Response Of Vascular Smooth Muscle Research Articles

Cobalt Contraction of Vascular Smooth Muscle is Calcium Dependent

Summary: We examined the mechanism by which cobalt causes contraction of vascular smooth muscle (VSM), determining whether contractile response of VSM from normotensive and hypertensive rats differed. Contraction of rings of rat thoracic aorta from normotensive Wistar-Kyoto rats (WKY) and hypertensive spontaneously hypertensive stroke-prone rats (SHRSP) in response to addition of cobalt chloride to the muscle bath was recorded. Threshold contraction occurred at 3 μM; maximum contraction occurred at 100 μM. There was no difference between rings from WKY and SHRSP in sensitivity or maximum response to cobalt. No contractile response occurred when cobalt was added to a calcium-free physiologic salt solution (PSS) to which 1.0 mM EGTA had been added. When no EGTA was added to the PSS, cobalt caused a contraction 20% as great as that observed in calcium-containing physiologic salt solution, but this small contraction was eliminated after intracellular sequestration of calcium had been prevented by treatment of the rings with cyclopiazonic acid (3 × 10−4M). A concentration-dependent contraction occurred when calcium was added back to the bath in the presence of cobalt. The contraction in response to this addition of calcium did not differ between rings from WKY and SHRSP. Threshold concentrations of cobalt produced marked potentiations of contractile responses to either norepinephrine (NE) or KCl. We conclude that cobalt causes contraction by activating both voltage-sensitive and receptor-operated calcium channels in the plasma membrane. Cobalt also caused release of intracellularly sequestered calcium. There was no difference between the responses to cobalt of VSM from WKY and SHRSP.

Cobalt Contraction of Vascular Smooth Muscle is Calcium Dependent

We examined the mechanism by which cobalt causes contraction of vascular smooth muscle (VSM), determining whether contractile response of VSM from normotensive and hypertensive rats differed. Contraction of rings of rat thoracic aorta from normotensive Wistar-Kyoto rats (WKY) and hypertensive spontaneously hypertensive stroke-prone rats (SHRSP) in response to addition of cobalt chloride to the muscle bath was recorded. Threshold contraction occurred at 3 microM; maximum contraction occurred at 100 microM. There was no difference between rings from WKY and SHRSP in sensitivity or maximum response to cobalt. No contractile response occurred when cobalt was added to a calcium-free physiologic salt solution (PSS) to which 1.0 mM EGTA had been added. When no EGTA was added to the PSS, cobalt caused a contraction 20% as great as that observed in calcium-containing physiologic salt solution, but this small contraction was eliminated after intracellular sequestration of calcium had been prevented by treatment of the rings with cyclopiazonic acid (3 x 10(-4) M). A concentration-dependent contraction occurred when calcium was added back to the bath in the presence of cobalt. The contraction in response to this addition of calcium did not differ between rings from WKY and SHRSP. Threshold concentrations of cobalt produced marked potentiations of contractile responses to either norepinephrine (NE) or KCl. We conclude that cobalt causes contraction by activating both voltage-sensitive and receptor-operated calcium channels in the plasma membrane. Cobalt also caused release of intracellularly sequestered calcium. There was no difference between the responses to cobalt of VSM from WKY and SHRSP.

Vascular smooth muscle cells grown on Matrigel. A model of the contractile phenotype with decreased activation of mitogen-activated protein kinase.

