Pharmacological characterization of the mechanisms involved in the vasorelaxation induced by progesterone and 17ß-estradiol on isolated canine basilar and internal carotid arteries.

Progesterone and 17ß-estradiol induce vasorelaxation through non-genomic mechanisms in several isolated blood vessels; however, no study has systematically evaluated the mechanisms involved in the relaxation induced by 17ß-estradiol and progesterone in the canine basilar and internal carotid arteries that play a key role in cerebral circulation. Thus, relaxant effects of progesterone and 17ß-estradiol on KCl- and/or PGF2α-pre-contracted arterial rings were investigated in absence or presence of several antagonists/inhibitors/blockers; the effect on the contractile responses to CaCl2 was also determined. In both arteries progesterone (5.6-180 µM) and 17ß-estradiol (1.8-180 µM): (1) produced concentration-dependent relaxations of KCl- or PGF2α-pre-contracted arterial rings; (2) the relaxations were unaffected by actinomycin D (10 µM), cycloheximide (10 µM), SQ 22,536 (100 µM) or ODQ (30 µM), potassium channel blockers and ICI 182,780 (only for 17ß-estradiol). In the basilar artery the vasorelaxation induced by 17ß-estradiol was slightly blocked by tetraethylammonium (10mM) and glibenclamide (KATP; 10 µM). In both arteries, progesterone (10-100 µM), 17ß-estradiol (3.1-31 µM) and nifedipine (0.01-1 µM) produced a concentration-dependent blockade of the contraction to CaCl2 (10 µM-10mM). These results suggest that progesterone and 17ß-estradiol produced relaxation in the basilar and internal carotid arteries by blockade of L-type voltage dependent Ca(2+) channel but not by genomic mechanisms or production of cAMP/cGMP. Potassium channels did not play a role in the relaxation to progesterone in both arteries or in the effect of 17ß-estradiol in the internal carotid artery; meanwhile KATP channels play a minor role on the effect of 17ß-estradiol in the basilar artery.

A new NO donor failed to release NO and to induce relaxation in the rat basilar artery.

Nitric oxide (NO)-donors are pharmacologically active substances that in vivo or in vitro release NO. Their most common side effect is headache caused by cerebral vasodilatation. We previously demonstrated that the new NO-donor Ru(terpy)(bdq)NO](3+) (Terpy), synthesized in our laboratory, induces relaxation of rat aorta. This study aimed to verify the effect of Terpy and sodium nitroprusside (SNP) in basilar artery. We conducted vascular reactivity experiments on endothelium-denuded basilar rings. The concentrations of iron (Fe) and ruthenium (Ru) complex were analyzed in basilar artery lysates after incubation with NO donors by mass spectrometry. We also evaluated the NO released from SNP and Terpy by using confocal microscopy. Interestingly, Terpy did not induce relaxation of the basilar artery. SNP induced relaxation in a concentration-dependent way. NO donors cross the membrane of vascular smooth muscle and entered the cell. In spite of its permeability, Terpy did not release NO in the basilar artery. Otherwise, SNP released NO in the basilar artery cells cytoplasm. Taken together, our results demonstrate that the new NO donor (Terpy) failed to release NO and to induce relaxation in the basilar artery. The NO donor SNP induces vascular relaxation due to NO release in the vascular smooth muscle cells.

Pharmacological evidence that Ca²+ channels and, to a lesser extent, K+ channels mediate the relaxation of testosterone in the canine basilar artery.

Testosterone induces vasorelaxation through non-genomic mechanisms in several isolated blood vessels, but no study has reported its effects on the canine basilar artery, an important artery implicated in cerebral vasospasm. Hence, this study has investigated the mechanisms involved in testosterone-induced relaxation of the canine basilar artery. For this purpose, the vasorelaxant effects of testosterone were evaluated in KCl- and/or PGF(2α)-precontracted arterial rings in vitro in the absence or presence of several antagonists/inhibitors/blockers; the effect of testosterone on the contractile responses to CaCl2 was also determined. Testosterone (10-180 µM) produced concentration-dependent relaxations of KCl- or PGF(2α)-precontracted arterial rings which were: (i) unaffected by flutamide (10 µM), DL-aminoglutethimide (10 µM), actinomycin D (10 µM), cycloheximide (10 µM), SQ 22,536 (100 µM) or ODQ (30 µM); and (ii) significantly attenuated by the blockers 4-aminopyridine (K(V); 1 mM), BaCl2 (K(IR); 30 µM), iberiotoxin (BK(Ca²+); 20 nM), but not by glybenclamide (K(ATP); 10 µM). In addition, testosterone (31, 56 and 180 µM) and nifedipine (0.01-1 µM) produced a concentration-dependent blockade of the contraction to CaCl2 (10 µM to 10 mM) in arterial rings depolarized by 60mM KCl. These results, taken together, show that testosterone relaxes the canine basilar artery mainly by blockade of voltage-dependent Ca²+ channels and, to a lesser extent, by activation of K+ channels (K(IR), K(V) and BK(Ca²+)). This effect does not involve genomic mechanisms, production of cAMP/cGMP or the conversion of testosterone to 17ß-estradiol.

