Dependence of nickel-induced coronary vasoconstriction on the activity of the electrogenic Na+, K+-pump

The possible interactions between the vasoactive trace metal nickel ion (Ni2+) and membrane Na-K-ATPase in the isolated perfused rat heart and in the isolated canine coronary artery have been studied. The characteristic features of 1 microM Ni2+-induced contractile response in the canine coronary artery strip were similar to those evoked by the inhibition of Na-K-ATPase. Inhibition of the pump activity by ouabain (10(-4)M) or by K+-deficient Krebs solution prevented Ni2+-action both in the canine coronary artery strip and in the perfused rat heart, indicating that when Ni2+ causes coronary vasoconstriction the Na, K-exchange is influenced. Further studies are needed to clarify whether Ni2+ acts directly on the enzyme, or the vascular action of this trace metal depends on the ionic gradients maintained by the electrogenic Na-K-pump.     

Hemodynamic effects of nicotine in canine skeletal muscle.

Studies were conducted in 36 artificially ventilated, anesthetized dogs to clarify hemodynamic effects of nicotine in resting gracilis muscle. In Series 1, effects of intravenous nicotine (36 micrograms/kg/min) were evaluated in (i) intact muscles (Condition 1), (ii) denervated muscles (Condition 2), (iii) denervated muscles following local alpha-adrenergic blockade (Condition 3), (iv) denervated muscles following combined local alpha- and beta-adrenergic blockade (Condition 4), and (v) intact muscles with aortic pressure maintained constant (Condition 5). In Series 2, nicotine was infused directly into the gracilis artery at a rate of 3.6 micrograms/kg/min. Muscle blood flow was obtained with an electromagnetic flowmeter and used to calculate vascular resistance and oxygen consumption (Fick equation). Plasma catecholamine levels were determined with a radioenzymatic method. Intravenous nicotine doubled mean aortic pressure under Conditions 1-4. In intact and denervated muscles (Conditions 1 and 2) proportional increases in vascular resistance, reflective of vasoconstriction, held blood flow constant. Muscle oxygen consumption was unchanged. alpha-Adrenergic blockade with phenoxybenzamine following denervation (Condition 3) converted muscle vasoconstriction to vasodilation during nicotine infusion. Additional beta-adrenergic blockade (Condition 4) restored muscle vasoconstriction. Nicotine-induced muscle vasoconstriction was maintained under controlled pressure (Condition 5). Intravenous nicotine significantly increased plasma catecholamine levels. Intra-arterial infusions of nicotine (Series 2) caused no hemodynamic changes in muscle. In conclusion, intravenous nicotine caused vasoconstriction in muscle, which was not due to reduced metabolic demand, pressure-flow autoregulation, or a direct [corrected] effect on vascular smooth muscle, but to stimulation of alpha-adrenergic receptors. Following denervation, this vasoconstriction was maintained by elevated plasma catecholamines. alpha-Adrenergic blockade unmasked nicotine-induced vasodilation mediated by beta-adrenergic receptors, whereas combined alpha- and beta-adrenergic blockade unmasked nicotine-induced vasoconstriction by a nonadrenergic mechanism.     

Coronary effects of cyclovirobuxine D in anesthetized pigs and in isolated porcine coronary arteries.

The present study was undertaken in anesthetized pigs and in isolated porcine coronary arteries to determine the primary coronary effects of cyclovirobuxine D. In six pigs, the intravenous administration of 1.5 mg/kg of cyclovirobuxine D whilst preventing changes in heart rate and aortic blood pressure caused increases in left ventricular dP/dtmax and coronary blood flow which respectively averaged 10% and 23.9%. These responses were progressively augmented by graded increases in the dose of the drug (four pigs) and were not affected by blockade of cholinergic and adrenergic receptors (five pigs). Intravenous blockade of nitric oxide synthase (L-NAME, five pigs) abolished both responses, while intracoronary injection of L-NAME (five pigs) abolished only the coronary vasodilatation. In ten isolated coronary segments, cyclovirobuxine D significantly reduced the degree of potassium chloride-induced contraction. This reduction was not affected by inhibition of cyclooxygenase with indomethacin (five segments) or potassium channels blockade with glibenclamide (five segments), but it was abolished by L-NAME (five segments) or removal of endothelium (five segments). The present study showed that cyclovirobuxine D caused a primary effect of coronary vasodilatation, which involved mechanisms related to the endothelial release of nitric oxide.     

