Vertebral Artery Infusions Research Articles

Intra-arterial papaverine for the treatment of cerebral vasospasm following aneurysmal subarachnoid hemorrhage

BACKGROUND Intra-arterial papaverine (IAP) has been described as a treatment for cerebral vasospasm refractory to standard therapy. METHODS We report a series of 15 consecutive patients with aneurysmal subarachnoid hemorrhage in which IAP was employed for the treatment of symptomatic vasospasm. All patients exhibited delayed ischemic neurologic deficits, focal cerebral hypoperfusion on stable xenon-enhanced computerized tomography cerebral blood flow studies, and angiographically defined arterial narrowing. Papaverine was infused into 32 arteries on 23 occasions. Six patients required multiple treatments between 1 and 8 days apart. In five instances, IAP was combined with angioplasty. RESULTS Angiographically defined vasospasm was at least partially reversed immediately following treatment on 18 of 23 occasions. The associated clinical improvement was major on 6 occasions, and either minor or none on 17. Post-treatment cerebral blood flow was assessed on 13 occasions and showed improvement in previously ischemic areas on six occasions and no improvement on seven. Complications were encountered on four occasions. Systemic hypotension and transient brain-stem depression were seen with vertebral artery infusions; a generalized seizure and paradoxical aggravation of vasospasm resulting in hemispheric infarction occurred with internal carotid artery infusions. CONCLUSIONS Intra-arterial papaverine resulted in reversal of arterial narrowing in the majority of cases (78%). However, this angiographic improvement was associated with cerebral blood flow augmentation in only 46% of cases analyzed, and major clinical improvement in 26%.

Central and peripheral vasopressin interact differently with sympathetic nervous system and renin-angiotensin system in renal hypertensive rabbits.

This study was designed to elucidate how central and peripheral arginine vasopressin (AVP) interacts with the sympathetic nervous system and the renin-angiotensin system to maintain blood pressure in two-kidney, one-clip hypertensive rabbits. We recorded renal sympathetic nerve activity (RSNA) in the conscious state as an index of sympathetic nervous system function. The changes in mean arterial pressure, heart rate, and RSNA were recorded continuously for 60 minutes after intravenous administrations of captopril (2.5 mg/kg) and nicardipine (3.2 micrograms.kg-1.min-1) in eight identical rabbits. Despite equivalent reductions in mean arterial pressure (10 +/- 1 mm Hg), the increase in RSNA was significantly larger with captopril than that with nicardipine, and the plasma concentration of AVP was elevated (from 100% to 255 +/- 24%) with captopril. Mean arterial pressure was reduced, and RSNA was increased by intravenous infusion of AVP antagonist d(CH2)5Tyr(Me)AVP (n = 8), whereas vertebral artery infusion of the antagonist (n = 6) did not change RSNA. During central and peripheral infusions of AVP antagonist, RSNA was exaggerated by blood pressure reduction with nicardipine as well as with captopril. Increases in RSNA induced by captopril and nicardipine were larger by central infusion of AVP antagonist than by intravenous infusion. The decrease in mean arterial pressure by captopril (30 +/- 4 mm Hg) in eight sinoaortic-denervated hypertensive rabbits was larger than that in hypertensive rabbits with intact baroreflex. These data suggest that compensatory activation of RSNA was revealed by central and peripheral attenuation of AVP and that the sympathetic nervous system became the most important mechanism for blood pressure maintenance in the absence of AVP. The interaction of AVP with the sympathetic nervous system may be independent of the state of the renin-angiotensin system, since the exaggeration of RSNA by AVP antagonist was qualitatively the same with nicardipine as with captopril. In conscious renal-hypertensive rabbits, AVP in the central nervous system played a substantial role when blood pressure was reduced, although it did not contribute to blood pressure maintenance in the basal condition.

Endothelin acts in feline and canine cerebral arteries from the adventitial side.