Vascular smooth muscle cells have been shown to exist in two phenotypic states which have been designated proliferative and contractile. The properties of rat aortic vascular smooth muscle cells grown on Matrigel were compared with cells grown on untreated plastic culture dishes. Cells grown on Matrigel manifested at least four important properties characteristic of the contractile phenotype as compared with cells grown on plastic. The cells grown on Matrigel had altered morphology similar to in vivo studies of contractile vascular smooth muscle. The cells had a low proliferative index, showed enhanced levels of the smooth muscle isoform of alpha-actin, and had an enhanced contractile response to the vasoconstrictor arginine vasopressin. All of these changes were maintained through at least five passages and could be reversed by replating cells grown on Matrigel back to uncoated plastic dishes. Changes in post-receptor signaling pathways which could account for the altered physiologic responses of the cells were investigated. Cells grown on Matrigel showed no alterations in agonist-induced mobilization of intracellular Ca2+ or agonist-stimulated cAMP levels. However, stimulation of mitogen-activated protein kinase (MAP kinase) by both vasoconstrictors and growth factors was inhibited by 50% in cells grown on Matrigel as compared with plastic. This decrease in agonist-induced MAP kinase was associated with a decrease in the levels of both p42 and p44 MAP kinase protein and a decrease in tyrosine phosphorylation of both isoforms in cells grown on Matrigel. Alterations in MAP kinase activation can account at least in part for the observed physiologic responses of contractile vascular smooth muscle. Growth of vascular smooth muscle cells on Matrigel represents a useful model to examine phenotypic-dependent alterations in post-receptor signaling.

Beneficial effect of SPM-5185, a cysteine-containing nitric oxide donor, in rat carotid artery intimal injury.

We studied the effects of an organic nitric oxide (NO) donor SPM-5185 in a rat carotid artery intimal injury model. Seven days after injury, the two end segments of the injured carotid arteries were studied for endothelial release of NO, and the middle segments were used for histological measurement of the intimal-to-medial (I/M) ratio and scanning electron microscopy of the luminal surface. The NO donor SPM-5185 or its non-NO-donating control compound SPM-5267 were infused intravenously at 30 micrograms/d. Full vasorelaxant responses of rat carotid arterial rings were obtained with the endothelium-dependent vasodilators acetylcholine (ACh), A23187, and the endothelium-independent vasodilator acidified NaNO2 in sham-operated control rings. Impaired relaxation occurred with 10 mumol/L ACh and 1 mumol/L A23187 in injured rings but not in rings infused with SPM-5185 for 7 days. Relaxation to 100 mumol/L acidified NaNO2 was not significantly different among any of the groups, indicating a normal vascular smooth muscle response after intimal injury. Morphometric analysis of injured carotid arteries given vehicle and SPM-5267 showed marked intimal thickening with an average I/M ratio of 0.78 +/- 0.03 and 0.74 +/- 0.05, respectively. SPM-5185 markedly attenuated intimal thickening, resulting in an I/M ratio of 0.13 +/- 0.03 (P < .01 from vehicle), representing an approximately 82% inhibition of intimal thickening. SPM-5185 infusion resulted in accelerated regeneration of endothelial cells on the intimal surface at 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model

Objectives. This study examined the effects of intracoronary Irradiation on neointimal proliferation after overstretch balloon angioplasty in a normolipemic swine model of restenosis.Background. Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that ionizing radiation, delivered by means of an intracoronary source, causes focal medial fibrosis. We therefore hypothesized that ntracoronary irradiation delivered at the time of balloon angtoplasty might impair the restenosis process.Methods. Nineteen juvenile swine underwent coronary angiography; a segment of the coronary artery was chosen as a target for balloon injury. In 10 swine, a ribbon of iridiun-192 was positioned at the target segment, and 2,000 cGy was delivered at the vessel wall. Subsequently, overdilation balloon angioplasty was perfromed at the irradiated segment. In nine control swine, overdilation balloon angioplasty was performed without previous irradiation. Eighteen animals survived and were killed at 30 days. Histopathologic analysis was performed by a pathologist in blinded manner. The area of maximal lumen compromise within the target segment was analyzed by computer-assisted planimetry.Results. In the control group, mean (± SD) neointimal area was 0.84 ± 0.60 mm2compared with that in the irradiated group, 0.24 ± 0.13 mm2(p = 0.01). In the control group, mean percent area stenosis was 47.6 ± 20.7%, whereas that in the irradiated group was 17.6 ± 10.5% (p = 0.001). This represents a 71.4% reduction in neointimal area and a 63.0% reduction in percent area stenosis in the irradiated group. Adjacent coronary segments and surrounding myocardium were unaffected.Conclusions. Intracoronary irradiation (2,000 cGy) delivered to a target porcine coronary segment before balloon overdilation markedly reduces neointima formation at 30 days and thus significantly impairs the restenosis process.