Role of beta 2-adrenergic receptors on coronary resistance during exercise

The effects of regional alpha- and specific beta 2-adrenergic receptor blockade on measurements of late diastolic coronary resistance (LDCR) and mean coronary blood flow velocity (CBFV) during exercise were examined in 14 conscious adult mongrel dogs. Specific beta 2-adrenergic receptor blockade (ICI 118.551) significantly decreased CBFV and increased LDCR by blockade of beta 2-vasodilator tone independent of alpha-adrenergic receptor-mediated tone and independent of altering myocardial metabolism. alpha-Adrenergic receptor blockade (phentolamine, 1 mg) significantly increased CBFV and decreased LDCR by blocking sympathetically mediated vasoconstrictor tone. There was no significant difference in the magnitude of response between alpha- and beta 2-adrenergic receptor blockade. These results demonstrate that alpha- and beta 2-adrenergic receptors have a significant and evidently equal influence on CBFV and LDCR during exercise. Four weeks of daily exercise and left stellate ganglionectomy (LSGx) prevented phentolamine-induced vasodilation but not ICI 118.551-induced vasoconstriction. This suggests that daily exercise and LSGx significantly decreased the alpha-adrenergic receptor-mediated vasoconstrictor tone on the coronary circulation, resulting in an apparently greater role for the coronary vascular beta 2-adrenergic receptor on the control of CBFV and LDCR during exercise.     

The adrenergic regulation of the cardiovascular system in the South American rattlesnake, Crotalus durissus

The present study investigates adrenergic regulation of the systemic and pulmonary circulations of the anaesthetised South American rattlesnake, Crotalus durissus. Haemodynamic measurements were made following bolus injections of adrenaline and adrenergic antagonists administered through a systemic arterial catheter. Adrenaline caused a marked systemic vasoconstriction that was abolished by phentolamine, indicating this response was mediated through alpha-adrenergic receptors. Injection of phentolamine gave rise to a pronounced vasodilatation (systemic conductance (G(sys)) more than doubled), while injection of propranolol caused a systemic vasoconstriction, pointing to a potent alpha-adrenergic, and a weaker beta-adrenergic tone in the systemic vasculature of Crotalus. Overall, the pulmonary vasculature was far less responsive to adrenergic stimulation than the systemic circulation. Adrenaline caused a small but non-significant pulmonary vasodilatation and there was tendency of reducing this dilatation after either phentolamine or propranolol. Injection of phentolamine increased pulmonary conductance (G(pul)), while injection of propranolol produced a small pulmonary constriction, indicating that alpha-adrenergic and beta-adrenergic receptors contribute to a basal regulation of the pulmonary vasculature. Our results suggest adrenergic regulation of the systemic vasculature, rather than the pulmonary, may be an important factor in the development of intracardiac shunts.     

Endothelin-1 induces vasoconstriction through two functionally distinct pathways in porcine coronary artery: contribution of phosphoinositide turnover

Endothelin-1 (ET1)-induced contraction of isolated porcine coronary artery strips was previously reported to be mainly dependent on extracellular Ca2+. However, even in a Ca2+-free, EGTA-containing solution relatively high concentrations of ET1 induced a weak vasoconstriction, which was markedly but not completely inhibited by pretreatment with caffeine. Over similar dose ranges, ET1 stimulated the production of inositol phosphates in a dose-dependent manner in intact arterial tissues, which was independent of extracellular Ca2+ and was not affected by receptor blockers such as atropine, methysergide and diphenhydramine. Moreover, ET1 was shown to induce an increase in 1,2-diacylglycerol. These results indicate that the activation of ET1 receptors on porcine coronary artery smooth muscle causes phosphoinositide breakdown, leading to intracellular Ca2+ mobilization and protein kinase C activation. It is suggested that phospholipase C-mediated phosphoinositide breakdown as well as previously reported activation of voltage-dependent Ca2+ channels are involved in the mechanism of ET1-induced vasoconstriction.     