We investigated the in vivo vasoconstrictor effect of endothelin, a recently characterized vasoconstrictor peptide from vascular endothelium, in the basilar arteries of five cats and five dogs. Basilar artery caliber was angiographically measured under anesthesia before (control) and after either vertebral artery infusion or cisternal injection of the peptide. In cats, 5-500 pmol endothelin induced a dose-dependent basilar artery contraction in vivo when injected intracisternally; within 3 minutes after injection of 500 pmol endothelin, basilar artery caliber was decreased by 73 +/- 4% compared with control diameter before injection. The vasoconstriction was extremely long-lasting; no significant recovery of basilar artery caliber was observed for up to 2 hours after injection. In contrast, infusion of up to 3,000 pmol endothelin into the vertebral artery had no appreciable effect on basilar artery caliber. Similar results were obtained in dogs; vasoconstriction was maintained for as long as 12 hours. Our observations suggest that endothelin acts in cerebral vessels from the adventitial side, not from the luminal side, possibly due to the presence of the blood-arterial wall barrier. The long-lasting nature of endothelin-induced constriction of the cerebral arteries in vivo suggests that the peptide might be involved in the pathogenesis of cerebral vasospasm.

Central effect of angiotensin II on baroreflex regulation in conscious rabbits

Central effects of angiotensin II (ANG II) on arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) were examined in conscious rabbits. Intravenous infusions of ANG II (5-320 ng.kg-1.min-1) significantly reduced the baroreflex inhibition of HR compared with phenylephrine (PE) (0.5-16 micrograms.kg-1.min-1), whereas reflex inhibition of RSNA was unaltered. Background intravenous infusions of ANG II did not alter the baroreflex responses of RSNA nor HR to increases (with PE) or decreases in mean arterial pressure (with nitroglycerin or inferior vena cava occluder). When ANG II was infused into the vertebral artery (VA) the integrated pressor response was greater than intravenous infusions. Progressive VA infusions of ANG II resulted in a significantly blunted baroreflex inhibition of HR compared with intravenous infusions, whereas the reflex inhibition of RSNA was identical between VA and intravenous infusions. These results suggest that ANG II produces central pressor effects via a hindbrain site and reduces baroreflex inhibition of HR without altering baroreflex inhibition of RSNA.

Phase I study of intracarotid PCNU.

A phase I study of the intracarotid administration of PCNU was conducted in patients with intracerebral tumors recurring after cranial radiation. Seventeen patients were treated including 16 with recurrent gliomas or glioblastomas and 1 with recurrent brain metastases from adenocarcinoma of the lung. An additional patient received a vertebral artery infusion of PCNU for a recurrent glioblastoma. Seven of 17 patients receiving intracarotid PCNU responded for a response rate of 41%. If only evaluable patients with gliomas are considered, the response rate was 44%. Tumor grade at time of initial diagnosis, exposure to prior chemotherapy, and dose of PCNU did not appear to have a major impact on response rate. Zubrod performance status 3 patients had a lower response rate (25%) than did patients with performance status 1 or 2 (response rate 63%). Thrombocytopenia and reversible central nervous system toxicity were dose limiting at a PCNU dose of 110 mg/m2. Two patients had possible permanent central nervous system toxicity. Three patients had permanent ipsilateral visual impairment, including one at the lowest dose used into the carotid artery (60 mg/m2). Orbital pain appeared to be substantially less than that seen with intracarotid BCNU but headaches may have been somewhat more common. The single patient receiving a vertebral artery infusion developed marked headaches and restlessness after receiving 25 mg/m2 of a planned 75 mg/m2 treatment into the vertebral artery and the treatment had to be discontinued. Symptoms were rapidly reversible upon stopping the medication. Our overall impression is that intracarotid PCNU causes less ocular pain but more transient central nervous system toxicity than does intracarotid BCNU.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined Intraarterial and Systemic Chemotherapy for Intracerebral Tumors

Twenty-six patients with intracerebral tumors (predominantly gliomas) were treated with intraarterial BCNU, VM-26, and cisplatin combined with the systemic administration of VM-26, methotrexate, vincristine, bleomycin, and procarbazine. Oral glycerol was given before i.v. VM-26. Twelve patients responded (46% of all patients and 63% of the fully evaluable patients). The response rate for gliomas was 50% if all patients were considered and 71% if only fully evaluable patients were considered. The response rate did not seem to be affected by glioma grade, prior chemotherapy, or pretreatment performance status. Median time to tumor progression for responders was 19 weeks. Median survival from initiation of treatment was 21 weeks for evaluable patients and 17 weeks for all patients. Median survival from initial diagnosis was 55 weeks. Myelosuppression was dose-limiting for the systemic chemotherapy. Reversible neurological toxicity was common, but tolerable. One patient developed ipsilateral blindness, and two patients developed prolonged neurological toxicity. Pulmonary toxicity was also seen. Vertebral artery infusions proved feasible, although difficult and more toxic than carotid infusions. Overall, this regimen was not more active than the intraarterial combination of BCNU, VM-26, and cisplatin without the systemic chemotherapy. Further studies of more intensive intracarotid therapy combined with different systemic drugs are being initiated.

