Monkey Basilar Artery Research Articles

Effects of a nitric oxide donor on and correlation of changes in cyclic nucleotide levels with experimental vasospasm.

Vasospasm after subarachnoid hemorrhage (SAH) may result from hemoglobin-mediated removal of nitric oxide (NO) from the arterial wall. We tested the ability of the long-acting, water-soluble, NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-1,2-diolate (DETA/NO), delivered via continuous intracisternal infusion, to prevent vasospasm in a nonhuman primate model of SAH. First, vasorelaxation in response to DETA/NO was characterized in vitro by using monkey basilar artery rings under isometric tension. Next, monkeys were randomized to undergo angiography, unilateral SAH, and no treatment (SAH only, n = 4) or treatment with DETA/NO (1 mmol/L, 12 ml/d, n = 4) or decomposed DETA/NO (at the same dose, n = 4). Vasospasm was assessed by angiography, which was performed on Day 0 and Day 7. Levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP) were measured in cerebral arteries on Day 7. DETA/NO produced significant relaxation of monkey arteries in vitro, which reached a maximum at concentrations of 10(-5) mol/L. In monkeys, angiography demonstrated significant vasospasm of the right intradural cerebral arteries in all three groups, with no significant difference in vasospasm among the groups (P > 0.05, analysis of variance). The ratios of cGMP or cyclic adenosine monophosphate levels in the right and left middle cerebral arteries were not different among the groups (P > 0.05, analysis of variance). There was no significant correlation between arterial cGMP contents and the severity of vasospasm. DETA/NO did not prevent vasospasm. There was no correlation between the severity of vasospasm and cyclic adenosine monophosphate and cGMP levels in the cerebral arteries. These results suggest that events downstream of cyclic nucleotides may be abnormal during vasospasm.

Subarachnoid hemorrhage as a cause of an adaptive response in cerebral arteries

It is not known whether the factors responsible for vasospasm after subarachnoid hemorrhage (SAH) cause the cerebral arteries to be narrowed independent of the subarachnoid blood clot or whether the continued presence of clot is required for the entire time of vasospasm. The authors undertook the present study to investigate this issue. To distinguish between these possibilities, bilateral SAH was induced in monkeys. The diameters of the monkeys' cerebral arteries were measured on angiograms obtained on Days 0 (the day of SAH), 1, 3, 5, 7, and 9. The subarachnoid blood clot was removed surgically on Day 1, 3, or 5 or, in control animals, was not removed until the animals were killed on Day 7 or 9. The concentrations of hemoglobins and adenosine triphosphate (ATP), substances believed to cause vasospasm, were measured in the removed clots and the contractile activity of the clots was measured in monkey basilar arteries in vitro. If the clot was removed 1 or 3 days after placement, vasospasm was significantly diminished 4 days after clot removal. Clot removal on Day 5 had no marked effect on vasospasm. There was a significant decrease over time in hemoglobin and ATP concentrations and in the contractile activity of the clots, although substantial hemoglobin and contractile activity was still present on Day 7. The authors infer from these results that vasospasm requires the presence of subarachnoid blood for at least 3 days, whereas by Day 5 vasospasm is less dependent on subarachnoid blood clot. Because the clot still contains substantial amounts of hemoglobin and contractile activity after 5 days, there may be an adaptive response in the cerebral arteries that allows them to relax in the presence of the stimulus that earlier caused contraction.

Effects of cell-permeant calcium chelators on contractility in monkey basilar artery.