Effect of nephrectomy and of adrenergic receptor blockers on the cardiorenal actions of endothelin

The cardiorenal actions of endothelin-1 (ET-1) were evaluated in rats following nephrectomy, in rats during alpha-adrenergic blockade with phentolamine, and in rats during beta-adrenergic blockade with propranolol. Female rats were anesthetized with pentobarbital and, following surgery, were allowed 60 min to stabilize before 3 x 20 min-control clearances were collected. ET-1 was then infused at a rate of 100 ng kg-1 min-1 for 30 min, the infusion was stopped, and three additional clearances were collected. Four groups of rats were studied: in Group 1 (n = 10), ET-1 was infused; in Group 2 (n = 5), a bilateral nephrectomy was performed 120 min before infusing ET-1; in Group 3 (n = 5), ET-1 was infused into rats treated with phentolamine (0.015 mg kg-1 min-1); and in Group 4 (n = 5), ET-1 was infused into rats treated with propranolol (0.015 mg kg-1 min-1). At 30 min during infusion of ET-1 into Group 1 rats, mean arterial blood pressure had increased (P less than 0.01) by 27 +/- 2% (SE) and the glomerular filtration rate had decreased (P less than 0.01) by 71 +/- 6% of baseline values. Nephrectomy potentiated and prolonged the ET-1-induced systemic vasoconstriction. Phentolamine had no effect on the cardiorenal actions of ET-1 whereas propranolol enhanced ET-1-induced changes in mean arterial blood pressure; mean arterial blood pressure increased 38 +/- 2% at 30 min during ET-1 + propranolol infusion (P less than 0.01 versus value with ET-1 alone). These data indicate that the kidney affects ET-1-induced systemic vasoconstriction and that beta-adrenergic (but not alpha-adrenergic) receptors are activated during infusion of ET-1 with a resultant attenuation of ET-1-induced changes in systemic blood pressure.     

Physiological antagonism caused by adrenergic stimulation of canine tracheal muscle

We studied the simultaneous alpha- and beta-adrenergic response characteristics of canine tracheal smooth muscle in 398 strips from 67 dogs in vitro. Experiments were performed to determine the effects of beta-adrenergic blockade on the expression of the alpha-adrenoceptor contractile responses elicited by norepinephrine (NE), phenylephrine (PE), and clonidine (CLO). Maximal active tension caused by NE increased from 39.1 +/- 27.0 to 241 +/- 75.0 g/cm2 as the concentration of propranolol (PROP) was increased from 10(-6) to 10(-4) M. Augmentation of tracheal smooth muscle contraction caused by PE and CLO was also observed with progressive beta-adrenoceptor blockade; contraction to NE, PE, and CLO was blocked selectively with 3 X 10(-5) M phentolamine (PA) and phenoxybenzamine (PBZ). The beta-adrenergic relaxing properties of the same three agonists were also studied. After alpha-adrenergic blockade with PA or PBZ, all three agonists caused relaxation (NE greater than CLO greater than PE) of methacholine-induced contraction of tracheal smooth muscle that was reversed selectively with PROP. We demonstrate that NE, PE, and CLO cause simultaneous stimulation of both the alpha- and beta-adrenergic receptors in tracheal smooth muscle; the net response elicited is the result of adrenergic physiological antagonism and depends on the relative degree of alpha- and/or beta-adrenoceptor blockade.     