Vagal involvement in the pressor responses to cranial artery infusions of bradykinin in anaesthetised greyhounds

In anaesthetised greyhounds, vertebral and carotid artery infusions of bradykinin increased blood pressure whereas intravenous infusions caused a decrease. With each route of administration, heart rate and cardiac output increased while total peripheral resistance fell. With cranial artery infusions, the consecutive pretreatments of propanolol, phentolamine and vagal cooling resulted in a progressive reduction in the heart rate responses and conversion of the pressor to depressor responses. The responses to intravenous infusions of bradykinin were little changed. In contrast, when the initial pretreatment was interruption of vagal transmission, cranial artery infusions of bradykinin were at once depressor and the depressor response to intravenous infusions immediately enhanced. Subsequent propranolol and phentolamine were without further effect on the blood pressure responses although propranolol did reduce the tachycardia responses. It is concluded that while the tachycardia induced by cranial artery infusions of bradykinin has both cardiac sympathetic and vagal withdrawal components, the hypertensive action is mediated by an increase in cardiac output due largely to withdrawal of cardiac vagal tone.

Role of prostaglandins and the areas postrema in the central pressor action of bradykinin

Vertebral and carotid artery infusions of bradykinin increased blood pressure and heart rate in anaesthetised greyhounds. Indomethacin pretreatment abolished the pressor response to vertebral infusion and reduced that to carotid infusion. Areas postrema ablation abolished the pressor response to bradykinin with both routes of administration. The tachycardia responses to cranial artery infusions and the entire cardiovascular response to intravenous infusion were unaffected by either treatment. It is concluded that intact areas postrema and normal prostaglandin synthesis are essential for the full expression of the central pressor action of bradykinin.

Intracarotid Chemotherapy with a Combination of 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU), cis-Diaminedichloroplatinum (Cisplatin), and 4'-O-Demethyl-1-O-(4,6-O-2-thenylidene-β-D-glucopyranosyl)epipodophyllotoxin (VM-26) in the Treatment of Primary and Metastatic Brain Tumors

Abstract Thirty-seven patients with intracranial primary or metastatic tumors were treated with an intraarterial combination of BCNU, cisplatin, and VM-26 to determine the efficacy, toxicity, and maximal tolerated doses for the combination. A transfemoral fluoroscopic approach was used to catheterize temporarily the internal carotid or vertebral artery. Thirteen of 19 (68%) evaluable primary brain tumors and 9 of 16 (56%) evaluable brain metastases responded. The response rate was lower in patients previously treated with both cranial irradiation and i.v. chemotherapy than in patients less heavily pretreated (54% vs. 82%), although even patients previously treated i.v. with all three of the study drugs responded. All five patients with both extracranial and intracranial evaluable tumor deposits experienced a greater response of their intracranial than of their extracranial tumor. Ipsilateral retinal and neurological toxicity were dose-limiting, with major toxicity (permanent decreased vision or hemiparesis) occurring in five of nine (56%) patients receiving doses of BCNU ≥ 100 mg/m2, plus cisplatin, 60 mg/m2, plus VM-26, 175 mg/m2. Only 9% of the patients treated with a lower VM-26 dose developed permanent severe toxicity, and the doses that we now recommend are: BCNU, 100 mg/m2; cisplatin, 60 mg/m2; and VM-26, 150 mg/m2. The response rate was also dose-related (100% at the highest doses tested vs. 57% at the lower doses). Fully reversible toxicity was also seen, including transient decrease in ipsilateral visual acuity (11%), transient hemiparesis or hemianesthesia (5%), transient increased intracranial pressure (5%), mild ototoxicity (3%), mild to moderate vomiting (80%), severe periorbital pain and erythema during BCNU infusion (94%), and myelosuppression (30%). Vertebral artery infusion must be performed with great caution because infusions of BCNU and VM-26 (but not of cisplatin) were associated with marked but rapidly reversible somnolence and potentially life-threatening cardiac and respiratory depression. No cardiorespiratory depression was seen with carotid artery infusions. The intraarterial infusion of this three-drug regimen is quite effective in reducing the size of the tumor as seen on the computed tomographic scan in this poor prognosis group of patients, but is also potentially quite toxic. We are now initiating other studies adding i.v. drugs to our intracarotid combination.