Endothelial and vascular smooth muscle responses are altered after left lung autotransplantation.

Left lung autotransplantation (LLA) increased the pulmonary vasoconstriction evoked by phenylephrine and attenuated the vasodilatation caused by acetylcholine or bradykinin in conscious dogs. To study the mechanisms responsible for these changes, pulmonary arterial rings were isolated from right (control) and left (LLA) lower lobes of dogs 1-26 mo after LLA and were suspended for isometric tension recording. Compared with control rings from the same anatomic location, contractions to phenylephrine were increased after LLA in rings with or without endothelium. In arterial rings contracted to 50% of their maximal response to phenylephrine, acetylcholine, bradykinin, and calcium ionophore caused endothelium-dependent relaxations that were reduced in LLA compared with control rings. In arterial rings from control and LLA lungs, relaxations to acetylcholine were not altered by inhibition of cyclooxygenase (indomethacin) but were reduced after inhibition of NO synthase [N omega-nitro-L-arginine methyl ester (L-NAME)]. After L-NAME, there was no longer any significant difference in acetylcholine-induced relaxation between arterial rings from control and LLA lungs. Relaxation to SIN-1, a NO donor, was similar in arterial rings (without endothelium) from control and LLA lungs. The results suggest that LLA causes an increased sensitivity of vascular smooth muscle to alpha 1-adrenergic activation and endothelial dysfunction that is mediated by a selective reduction in the activity of endothelium-derived relaxing factor/NO.

Effect of subthreshold ouabain on the tone of guinea-pig aortic strips following repeated noradrenaline stimulation.

1. The effect of ouabain at a concentration (0.8 microM) that does not induce contractile response in guinea-pig aortic strips has been studied on endothelium-denuded strips repeatedly stimulated with 1 microM noradrenaline or 60 mM K+ applied for 5 min every 30 min. 2. The resting tone (i.e. the tone between one noradrenaline stimulation and the following) of the aortic strips exposed to ouabain increased progressively, whereas the control strips (no ouabain) completely relaxed on washout of the agonist. In the aortic strips stimulated by 60 mM K+, the resting tone did not increase. 3. The calcium antagonist, verapamil, did not affect the increase in tone, that was nevertheless strictly dependent on external calcium, since the contracted strips completely relaxed on calcium removal and promptly contracted again on calcium readdition. This finding indicates a mechanism independent of voltage-gated calcium channels. 4. Caffeine-induced contractions, taken as a measure of sarcoplasmic reticulum calcium content, were amplified by the presence of ouabain in aortic strips either stimulated by noradrenaline or unstimulated, with a larger increase in the former. 5. These results suggest that the repeated stimulation of guinea-pig aortic strips by noradrenaline in the presence of ouabain, by raising both intracellular Na+ and Ca2+, decreases the ouabain threshold concentration required for contraction, thus increasing the responsiveness of vascular smooth muscle to the glycoside.

Indomethacin-sensitive CO2 reactivity of cerebral arterioles is restored by vasodilator prostaglandin.