Aging and total stenosis triggers differential responses of carotid and basilar arteries to endothelin-1 and phenylephrine.

Our aim was to investigate the effects of ageing on the vascular contractility of carotid and basilar arteries from guinea-pigs, in a model of total stenosis. Moreover, we attempted to identify whether total stenosis of the left common carotid (stenosed) in adult guinea-pigs, would affect the contractions of contralateral carotid (intact) and basilar arteries to different vasoconstrictors. With this purpose, the left carotid was occluded with a silk thread at a position close to its origin. Vascular reactivity experiments using standard muscle bath were performed 7, 15, 30, and 90 days after carotid occlusion. Reactivity of carotid and basilar arteries to endothelin-1, phenylephrine and KCl was reduced with ageing in naive guinea-pigs. The endothelin-1 and KCl-induced contractions were unaltered in arteries from SHAM-operated animals. Moreover, phenylephrine-induced contractions were reduced in both carotids from 7 days SHAM-operated guinea-pigs, when compared to naive group. Stenosis induced progressive reduction in the contraction induced by endothelin-1, phenylephrine and KCl in the stenosed carotid, when compared to their respective age-matched naive and SHAM groups. Interestingly, an increased contractile-response to vasoconstrictor agents in all the contralateral carotids was observed. Stenosis (30 and 90 days) also induced an increase in the contractions induced by endothelin-1 in the basilar artery. Conversely, phenylephrine and KCl-induced contractions were reduced in basilar arteries 7, 15, 30 and 90 days after stenosis. These results showed that stenosis in adult guinea-pigs induce alterations of vascular reactivity in arteries distant from the site of injury. Thus, in spite of the common use of contralateral carotid as control, it must be aware of the potential alteration induced by stenosis in the vascular motility of such vessels. Additionally, it was verified a relationship between the period of stenosis and the alterations in the vascular reactivity to these vasoconstrictors.

Total stenosis triggers compensatory responsiveness of carotid and basilar arteries to endothelin-1 and phenylephrine.

The aim of this study was to investigate whether total stenosis of the common carotid artery (ipsilateral) would affect the vascular responsiveness of the contralateral carotid as well as the basilar artery from guinea pigs. With this purpose, the carotid artery was occluded with a silk thread at a position close to its origin. Vascular reactivity experiments using standard muscle bath were performed 7, 15, 30, and 90 days after carotid occlusion. Stenosis induced a progressive reduction in the contraction induced by endothelin-1, phenylephrine and KCl in the ipsilateral carotid, when compared to their respective age-matched SHAM groups. Endothelial removal or incubation of endothelium-intact ipsilateral carotids with L-NAME, a nitric oxide synthase inhibitor, did not alter the response to endothelin-1 or phenylephrine, when compared to the endothelium-intact ipsilateral carotid in the absence of the inhibitor. Interestingly, an increased contractile response to endothelin-1, phenylephrine and KCl was observed in the contralateral carotid. Indomethacin, a non-selective cyclooxygenase inhibitor, prevented the increased contraction to endothelin-1 in the contralateral carotid. Stenosis also induced an increase in the contractile response to endothelin-1 in the basilar artery while the contractile response to phenylephrine and KCl were reduced. Indomethacin, but not L-NAME, prevented the increased contraction to endothelin-1 in the basilar artery. Morphometric analysis showed no differences in the medial area (wall thickness) of carotid or basilar arteries from the stenosis group when compared to their respective age-matched SHAM groups. The present study confirms the importance of adaptation to stenosis on the vascular reactivity of the stenosed artery to different vasoconstrictor agents. Moreover, our results show that stenosis induces alterations of the vascular reactivity on arteries distant from the site of injury. The increased response to endothelin-1 in the contralateral carotid artery and basilar artery seems to involve the release of vasoconstrictor prostanoids from endothelial origin.

Control and autoregulation of the blood circulation in the vertebrobasilar system.