Effect of vertebral artery infusions of oxytocin on plasma vasopressin concentration, plasma renin activity, blood pressure and heart rate and their responses to hemorrhage.

Infusion of oxytocin into one vertebral artery of anesthetized dogs did not alter plasma vasopressin concentration, blood pressure or heart rate. However, there was a significant (p less than 0.01) increase in plasma renin activity (PRA; delta = 7.6 +/- 2.3 ng/ml X h). A 35% hemorrhage caused blood pressure to fall by 9.4 +/- 4.0 mm Hg (p less than 0.01) and PRA to rise by 8.8 +/- 2.7 ng/ml X h (p less than 0.05). In 8 dogs that were subjected to a similar hemorrhage and that also received an intravertebral infusion of oxytocin, blood pressure was maintained and PRA increased by 14 +/- 4.3 ng/ml X h (p less than 0.05). Heart rate and plasma vasopressin responses were similar in both hemorrhage groups. The results indicate that oxytocin prevented the fall in blood pressure associated with a hemorrhage, possibly by increasing renin release.

Arginine vasopressin modulates the central action of angiotensin II in the dog.

Endogenous vasopressin may interact with central autonomic nervous system factors in the regulation of cardiovascular function. In 25 morphine/chloralose-anesthetized dogs, we studied the magnitude of the pressor response produced by an infusion of angiotensin II (AII) into the vertebral arteries (VA), before and after intracisternal (n = 10), intravertebral (n = 9), or intravenous (n = 6) administration of a competitive antagonist of arginine vasopressin (AVP) [d(CH2)5Tyr(Me) AVP]. The dose response curve to vertebral artery infusion of AII (range 2-20 ng/kg/min) was significantly (p less than 0.05) shifted to the right of control after injection of the AVP antagonist (10 micrograms/kg) into the cisterna magna; the ED at 20 mm Hg being almost double after central AVP blockade. This effect of AVP blockade was confined only to the cardiovascular response mediated by AII via the vertebral arteries. When pressor doses of AII were injected into either a vein (i.v.) or the cisterna magna of these same dogs, the increases in mean blood pressure were the same before and after AVP antagonist treatment. In another group of anesthetized dogs, we investigated whether the reduced reactivity to intravertebral AII could be duplicated by giving the AVP antagonist either via the vertebral artery or i.v. Only the cisterna magna route was effective in causing a blunting of the pressor response to vertebral artery AII. These data demonstrate a previously unknown interaction between vasopressin and the centrally mediated pressor response to intravertebral AII.

Intraarterial cis-platinum chemotherapy for patients with primary and metastatic brain tumors.

A total of 49 patients were treated using intraarterial cis-platinum infusions at a dose of 100 mg/m2. The patients were separated into three groups. There were 13 patients with metastatic tumors, 10 with recurrent malignant gliomas, and 22 patients with high-grade gliomas who received intraarterial cis-platinum as part of an adjuvant program. In addition, four nongliomatous primary brain tumors were treated in this fashion. Cis-platinum was filtered immediately prior to intraarterial infusion using a 0.22-micron filter. Response to treatment was evaluated by follow-up CAT scans and neurologic examinations. There were three complete and eight partial responses in metastatic tumors, and eight partial responses in recurrent gliomas. The median survival was 19 weeks for patients with metastatic disease, and 16 weeks for patients with recurrent gliomas. Those high-grade glioma patients who received intraarterial cis-platinum as adjuvant chemotherapy along with CCNU and radiation therapy had a projected median survival of 91+ weeks. Toxicity from intraarterial cis-platinum following drug filtration was markedly reduced when compared with previous reports. Only five patients experiencing visual or central nervous system toxicity utilizing filtered cis-platinum and no radiographic or histopathologic evidence of central nervous system toxicity was observed. Bilateral deafness was observed following vertebral artery infusion in both patients treated in this manner and thus vertebral artery infusions should be avoided. Systemic toxicity was mild. Intracarotid infusion is a safe, well-tolerated delivery system for filtered cis-platinum with a high response rate for patients with both metastatic and primary malignant brain tumors.