To investigate the role of vasodilator prostanoids in the CO2-induced relaxation of cerebral arterioles, the present study examined the effect of exogenous prostaglandin (PG) E2 and nonprostanoid vasodilators, adenosine and sodium nitroprusside, on the indomethacin-impaired pial arteriolar response to CO2 in newborn piglets. Reactivity of pial arterioles (52-131 microns diam) was determined using a closed cranial window with intravital microscopy. Cortical prostanoid synthesis was assessed by analyzing for select prostanoids in cerebrospinal fluid sampled from under the cranial window. Inhalation of 7% CO2 caused an elevation of cortical 6-keto-PGF1 alpha and thromboxane (Tx) B2 and increased pial arteriolar diameter by 34 +/- 5%. Two cyclooxygenase inhibitors, indomethacin (5 mg/kg i.v.) and ibuprofen (30 mg/kg i.v.), abolished the CO2-induced elevation of cortical prostanoids. Indomethacin, but not ibuprofen, blocked the CO2-induced increase in pial arteriolar diameter. The indomethacin-impaired vasodilator response to CO2 was restored when PGE2 (0.1-1 microM) was applied topically to the cortical surface. Adenosine (1-100 microM) and sodium nitroprusside (0.5 microM) only partially restored the vasodilator response to CO2. The data suggest that vasodilator prostanoids facilitate cerebrovascular relaxation to CO2 and may play a permissive role in the relaxation response of vascular smooth muscle. The fact that adenosine (adenosine 3',5'-cyclic monophosphate-mediated dilator) and sodium nitroprusside (guanosine 3',5'-cyclic monophosphate-mediated dilator), were partially effective suggests a role for those intracellular signaling pathways. We speculate that receptor activation of intracellular pathways may alter Ca2+ sensitivity of the contractile apparatus in such a way that the relaxation response to CO2 can occur.(ABSTRACT TRUNCATED AT 250 WORDS)

Light-Activated Release of Nitric Oxide from Vascular Smooth Muscle of Normotensive and Hypertensive Rats

A porphyrinic sensor was used to monitor nitric oxide release from vascular smooth muscle in response to exposure to ultraviolet light. Aortic rings exposed to UV light relaxed with a time course that parallels this observed NO release. With repeated UV light treatments, the magnitude of the relaxations diminished, suggesting that a store of NO was being exhausted. Photorelaxation in response to UV light was studied in aortic rings from two types of hypertensive rats, genetic (SHRSP) and nitroarginine-induced. These aortic rings showed greater photorelaxation and evidenced less tolerance than did aortic rings from control normotensive rats. Since NO synthase activity is depressed in both types of hypertension, it appears, paradoxically, that the UV light-releasable store of NO is augmented when NO synthase activity is depressed.

Altered endothelium-dependent alpha-adrenergic vascular reactivity following exposure to Pasteurella haemolytica antigens.

Rats were injected with sterile saline (controls), 10(5) cfu of Pasteurella haemolytica (biotype A) obtained from a commercial vaccine, or a commercial Pasteurella leukotoxoid vaccine. Three days after vaccination, the animals were killed and the thoracic aorta was removed. In some experiments the vascular endothelium was mechanically removed. Each isolated aorta was placed in a tissue bath and the biophysical responses to methoxamine (alpha-1 agonist) were determined. In separate experiments the endothelial surface was examined by scanning electron microscopy. In endothelium-intact vessels both vaccines appeared to enhance the contractile response to methoxamine. On the other hand, in endothelial-denuded vessels, the methoxamine-mediated contractile response was enhanced in the P. haemolytica-treated group but not in animals vaccinated with leukotoxoid. Furthermore, scanning electron microscopy revealed deposition of a fibrin-like material on the endothelial surface of vaccinated animals. These results suggest that exposure to vaccine-derived P. haemolytica antigens alters the morphology and adrenergic responsiveness of vascular smooth muscle.

Arterial smooth muscle responses in adult and moderately aged spontaneously hypertensive rats.

In order to further clarify differences between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats as well as the effects of ageing, vascular smooth muscle responses of mesenteric arterial rings and intracellular free calcium concentration ([Ca2+]i) in platelets and lymphocytes were studied in 20-week-old and 32-week-old animals. Arterial contractile responses induced by noradrenaline and potassium chloride were comparable in 20-week-old SHR and WKY rats, whereas at 32 weeks of age maximal contractile force generation to both of these agents was clearly lower in SHR. In both age groups the calcium entry blocker nifedipine was more effective in inhibiting potassium chloride-evoked responses in SHR than in WKY rats, and arterial relaxation responses by endothelium-dependent (acetylcholine) and endothelium-independent (nitroprusside, isoprenaline) mechanisms were more pronounced in WKY rats when compared with SHR. The ability of vascular smooth muscle cells to sequester calcium was evaluated by first depleting cellular calcium stores with maximal contractions to noradrenaline in calcium-free buffer, whereafter calcium was returned to the organ bath. After a 10 min. calcium loading period the arterial rings were rechallenged with noradrenaline. Both in 20-week-old and 32-week-old rats these responses were less marked in SHR than in WKY rats, suggesting reduced ability of smooth muscle cells to sequester calcium. In addition, platelets and lymphocytes were used as cell models to examine [Ca2+]i in the experimental groups by the fluorescent indicator quin-2. In these two cell types [Ca2+]i was higher in SHR than in WKY rats in both of the age groups studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of trichothecene mycotoxins on the ex vivo vascular smooth muscle responses to β-adrenergic agonists

