitive K⁺ channels in CGRP-induced vasodilation, we determined arteriolar responses to CGRP in the absence and presence of glibenclamide (10^-5 mmol/L) in another set of animals. Glibenclamide is an inhibitor of ATP-sensitive K⁺ channels.²¹ We have shown previously that this dose of glibenclamide is able to completely block arteriolar dilation to 10^-8 and 10^-6 mmol/L aprikalim (a specific inhibitor of ATP-sensitive K⁺ channels) but not to alter arteriolar responsiveness to severe arterial hypercapnia.²²

In another set of animals, we also examined the role of cyclooxygenase-derived radicals in altered responses to CGRP. Before ischemia, arteriolar responses to CGRP (10^-9, 10^-8, and 10^-7 mmol/L) were determined. Then, indomethacin (5 mg/kg IV) was given 20 minutes before ischemia. We have shown that superoxide anion production in piglet cortex during reperfusion is due to metabolism of arachidonic acid by cyclooxygenase and that this dose of indomethacin blocks superoxide anion production.²⁰ At 1 hour and 2 hours after 10 minutes of ischemia, arteriolar responses to CGRP were again determined.

Statistical Analysis
All values are expressed as mean±SEM. Where appropriate, data were analyzed with the paired t test or repeated-measures ANOVA. When the F value was significant, pairwise comparisons were made with the Student-Newman-Keuls test. A value of P<.05 was considered statistically significant.

	Results

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In both sham and ischemia groups, initial exposure to CGRP dilated arterioles in a dose-dependent fashion. In sham animals, arteriolar dilation to CGRP did not change over time (Table, Fig 1). Cerebral ischemia had minimal effects on control arteriolar diameter at 1 to 4 hours, and control diameters at various times were similar in the sham and ischemia groups. In contrast to sham animals, exposure to ischemia virtually abolished arteriolar dilation to CGRP for up to 4 hours (Table, Fig 2).

View this table: [in this window] [in a new window]   Table 1. Arteriolar Responses to Calcitonin Gene–Related Peptide

View larger version (42K): [in this window] [in a new window]   Figure 1. Bar graph shows percent change from control diameter during application of calcitonin gene–related peptide (CGRP) in sham animals. Values are mean±SEM for 8 animals. Arteriolar dilation to CGRP did not change over time.

View larger version (31K): [in this window] [in a new window]   Figure 2. Bar graph shows percent change from control diameter during application of calcitonin gene–related peptide (CGRP) before and after ischemia. Values are mean±SEM for 6 animals at 10-9 mmol/L and 7 animals at 10-8 mmol/L. *P<.05 compared with response for that dose before ischemia.

Administration of glibenclamide did not alter resting arteriolar diameter (112±11 µm before and 110±12 µm with glibenclamide; n=4). Coadministration of glibenclamide reduced arteriolar dilation to CGRP at both 10^-8 and 10^-7 mmol/L (Fig 3).

View larger version (34K): [in this window] [in a new window]   Figure 3. Bar graph shows percent reduction in arteriolar dilation to calcitonin gene–related peptide (CGRP) with coadministration of 10-5 mmol/L glibenclamide (GLIB). Values are mean±SEM for 4 animals. *P<.05 compared with response in the absence of glibenclamide.

Indomethacin pretreatment had minimal effects on baseline arteriolar dilation. Arteriolar diameter was 95±3 µm before the first exposure to CGRP and was 92±9 µm after indomethacin treatment and before ischemia. Indomethacin given before ischemia failed to preserve normal responsiveness to CGRP at 1 hour (Fig 4). In contrast to responses at 1 hour, arteriolar responses to CGRP in indomethacin-treated animals at 2 hours after ischemia were not different from preischemia responses (Fig 5). Each of the animals that showed normal responsiveness at 2 hours had shown reduced arteriolar responsiveness to CGRP at 1 hour. For these five animals, arterioles dilated at 1 hour by 4±1% at 10^-9 mmol/L, 5±2% at 10^-8 mmol/L, and 12±3% at 10^-7 mmol/L (P<.05 compared with baseline for all comparisons).

View larger version (27K): [in this window] [in a new window]   Figure 4. Bar graph shows percent arteriolar dilation to calcitonin gene–related peptide (CGRP) before ischemia and 1 hour after ischemia in indomethacin-treated animals. Values are mean±SEM for 10 animals. *P<.05 compared with corresponding value.

View larger version (25K): [in this window] [in a new window]   Figure 5. Bar graph shows percent arteriolar dilation to calcitonin gene–related peptide (CGRP) before ischemia and 2 hours after ischemia in animals pretreated with indomethacin. Values are mean±SEM for 5 animals. There were no significant differences in arteriolar responses before and after ischemia.

	Discussion

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There are three major findings from these experiments. First, CGRP-induced cerebrovascular dilation is markedly reduced for up to 4 hours after ischemia. Second, activation of ATP-sensitive K⁺ channels is a major mechanism of CGRP-induced dilation of pial arterioles in piglets. Third, indomethacin alters effects of ischemia on arteriolar dilation to CGRP.