Phase II study--intra-arterial BCNU therapy for metastatic brain tumors.

Thirty-one patients with metastatic brain tumors (MBT) from lung cancer and ten patients with MBT from melanoma received BCNU, 100 mg/m2, every four weeks by intracarotid and/or vertebral artery infusion into each involved site. Twenty-five patients with lung cancer and all melanoma patients are currently evaluable. Twelve patients with lung cancer had complete and partial responses lasting from 1 to 14 months. Four of them with the histologic diagnosis of small cell carcinoma, one with large cell carcinoma and one with squamous cell carcinoma showed complete response. None of the patients with melanoma MBT experienced any response. All of the patients had periorbital erythralgia and/or occipital pain during the infusion. Four patients manifested mild focal seizures during the infusion or 6 to 24 hours after the treatment. Transient confusion with disorientation was observed in two patients 4 and 24 hours, respectively, after a BCNU infusion. Two patients developed reversible thrombocytopenia after the fifth course of the IA chemotherapy. Median survival of patients with MBT from lung carcinoma was 4 months, with two of them still alive at 10 and 14 months, respectively. Only one patients of the 25 with lung carcinoma died from MBT. Failure to control the primary disease resulted in the deaths of a vast majority of the patients.

Modulation of the baroreceptor reflex by angiotensin II and other vasoactive drugs in anaesthetized greyhounds.

1. The effects of vascular infusions of acetylcholine, angiotensin II, noradrenaline and prostaglandin F2 alpha on the baroreceptor reflex were studied in the anaesthetized greyhound. 2. Vertebral artery infusions of low doses of angiotensin II, but not of acetylcholine or prostaglandin F2 alpha, resulted in a significant reduction in the depressor response to carotid sinus nerve stimulation. 3. The increases in blood pressure and heart rate in response to bilateral carotid artery occlusion were not significantly changes during vertebral artery infusions of acetylcholine, angiotensin II or prostaglandin F2 alpha. 4. The increases in blood pressure in response to intravenous infusions of noradrenaline were significantly enhanced during vertebral artery infusions of acetylcholine and angiotensin II, but not of prostaglandin F2 alpha. The bradycardia during noradrenaline infusions was significantly enhanced by angiotensin II alone. 5. The depressor response to carotid sinus nerve stimulation was significantly reduced during intravenous infusions of both noradrenaline and angiotensin II. 6. It is considered that although angiotensin II can be shown to have a specific central action to attenuate the response to carotid sinus nerve stimulation, the role of this action in the complete baroreceptor reflex is unproven.

Central action of angiotensin and hypertension--increased central vasomotor outflow by angiotensin.

Sympathetic nerve activities in chloralose-anesthetized dogs were recorded directly during infusions of angiotensin into vertebral artery and femoral vein. 1. With vertebral artery infusion of angiotensin arterial pressure increased to 27 ± 11.1 mmHg and pressure rising began 20 ± 6.6 seconds after starting the infusion. Intravenous infusion of the same doses of angiotensin induced arterial pres-sure rise of 10 ± 6.6 mmHg and its onset was 68 ± 29.8 seconds. 2. Rise in arterial pressure was associated with initial augmentation of nerve activity in splanchnic and renal nerves. Cardiac nerve activity was not increased. 3. During arterial pressure was maintained at a higher level, a characteristic change in nerve activity was that rhythmical discharges in renal nerve activity disappeared completely and small non-rhythmical activity occurred instead, while the large bursts of discharges in splanchnic nerve activity never disappeared. 4. The pressor response to angiotensin was inhibited by pretreatment with guanethidine, but not with atropin. The results suggest that angiotensin acts on central nervous system to increase central sympathetic outflow in splanchnic nerves, resulting in a rise in arterial pressure.

Cardiovascular responses to carotid and vertebral artery infusions of propranolol.