The ex vivo biophysical response of isolated rat aorta to T-2 toxin, diacetoxyscirpenol (DAS) and Roridin-A were determined. Roridin-A caused a dose-dependent relaxation of precontracted (30 mM KCl) aorta, while T-2 toxin and DAS were without effect. On the other hand, the relaxation response of aorta to isoproterenol and sodium fluoride is impaired in the presence of T-2 toxin or DAS. Roridin-A did not alter the relaxation response to isoproterenol or sodium fluoride. These experiments suggest that macrocyclic trichothecenes (e.g., Roridin-A) are capable of altering vascular smooth muscle tone directly, while simple trichothecenes (e.g., T-2 toxin, DAS) interfere with β-adrenergic responses.

Effect of the Endothelium on the Response to Phorbol Ester in Smooth Muscle from Spontaneously Hypertensive Rats.

Problem: The phorbol ester-induced contractile response of blood vessels from spontaneously hypertensive rats (SHR) is greater than that from normotensive Wistar-Kyoto rats (WKY), which suggests that protein kinase C activity is abnormally high in vascular smooth muscle from SHR. However, the role of the overlying endothelium in these responses has not been tested. Hypothesis: The response of vascular smooth muscle to protein kinase C activation is influenced by the presence of the endothelium. Methods: We examined the isotonic contraction of aortic rings (with or without endothelium) from 12-14-week-old SHR and WKY in response to KCl, norepinephrine, and the phorbol ester PDBu (with and without staurosporine). We also tested these responses in the presence of L-NMMA. Results: PDBu (1nM-1 mM) dose-dependently increased contractile force, with an EC50 of 100nM. Aortic rings from SHR were more sensitive than those from WKY at all doses tested. Removal of the endothelium abolished this difference: the sensitivity of aortic rings from WKY increased and the contractility of rings from SHR decreased. Preincubation with L-NMMA (10-5M) for 20min also abolished the difference in contractile response in the same fashion. The response to norepinephrine was increased by L-NMMA in both SHR and WKY. Conclusions: The difference between SHR and WKY in phorbol ester-induced contraction of aortic rings is due to a difference in endothelial cell function, rather than to a difference in vascular smooth muscle. We suggest that PKC may mediate the release from endothelial cells of a vasodilator, which may be nitric oxide. This effect may be abnormally weak in the endothelium of SHR. (Hypertens Res 1994; 17: 193-197)

Insulin attenuates agonist-evoked calcium transients in vascular smooth muscle cells.

Insulin may decrease the contractile response of vascular smooth muscle to vasoactive agents. This could be due to interactions of insulin with the effects of vasoactive agonists on intracellular free calcium transients in vascular smooth muscle cells. This study assesses the effects of physiological doses of insulin (70 microU/mL) on calcium responses in cultured vascular smooth muscle cells (primary unpassaged and passaged) to angiotensin II (1 nmol/L), arginine vasopressin (10 nmol/L), and norepinephrine (10 mumol/L). Intracellular free Ca2+ concentrations in single cells were measured microphotometrically using fura 2-AM. Insulin, angiotensin II, arginine vasopressin, and norepinephrine significantly increased calcium (to 115 +/- 7, 183 +/- 20, 184 +/- 15, and 168 +/- 12 nmol/L, respectively, from basal calcium of 90 +/- 10 nmol/L). Insulin significantly attenuated the agonist-induced calcium responses. The effects of insulin were almost completely inhibited by diltiazem, staurosporine, calphostin C, and thapsigargin. In conclusion, insulin stimulates calcium transients but blunts agonist-mediated calcium rises in vascular smooth muscle cells. These responses are related to regulatory effects of insulin on cellular calcium homeostasis and may explain how insulin modulates vascular smooth muscle contraction.