Vasospasm after traumatic or aneurysmal subarachnoid hemorrhage is associated with smooth muscle contraction, a process that results in part from increased intracellular calcium in smooth muscle cells. These experiments tested the hypothesis that chelation of intracellular calcium with the cell-permeant calcium chelator, 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetracetic acid acetoxymethyl ester (BAPTA-AM), decreases smooth muscle contraction in response to agents that cause contraction by increasing intracellular calcium. Effects of BAPTA-AM on vasoconstriction induced by KCl, prostaglandin F2alpha (PGF2alpha), caffeine, and erythrocyte hemolysate were tested on monkey basilar artery under isometric tension. BAPTA-AM, 30 and 100 micromol/L, caused a significant decrease in resting tension in rings with and without endothelium (30 micromol/L; 8+/-6% [n.s.] and 14+/-5%, 100 micromol/L; 19+/-3% and 32+/-6%,p < 0.05, paired t test). Contractions to caffeine were significantly decreased by 30 micromol/L BAPTA-AM and were abolished at 100 micromol/L in rings with and without endothelium (p < 0.05). BAPTA-AM, 100 micromol/L, competitively inhibited contractions to PGF2alpha. BAPTA-AM, 100 micromol/L, significantly decreased the maximum contractions to KCI in rings with and without endothelium (p < 0.05). There were no significant effects of BAPTA-AM on contractions induced by hemolysate in rings with endothelium but in rings without endothelium, BAPTA-AM, 100 micromol/L, significantly inhibited contractions. In rings with endothelium contractions to hemolysate could be significantly reduced by BAPTA-AM plus indomethacin or indomethacin alone, suggesting that hemolysate releases an eicosanoid from the endothelium by a pathway that is not inhibited by BAPTA. These results suggest that the ability of BAPTA-AM to inhibit smooth muscle contractions will depend on the agonists mediating the contraction. In response to erythrocyte hemolysate, loading of endothelial cells with BAPTA-AM increases the release of a vasoconstricting eicosanoid from these cells that counteracts the decreased contraction caused by loading of smooth muscle cells with BAPTA-AM.

Basilar arterial constriction caused by intracisternal NG-nitro-L-arginine in anesthetized monkeys

The present study was designed to determine whether tonic nitric oxide (NO)-mediated vasodilator innervation participates in basilar arterial dilatation in the anesthetized Japanese monkey. The basilar arterial diameter was angiographically measured, and NG-nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor, was intracisternally applied. The injection of L-NNA produced a sustained constriction of the basilar artery, the effect being reversed by the cisternal injection of L-arginine. The vasoconstriction tended to be accelerated by treatment with phentolamine. Under alpha-adrenoceptor blockade, hexamethonium significantly attenuated the vasoconstrictor response to L-NNA. Intracisternal injections of this inhibitor did not alter the systemic blood pressure and heart rate. These findings suggest that construction by the NO synthase inhibitor of the monkey basilar artery is associated with suppression of synthesis of NO in vasodilator nerves receiving tonic impulses from the central nervous system. The basilar arterial tone appears to be regulated by nitroxidergic and adrenergic nerves and by NO derived from the endothelium in anesthetized monkeys.

Endothelium-dependent contraction produced by acetylcholine and relaxation produced by histamine in monkey basilar arteries

The present experiments were carried out to investigate endothelium-dependence of the responses to ACh, arachidonic acid and histamine in monkey basilar arteries. As we reported previously (1), ACh (10 −7 M) and arachidonic acid (5 × 10 −7 M) caused endothelium-dependent contraction (EDC) in both monkey and canine basilar arteries. The endothelium-derived contracting factor (EDCF) is probably TXA 2, since the EDC was attenuated by a cyclooxygenase inhibitor (aspirin, 5 × 10 −5 M), thromboxane A 2 (TXA 2) synthetase inhibitors (OKY-046, 10 −5 M; RS-5186, 10 −6 M) and TXA 2 antagonists (ONO-3708, 10 −8 M; S-145, 5 × 10 −9 M). Histamine caused endothelium-dependent relaxation (EDR) in monkey basilar arteries and EDC in canine basilar arteries. The EDR in monkey basilar arteries was attenuated by nitric oxide synthetase inhibitor, N G-monomethyl-L-arginine (L-NMMA) in a concentration-dependent manner and the EDC in canine basilar arteries was attenuated by aspirin, TAX 2 synthetase inhibitors and TXA 2 antagonists. The EDR and EDC were antagonized by tripelennamine (10 −6 M) but not by cimetidine (10 −5 M), indicating that they are mediated by H 1-receptors. From these results, we suggest that in the monkey basilar artery, either there are two types of endothelium, an EDCF type for ACh and arachidonic acid and an EDRF type for histamine, or there is single type of endothelium with two types of signalling processes, one for EDC and one for EDR.