Cerebrovascular Effects of CGRP
CGRP is one of the most potent dilator stimuli in the cerebral circulation.^{1 2 3 6 13} Exogenous CGRP dilates pial arterioles in a dose-dependent manner, and the mode of dilation, at least in piglets, is independent of major effects of prostaglandins and NO.¹ Normal access of CGRP to cerebrovascular smooth muscle is primarily via release from perivascular sensory fibers, which originate from the ophthalmic branch of the trigeminal nerve.^{4 5} Several studies indicate that CGRP exerts important dilator effects on cerebral resistance vessels during a number of conditions. For example, cerebral arteriolar dilation during cortical spreading depression is mediated in part by endogenous release of CGRP.⁸ In addition, CGRP appears to participate in cerebrovascular dilation during arterial hypotension.⁹ Furthermore, trigeminal ganglionectomy, which removes effects of CGRP as well as other peptides such as substance P and neurokinin A from cerebral vessels, also influences vascular tone during arterial hypertension, seizure activity, and ischemia.^{10 11 12} Thus, endogenous CGRP is an important factor to consider in cerebral vascular control.

Role of ATP-Sensitive K⁺ Channels in CGRP Responses
Several recent reports suggest that activation of ATP-sensitive K⁺ channels is an important mechanism of vasodilation in cerebral as well as peripheral resistance vessels. Selective agonists of ATP-sensitive K⁺ channels such as aprikalim promote cerebral arteriolar dilation,^{23 24} and arteriolar dilation is blocked by glibenclamide.²⁴ Glibenclamide selectively inhibits the opening of ATP-gated K⁺ channels.²¹ In addition, glibenclamide has been shown to attenuate arteriolar dilation to CGRP. For example, Kitazono et al⁶ have shown that glibenclamide inhibits the dilatory response to CGRP by 70% and 40% at 10^-9 and 10^-8 mmol/L, respectively. In our experiments, we showed that glibenclamide inhibited dilation to CGRP by more than 80% at 10^-8 mmol/L and by approximately 60% at 10^-7 mmol/L. Taken together, these results indicate that activation of ATP-sensitive K⁺ channels is a major component of CGRP-induced cerebral vascular dilation. The remaining vasodilation, especially at higher doses of CGRP, may be mediated (depending on the species examined) by other cyclic AMP–dependent mechanisms not involving ATP-sensitive K⁺ channels⁶ or perhaps by cyclic GMP–dependent mechanisms.^{6 7}

Responses to CGRP After Ischemia
There have been few systematic studies of cerebrovascular responses to dilator neurotransmitters during the immediate postischemic period. In general, arteriolar responses are either transiently affected or not changed at all by ischemia. For example, pial arteriolar dilation to isoproterenol²⁵ and sodium nitroprusside²⁶ is intact in piglets after ischemia. On the other hand, arteriolar dilator responses to N-methyl-D-aspartate^{17 26} in piglets and acetylcholine¹⁸ in cats are reduced or reversed, respectively, after anoxic stress, but normal responsiveness returns within 2 to 4 hours. Both N-methyl-D-aspartate and acetylcholine dilate via mechanisms involving synthesis and actions of NO, and altered vascular responsiveness is due to effects of oxygen radicals.^{17 18 27 28} Our present findings are unique in that CGRP-induced dilation is almost completely eliminated for up to 4 hours after ischemia. Elimination of arteriolar dilation to CGRP after ischemia may be due to factors such as dysfunction or uncoupling of CGRP receptors, disruption of second-messenger systems,¹⁹ decrease in numbers of ATP-sensitive K⁺ channels,²² and/or inactivation of ATP-sensitive K⁺ channels.¹⁶

Potential agents of vascular dysfunction to CGRP after ischemia could involve oxygen radicals such as superoxide anion. We have shown that superoxide anion is produced in large quantities in cerebral cortex after ischemia in piglets and that indomethacin pretreatment blocks superoxide anion production during these conditions.²⁰ This latter finding is consistent with the view that oxygen radical production in cerebral cortex occurs predominantly via metabolism of arachidonic acid by cyclooxygenase.^{20 29 30} In the present study, we found that administration of indomethacin before ischemia was unable to preserve normal arteriolar responsiveness to CGRP at 1 hour but was able to restore dilation to preischemic values at 2 hours. These results are somewhat consistent with the findings of Kontos and Wei,¹⁹ who showed that oxygen radicals, possibly superoxide anion, were able to eliminate cerebral arteriolar dilation to CGRP.

Implications
There has been intense interest in the development of therapeutic agents that can improve outcome in patients with stroke, perhaps by selectively dilating cerebral resistance vessels. CGRP, because of its potent dilator effects, might be one such agent. Recently, Holland et al¹⁴ showed that intravenous CGRP reduces brain injury in a rat model of focal cerebral ischemia if given before insult. However, for CGRP to be a truly useful therapeutic agent in humans, it must be effective at times after the onset of cerebral ischemia or stroke because it is at this time that patients seek treatment. Our results indicate that CGRP has minimal arteriolar dilator effects if given after only 10 minutes of ischemic stress. It is possible that CGRP administration could dilate collateral blood vessels in adjacent healthy brain after stroke and thus improve blood flow to ischemic tissue. However, arterioles in the areas directly affected by stroke may be minimally responsive to CGRP. In addition, our results show that relatively large amounts of CGRP applied to the brain surface before ischemia fail to preserve arteriolar dilator responses for up to 4 hours after ischemia.

Summary
Our findings indicate that 10 minutes of ischemic stress is sufficient to virtually eliminate cerebral arteriolar dilation to CGRP for up to 4 hours. The mechanism of impaired CGRP-induced vasodilation is unclear but could involve effects of oxygen radicals. Possible sites of dysfunction could be at the level of CGRP receptors, second-messenger systems, or ATP-sensitive K⁺ channels in cerebral vascular smooth muscle.

	Acknowledgments

 
This study was supported by grants HL-30260, HL-46558, and HL-50587 from the National Institutes of Health. Merck, Sharpe, and Dohme kindly provided the indomethacin.

Received August 30, 1995; revision received October 13, 1995; accepted October 13, 1995.

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