Influence of Hydralazine Treatment on the Vascular Reactivity of DOCA-Salt Hypertensive Rats

To investigate if anti-hypertensive drug therapy is effective in correcting the altered endo-thelial responses observed in blood vessels of DOCA-salt hypertensive rats, cumulative concentration-effect curves to noradrenaline, acetylcholine and sodium nitroprusside were constructed in rings of thoracic aortas with or without endothelium isolated from DOCA-salt hypertensive and control rats treated with hydralazine for 24 h (acute) or 15 d (chronic). Effective concentrations (EC50s) and maximal responses were analysed. Blood pressures of both control and DOCA-salt hypertensive rats decreased within 24 h to levels at or below those obtained before treatment and were maintained at reduced levels during the remainder of the treatment period (15 d). In preparations with endothelium, lower EC50s for noradrenaline were observed in aortas from DOCA-salt hypertensive rats in comparison with corresponding controls except for hydralazine (15 d) -treated group. The maximal responses to noradrenaline did not differ significantly between the different groups Similar EC50s and maximal responses to noradrenaline were observed in preparations without endothelium from DOCA-salt hypertensive and corresponding control rats. After acute and chronic hydralazine treatment similar responses to acetylcholine were found. An increased sensitivity to sodium nitroprusside, an endothelium-independent vasodilator, was found 15 days after hydralazine treatment. We concluded that: a) the increased sensitivity to noradrenaline observed in aortic rings with endothelium from DOCA-salt hypertensive rats was not corrected by acute treatment; chronically administered hydralazine potentiated noradrenaline responses in control aortas, therefore it was not possible to conclude about the influence of the anti-hypertensive treatment on the potentiated response observed in hypertensive aortas; b) acute and chronic hydralazine treatments corrected the impaired endothelium-dependent relaxation observed in aortas of DOCA-salt hypertensive rats; c) acute hydralazine treatment did not alter the relaxing response of smooth muscle in DOCA-salt rats; however, the chronic treatment increased the sensitivity to sodium nitroprusside in aortas of DOCA-salt rats. Therefore, correction of the decreased response to acetylcholine might, at least partially, be due to an increased response of vascular smooth muscle to nitrovasodilators such as NO that is released by acetylcholine.

Gap junctional communication and vascular smooth muscle reactivity: use of tetraethylammonium chloride.

Oscillatory contractions in uterine smooth muscle are mechanistically related to gap junction complex formation. We have tested the hypothesis that agonist-induced oscillations in vascular smooth muscle are also mediated by gap junctions and that gap junctions are important for vascular smooth muscle cell communication. Total RNA from cultured Wistar-Kyoto rat (WKY) mesenteric arterial cells hybridized strongly with a cDNA probe for the message for connexin43, a monomer of the gap junction. In these same cells, the quaternary ion tetraethylammonium (TEA) (10 mM) increased Lucifer yellow dye transfer between contiguous cells, a measure of cell-to-cell communication via gap junctions, approximately 35% above basal levels. Heptanol, an established inhibitor of gap junction communication, completely blocked both basal- and TEA-stimulated dye transfer between neighboring cells. In other experiments, helical strips of superior mesenteric and tail arteries from WKY rats were mounted in tissue baths for measurement of isometric contractile force. TEA (10(-3)-10(-1) M) induced oscillatory contractions (1-5 cycle/min) in both mesenteric and tail arteries. Removal of endothelium did not affect the pattern of TEA-stimulated oscillations. Oscillations to TEA were blocked in a concentration-dependent manner in both arteries by heptanol (10(-7)-10(-3) M). Heptanol (10(-3) M) also significantly reduced (40%) acetylcholine-induced relaxation in the mesenteric artery (contracted with phenylephrine).(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Blood Flow and Metabolism