Endothelium-dependent contraction produced by acetylcholine and relaxation produced by histamine in monkey basilar arteries.

The present experiments were carried out to investigate the endothelium dependence of the responses to acetylcholine (ACh), arachidonic acid, and histamine in monkey basilar arteries. ACh and arachidonic acid caused endothelium-dependent contraction (EC) in both monkey and canine basilar arteries. The endothelium-derived contracting factor (EDCF) was probably thromboxane A2 (TxA2), as the EDC was attenuated by a cyclooxygenase inhibitor, TxA2 synthetase inhibitors, and TxA2 antagonists. On the other hand, histamine caused endothelium-dependent relaxation (EDR) in monkey and EDC in canine basilar arteries. The EDR in monkey basilar arteries was attenuated by a nitric oxide synthase inhibitor. The EDR and EDC were antagonized by tripelennamine but not by cimetidine, indicating that they are mediated by H1-receptors. From these results, we suggest that in the monkey basilar artery, either there are two types of endothelium (an EDCF type for ACh and arachidonic acid and an EDRF type for histamine) or there is a single type of endothelium with two types of signalling processes (one for EDC and one for EDR).

Constrictor action of oxyhemoglobin in monkey and dog basilar arteries in vivo and in vitro

Angiographic studies on anesthetized dogs and Japanese monkeys showed that oxyhemoglobin (HbO2) injected into the cisterna magna produced a constriction of the basilar artery; the maximal constriction was attained 2-4 h later. Intracisternal injections of autologous blood, prostaglandin (PG) E2 and PGF2 alpha also constricted the artery to a similar extent, although the peak response was obtained much later (approximately 1 wk) with blood and was earlier (approximately 20 min) with PGs. The vasoconstrictor action of HbO2 was almost abolished by treatment for 5 h with aspirin in dogs and monkeys, whereas treatment of dogs with OKY 046, a thromboxane A2 synthesis inhibitor, did not significantly alter the action. In isolated monkey basilar arteries, HbO2 elicited a concentration-related contraction, which was suppressed by treatment with aspirin and by endothelium denudation. The basilar arteries responded to PGE2 and PGF2 alpha with contractions comparable to those caused by elevated external K+. Levels of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha in the nutrient solution bathing dog and monkey cerebral arteries were increased by HbO2; the increment was depressed by endothelium denudation and by treatment with indomethacin. These findings suggest that cerebral artery constriction caused by HbO2 in vivo and in vitro is associated mainly with the release of vasoconstrictor PGs, such as PGE2 and PGF2 alpha. Endothelium appears to play an important role in the release of PGs. Cerebral vasospasm elicited by intracisternal injections of HbO2 may be a useful model for the analysis of mechanisms underlying the provocation of delayed vasospasm after subarachnoid hemorrhage.

Effect of γ-Aminobutyric Acid (GABA) on Vasodilation in Resistance-Sized Arteries Isolated from the Monkey, Rabbit, and Rat