The author establishes an analogy between the control mechanism and autoregulation of the cerebral blood flow and the protection of the vascular wall of the internal carotid artery constituted by the conjunction of the 'internal carotid-cavernous sinus' system with the 'vertebrobasilar-transverse-occipital dural sinus or basilar' 'sinus' system (an extension of the cavernous sinus) in the autoregulation and control of the encephalic circulation carried out through this latter vessel, together with the protection of its vascular walls. The author believes it to be very difficult to demonstrate in practice the functioning of these mechanisms, but he argues that the unusual anatomical features of the systems are indicative of their particular physiological roles.

Synthesis of 3-amino-2-(3-indolyl)propanol and propanoate derivatives and preliminary cardiovascular evaluation in rats.

A series of tryptamine analogues has been prepared and tested for their 5-HT1 receptor agonist properties. The incorporation of an alkoxy group at the C-5 position of the indole nucleus resulted in a short-lived and dose-dependent immediate antihypertensive and bradycardic response in anaesthetized spontaneously hypertensive rats (SHR). In addition, a carbomethoxy function at the beta-position of the side-chain of the tryptamines significantly increased the mean resting arterial blood pressure (MAP) in pithed rats and also produced contraction of the canine basilar artery in a dose-dependent fashion. Structure-activity relationships (SAR) suggest that the 5-alkoxy group is an important pharmacophore in the production of the antihypertensive effect and that the introduction of a hydroxymethylene group on the side-chain, instead of the carbomethoxy group, changed the receptor affinity profile.

Changes of blood flow velocity indicating mechanical compression of the vertebral arteries during rotation of the head in the normal human measured with transcranial Doppler sonography.

The dynamical changes of blood flow velocity of the intracranial vertebral arteries (VA's) and proximal basilar artery (BA) provoked by rotation of the head in normal volunteers were measured using pulsed-wave transcranial Doppler sonography (TCD). In another group both VA's were examined simultaneously with 2-channel TCD. Blood flow velocities diminished compared to the neutral position in all vessels, independently of the side. Total obstruction of the flow was not observed. Our findings reveal a definitive decrease of blood flow velocity at the vertebrobasilar artery system provoked by rotation of the head in normal humans. This physiological phenomenon is suggested to have an impact on the cerebral blood flow in patients with impaired autoregulation of the cerebral vessels, low volume flow reserve in the contralateral VA or insufficient collateral channels because of normal anatomical variation, especially those patients under general anesthesia or comatose.

Changes of blood flow velocity indicating mechanical compression of the vertebral arteries during rotation of the head in the normal human measured with transcranial doppler sonography

Estudos anatômicos, angiografias em voluntários normais e relatos clínicos de pacientes com sintomas atestam o fato de que o fluxo sanguíneo através das artérias vertebrais (VA's) é parcialmente obstruido ao nível da articulaçäo atlanto-axial (C1-C2) durante a rotaçäo da cabeça. Variaçöes anatômicas as artérias cerebrais basais, trauma e outros processos patológicos têm sido relacionados à compressäo mecânica fisiológica das VA's na patogenia de insuficiência vertebrobasilar. No presente estudo, as alteraçöes dinâmicas da velocidade do fluxo sanguíneo (BFV) nas artérias do sistema vertebrobasilar, provocadas por rotaçäo da cabeça em voluntários adultos normais, säo medidas com Doppler trnscraniano (TCD) das VA's (segmento intracraniano V4) e artéria basilar (BA). Em 8 indivíduos o estudo foi repetido com um instrumento de TCD de dois canais, permitindo o estudo simultâneo das VA's (grupo 2). A artéria basilar foi examinada com a técnica transforaminal e as VA's com o método transoccipital. Resultados: A BFV na BA e VA's diminuiu de modo significante durante rotaçäo da cabeça no grupo I, idenpendentemente do lado da rotaçäo (p ó 0.001). A mais acentuada diminuiçäo do BFV ocorreu na VA do lado direito durante rotaçäo episilateral (-18 por cento)...

[Control and regulation of the blood circulation in the vertebro-basilar system. Review of the literature]. / Contrôle e regulação da circulação sanguínea no sistema vértebro-basilar. Revisão de literatura.

The author establishes an analogy between the control mechanism and regulation of the cerebral blood flow and of protection of the vascular wall of the internal carotid constituted by the conjunction "internal carotid-cavernous sinus" with the group represented by the system "vertebro basilar-transverse occipital sinus or basilar" (an extension of the cavernous sinus) in the regulation and control of the encephalic circulation carried out through this latter vessels, together with the protection of its vascular walls. The author believes to be very difficult to demonstrate in practice the functioning of these mechanisms, but it is very logical and easy to reason about them, to value them and to give the importance and meaning or motive which forcibly they should have and not simply consider them as freaks of nature and bizarre anatomical features.