Part 1 The anatomic bases: general and comparative anatomy of the cerebral circulation the blood vessel wall - endothelial and smooth muscle cells perivascular nerve fibres in brain vessels functional circuitry. Part 2 The physiological bases: vascular smooth muscle reactivity in vitro and in situ the blood-brain barrier - permeability and substrate transport energy generation in the central nervous system neurotransmitters - metabolic and vascular effects in vivo. Part 3 The pharmacological bases: adrenergic mechanisms dopamine 5-hydroxytryptamine acetylcholine histamine adenosine prostaglandins and other elcosanoids calcium antagonists anaesthetic agents neuropeptides aminobutyric acid (GABA) glutamic acid. Part 4 Fundamental responses of the cerebral circulation: aspects on methods used in vivo changes in arterial gas tensions autoregulation - arterial and intracranial pressure functional depression and stimulation. Part 5 Disordered control - pathophysiological aspects: disturbed cerebral autoregulation disordered substrate supply cerebral ischemia migraine and cluster headache subarachnoid haemorrhage the aged brain.

Prenatal cocaine exposure affects the development of aortic adrenergic innervation and contractile responses

This study examines the effects of prenatal cocaine administration on the development of vascular sympathetic innervation and contractile responsiveness. Rabbits received cocaine (4 mg/kg, iv, bid) or saline during gestational days 8 to 29. Aortas were obtained on postnatal days 10, 20, 30 and 50. Vascular smooth muscle responsiveness was assessed by measuring aortic contractile responses to norepinephrine (NE) and to other vasoconstrictors. Vascular adrenergic innervation was evaluated by measuring desipramine sensitive [ 3H]-NE uptake into aortic ring segments and aortic NE content. [ 3H]-NE uptake and NE content were reduced at postnatal days 10 and 20 in the rabbits exposed prenatally to cocaine. Differences were not observed at postnatal days 30 or 50. The contractile response to NE was reduced in rabbits exposed to cocaine prenatally. Maximal response and potency were decreased at postnatal day 10 and potency was still decreased at day 20, but not at the older ages. Contractile responses to serotonin (5-HT) and angiotensin II (AII) were not affected by prenatal cocaine exposure. These results suggest that prenatal cocaine exposure delays the development of aortic adrenergic innervation and alpha adrenoceptor responsiveness.

Hemodynamic and electrophysiologic effects of first- and second-generation calcium antagonists

The calcium antagonists currently available exert significantly different in vitro and in vivo electrophysiologic, hemodynamic, and contractile effects on cardiovascular function, mediated through differential cardiac and vascular smooth muscle responses to calcium channel blockade. These differences have important implications regarding choice of agent in specific clinical conditions, such as sinus or atrioventricular nodal disease, depressed left ventricular function, or congestive heart failure—conditions that may coexist with angina or hypertension. Recognizing and utilizing the properties of the different calcium antagonists is important to ensure maximally effective clinical outcomes. For example, in patients with hypertrophic cardiomyopathy and supraventricular arrhythmias, verapamil is singularly effective, whereas in post-myocardial infarction patients with pulmonary congestion, diltiazem may produce an added risk. Calcium antagonists of the dihydropyridine class, such as nifedipine and amlodipine, have the greatest peripheral vasoselective effects and thus the greatest potential to reduce afterload, minimizing direct left ventricular depression of contractility. Despite favorable effects of calcium antagonists, most of the agents currently available are not clearly safe in congestive heart failure and may adversely affect left ventricular function. However, newer calcium antagonists such as amlodipine are being investigated with regard to their safety in congestive heart failure.

Halogen-substituted trimetoquinol analogs as thromboxane A 2 receptor antagonists in platelets and aorta

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H 2/ thromboxane A 2 (TXA 2) receptor-mediated responses initiated by a prostaglandin (PG) H 2 analog, U46619, in human platelets and rat aorta. Ring flourine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro-TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TNQ > 8-iodo- TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole bloods as well as in platelet-rich plasma. Inhibition of specific [ 3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies differece in comparison with human platelets. The rank order of inhibitorypotencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ ⩾ 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA 2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA 2-mediated functional responses in vascular smooth muscle and platelets.