The effect of gamma-aminobutyric acid (GABA) and papaverine on cerebral arteries of rat, rabbit, and monkey and the small mesenteric arteries of the rat were studied in vitro with a microvessel apparatus. GABA (1 x 10(-7) to 1 x 10(-3) M) did not affect the basal tension of arteries of rats at rest. In PGF2 alpha-contracted monkey basilar artery and middle cerebral artery and rat basilar artery, cumulative addition of GABA (1 x 10(-7) to 1 x 10(-3) M) did not produce any relaxation. Also in K+-contracted rat basilar artery and small mesenteric artery, cumulative additions of GABA, muscimol, or bicuculline did not result in relaxation. In K+-contracted rabbit basilar artery, GABA did not produce relaxation. However, the addition of papaverine (1 x 10(-7) to 1 x 10(-4) M) in either PGF2 alpha- or K+-contracted arteries, produced a concentration-dependent relaxation in all arteries tested. These results suggest that the failure of GABA or muscimol to induce relaxation is not due to a defect of the arterial smooth muscle relaxant mechanism, but rather is due to the inability of GABA or muscimol to directly relax the artery in this in vitro preparation. Therefore, the hypotensive effect of GABA seen in the rat is probably not due to direct vasodilation of mesenteric or cerebral arteries. These findings lend further support to the idea that GABA mediates its hypotensive effect through its action as an inhibitory neurotransmitter, as previously suggested by others.(ABSTRACT TRUNCATED AT 250 WORDS)

Responses of isolated canine and simian basilar arteries to thiopentone by a newly designed pharmacological method for measuring vascular responsiveness.

The stainless steel cannula inserting method was modified for application to observe vascular responses to thiopentone in the isolated basilar arteries of the dog and monkey. In the dog, thiopentone (0.01-3 mg) induced a monophasic vasoconstriction in a dose-dependent manner. On the other hand, in the monkey, thiopentone (0.01-3 mg) showed a biphasic vascular response, i.e., an initial vasoconstriction followed by a vasodilatation in a dose-dependent manner. Thiopentone usually produced much more potent vasoconstriction in the dog than that in the monkey, while potassium chloride made little difference of vasoconstriction between the dog and monkey basilar arteries. These findings suggest that thiopentone exerts a direct constrictive effect on cerebral vessels, the actions of which decrease the total cerebral blood volume and the brain bulk, allowing a reduction in intracranial pressure.

Dependence of cerebral arterial contractions on intracellularly stored Ca++.

The purpose of the present study was to evaluate the dependence of the arterial contractions induced by different vasoactive agents upon intracellularly stored calcium in canine versus monkey cerebral arteries. The potency for inducing contractions in Ca++-free media was in the order of 9,11-epithio-11,12-metano-thromboxane A2 (STXA2) greater than prostaglandin F2 alpha (PGF2 alpha) much greater than serotonin greater than K+ in canine basilar arteries, and STXA2 greater than PGF2 alpha much greater than serotonin = K+ in monkey basilar arteries.

Pharmacological comparison of isolated monkey and dog cerebral arteries.

Pharmacological differences between canine and monkey basilar arteries were studied in vitro. The constrictor response of canine basilar artery to either norepinephrine or an alpha 1-adrenoceptor agonist phenylephrine was partly inhibited by an alpha 2-adrenoceptor antagonist yohimbine but not by an alpha 1-adrenoceptor antagonist prazosin. The contraction elicited by an alpha 2-adrenoceptor agonist clonidine was inhibited by neither prazosin nor yohimbine. These results suggest that the receptors in canine basilar artery which mediate norepinephrine-induced contraction are different from classical alpha 1 or alpha 2-adrenoceptors, although they more closely resemble the alpha 2- rather than the alpha 1-subtype. Using monkey basilar artery, phenylephrine produced the same amplitude of maximum contractile response as norepinephrine, though a much higher concentration of phenylephrine than norepinephrine was needed in order to elicit that maximum response. Clonidine did not elicit contractions. The contraction induced by norepinephrine was markedly suppressed by both prazosin and yohimbine in a noncompetitive fashion. The constrictor response of monkey basilar artery to norepinephrine, therefore, appears to be mediated by alpha 1-like adrenoceptors. Comparison of ED50 values for thromboxane A2 revealed that the monkey basilar artery was more sensitive to thromboxane A2 than that of the canine. Prostaglandin F2 alpha produced a larger maximum contraction in monkey basilar arteries than in canine basilar arteries, although the ED50 values for monkey basilar arteries were larger than those for canine basilar arteries. The ED50 values for serotonin in canine basilar arteries were a little less than those for monkey basilar arteries, although both arteries produced nearly identical maximum contractions.