Production of NAADP and its role in Ca2+ mobilization associated with lysosomes in coronary arterial myocytes

The present study was designed to determine the production of nicotinic acid adenine dinucleotide phosphate (NAADP) and its role associated with lysosomes in mediating endothelin-1 (ET-1)-induced vasoconstriction in coronary arteries. HPLC assay showed that NAADP was produced in coronary arterial smooth muscle cells (CASMCs) via endogenous ADP-ribosyl cyclase. Fluorescence microscopic analysis of intracellular Ca2+ concentration ([Ca2+]i) in CASMCs revealed that exogenous 100 nM NAADP increased [Ca2+]i by 711 +/- 47 nM. Lipid bilayer experiments, however, demonstrated that NAADP did not directly activate ryanodine (Rya) receptor Ca2+ release channels on the sarcoplasmic reticulum. In CASMCs pretreated with 100 nM bafilomycin A1 (Baf), an inhibitor of lysosomal Ca2+ release and vacuolar proton pump function, NAADP-induced [Ca2+]i increase was significantly abolished. Moreover, ET-1 significantly increased NAADP formation in CASMCs and resulted in the rise of [Ca2+]i in these cells with a large increase in global Ca2+ level of 1,815 +/- 84 nM. Interestingly, before this large Ca2+ increase, a small Ca2+ spike with an increase in [Ca2+]i of 529 +/- 32 nM was observed. In the presence of Baf (100 nM), this ET-1-induced two-phase [Ca2+]i response was completely abolished, whereas Rya (50 microM) only markedly blocked the ET-1-induced large global Ca2+ increase. Functional studies showed that 100 nM Baf significantly attenuated ET-1-induced maximal constriction from 82.26 +/- 4.42% to 51.80 +/- 4.36%. Our results suggest that a lysosome-mediated Ca2+ regulatory mechanism via NAADP contributes to ET-1-induced Ca2+ mobilization in CASMCs and consequent vasoconstriction of coronary arteries.     

The effect of alpha and beta adrenergic blockade on Ni induced coronary spasm in scalded rats

After 20% total body surface scalding inducing 3d degree burn in rats the following parameters were studied in ebb and flow phases, as well as in burn disease, 2 hours, 2 and 7 days postburn: atomic absorption spectrophotometric study of the serum and myocardial Ni levels; the effect of Ni ions (10(-8)-10(-4) M/l) in vitro on total coronary resistance in the isolated perfused rat heart; the effect of alpha and beta adrenergic blocking agents (phenoxibenzamine, oxprenolol) on Ni-induced coronary vasoconstriction; electron cytochemical study of the ultrastructural changes of the myocardium 7 days after scalding. It was found that: During the first 2-3 hours after scalding or bleeding there was a significant elevation of serum Ni level which levelled off by the end of the first week. Total coronary resistance (TCR) increasing effect of Ni ions was significantly augmented during the first 2-3 hours after burn and bleeding (ebb phase). In the scalded group it decreased to the control value by the 2-3d day (flow phase) and increased again a week later (burn disease). In the scalded groups in vivo pretreatment with oxprenolol (10(-4) g/kg) completely inhibited the Ni induced coronary spasm. PBZ treatment in vitro (10(-5) M/l) had similar effect in the three postburn periods tested. Ultrastructural changes and intracellular Ni-dimetilglyoxim complexes could be detected. Oxprenolol treatment continuously applied from the 4th day postburn (2 X 0.5 mg/kg) prevented the development of myocardial damage, while the electron dense complexes containing Ni were still detectable. In view of our previous data we assume that the endogenous Ni increase in the serum after burn may be cardiopathogenic. The phasic changes of the sensitivity of the coronary vessels to Ni ion and the similarity of the effects of alpha and beta adrenergic blocking agents may be explained by the alterations in the neuroendocrine system and metabolic disturbances.     

Calcium fluxes in isolated acinar cells from rat parotid. Effect of adrenergic and cholinergic stimulation.