The cardiovascular effects of intracarotid and intravertebral injections of propranolol were studied in open-chest anaesthetized dogs. After injection of 0.1 mg/kg propranolol into the common or internal carotid artery, a decrease in blood pressure started after a latent period of 2–3 sec. There was a slight but not significant decrease in heart rate, but no change in aortic flow or myocardial contractile force. Injection of propranolol into the vertebral artery induced a decrease in blood pressure after a latent period of 3–4 sec. By contrast, injection of the drug into the femoral artery caused a decrease in blood pressure only after a latent period of 7–8 sec. The injection of propranolol proximal or distal to the carotid bifurcation – that is, proximal or distal to the carotid chemo- and baro-receptors – did not change the magnitude or latent period of the pressure drop. We conclude that propranolol acts on some structure or structures in the central nervous system within the area of distribution of the carotid and/or vertebral arteries, and that this effect contributes to its hypotensive action. The carotid chemo- and baro-receptors apparently play no part in the decrease in blood pressure induced by the drug.

A hypertensive response to infusion of prostaglandin F2α into the vertebral artery of the conscious dog

Prostaglandin F2α can increase blood pressure acutely by an action on the central nervous system in the anesthetized dog. The present study was undertaken to determine whether a hypertensive response could be obtained from continuous infusion of prostaglandin F2α into the vertebral arteries of conscious dogs previously prepared with indwelling catheters. Continuous vertebral artery infusions of prostaglandin F2α (4–40 ng/kg per min) significantly increased mean arterial pressure by 20 mm Hg during infusions lasting 2 hr. Mean arterial pressures also were increased during infusions into the vertebral artery lasting 24 hr. Heart rates were not significantly changed. These data suggest that prostaglandin F2α, by activating areas in the distribution of the vertebral artery, can elevate arterial pressure in the conscious dog.

Chronic Hypertension Elicited by Infusion of Angiotensin into Vertebral Arteries of Unanaesthetized Dogs

1. Synthetic angiotensin II was infused chronically through catheters implanted into a vertebral artery and an external jugular vein of unanaesthetized dogs. Arterial pressure was recorded daily from an indwelling catheter in the abdominal aorta before, during and after the infusions. 2. Infusion of angiotensin 1 μg kg−1 day−1 into a vertebral artery caused mean arterial pressure to increase by an average of 12 mmHg in five dogs, and the rise was sustained throughout the infusion period of 7 days in all dogs. 3. When the infusion rate of angiotensin was increased to 10 μg kg−1 day−1, arterial pressure during vertebral artery infusion rose initially to a slightly greater extent but decreased at the end of the infusion, indicating tachyphylaxis. 4. During infusion of angiotensin into the vertebral circulation, arterial pressure rose rather than fell during sleep; awakening was accompanied by sharp fall in pressure. 5. It is concluded that there is an area in the central nervous system responsive to angiotensin that can cause a sustained rise in arterial pressure.

The site of cardiovascular action of angiotensin II in the brain.

1. The site of action of vertebral artery infusions of angiotensin was studied in the chloralose-anaesthetized greyhound. 2. The cardiovascular response to vertebral artery infusion of angiotensin (0·25–2·0 ng kg−1 min−1) was not reduced by clamping the basilar artery between the pons and the pyramidal decussation. There was no response to infusion of angiotensin through a catheter inserted in a rostral direction into the basilar artery above the clamp. The site of action must therefore lie caudal to the pons. 3. Transection of the spinal cord at the first cervical segment did not abolish the response to vertebral artery infusions, which was still mediated by the vagus nerve and abolished by subsequent vagotomy. The site of action must therefore lie rostral to the cervical cord. 4. Local infusions of angiotensin into the small arteries supplying the medulla produced a response similar to that obtained with vertebral artery infusion of angiotensin. 5. These results indicate that the site responsible for these central effects of angiotensin lies in the medulla.

Cardiovascular effects of angiotensin mediated by the central nervous system of the rabbit.

In rabbits, injection of angiotensin II into the lateral cerebral ventricle caused a rise of blood pressure, bradycardia, and tachypnoea. Vertebral artery infusions of angiotensin caused tachycardia and a larger increase in blood pressure than the same dose infused intravenously. Angiotensin produces cardiovascular effects by activation of the central nervous system and one site of action is within the area of distribution of the vertebral artery.