Rat parotid acinar cells dispersed by a combination of enzymatic treatments remain sensitive to adrenergic and cholinergic agonists. Previous studies have implicated Ca2+ in both adrenergic and cholinergic responses. This paper describes the effects of adrenergic and cholinergic stimulation upon 45Ca2+ fluxes in isolated parotid acinar cells. Suspensions of dispersed cells took up 45Ca2+ from the medium. The net rate of isotope influx was increased by the adrenergic agonists epinephrine, norepinephrine, isoproterenol, and phenylephrine, and by the cholinergic agonists acetylcholine and carbamylcholine. In 1 mM Ca2+, epinephrine was capable of increasing the 45Ca2+ influx in 40 min to three times that of resting cells. Isoproterenol, a beta-adrenergic agonist, was only half as effective as epinephrine in stimulating maximal calcium uptake although it was equally effective in stimulating maximal amylase release in the same cells. Experiments with the alpha-adrenergic antagonist phentolamine, the beta-adrenergic antagonist propranolol, and the cholinergic antagonist atropine confirmed that alpha- and beta-adrenergic and cholinergic stimulation each had a direct stimulatory effect on 45Ca2+ uptake. N6,O2'-Dibutyryl adenosine 3':5'-monophosphate also caused some stimulation of net calcium uptake. Direct measurement of Ca2+ efflux indicated that the increased calcium uptake in the presence of epinephrine was not the indirect result of a decrease in efflux. The rates of both basal and epinephrine-stimulated calcium uptake increased with increasing calcium concentration in the medium. Epinephrine had little effect on the rate of calcium uptake at 0.15 mM Ca2+. Although the energy poison NaCN had little effect on the basal rate of calcium uptake, the stimulable component of calcium uptake was inhibited by NaCN at all calcium concentrations tested (0.2 to 4.1 mM).     

Chronic propranolol treatment decreases pulmonary artery pressure in conscious dogs

Daily administration of propranolol to 9 chronically instrumented, trained dogs for 2 weeks caused significant (p less than 0.05) decreases in heart rate (70 +/- 8 to 57 +/- 6 beats/min), cardiac output (3.6 +/- 0.3 to 2.9 +/- 0.2 liters/min), pulmonary arterial pressure (15.7 +/- 0.5 to 10.0 +/- 0.5 mm Hg) and total pulmonary vascular resistance (4.6 +/- 0.6 to 3.3 +/- 0.4 units). Nadolol, a structurally dissimilar beta-adrenergic receptor antagonist, caused a similar decrease in total pulmonary resistance. Acute meclofenamate administration did not return to normal pulmonary arterial pressure and resistance in the dogs chronically treated with beta-adrenergic receptor blockers. We therefore conclude that chronic beta-adrenergic receptor blockade lowered pulmonary arterial pressure and resistance by a mechanism independent of cyclooxygenase. In addition, chronic beta-adrenergic receptor blockade did not affect the potential for hypoxic vasoconstriction.     

Hepatic sodium-potassium exchange induced by adrenomimetic amines.

The effects of catecholamines on hepatic K+ and Na+ movements were studied in anesthetized dogs by measuring systemic arterial and hepatic venous electrolyte composition following intraportal injections of adrenergic agonists. All catecholamines studied caused the initial loss and subsequent uptake of K+ by the liver. The loss of hepatic K+ was accompanied by an uptake of Na+ at a 1:1 ratio. This accumulation of Na+ continued, although at a slower rate, for at least 8 min. Epinephrine and norepinephrine were much more potent in these effects than either phenylephrine or isoproterenol. Neither alpha- nor beta-adrenergic blockade, singly or in combination, had an appreciable effect on the magnitude or duration of the observed ion shifts. It is concluded that the predominant effect of catecholamines is to produce a net accumulation of hepatic Na+, and that the mechanism governing hepatic ion movements is nonadrenergic as defined by stimulation by specific adrenergic agonists and inhibition by specific adrenergic antagonists.     

Heat production as a criterion of adrenergic regulation of metabolic processes of the myocardium

Bolus injection of adrenaline in coronary perfusion blood flow caused different-directed changes in coronary venous blood temperature. Directivity and myocardium heat production changes are determined by peculiarities of interactions between adrenergic and cholinergic mechanisms of cardiodynamics and myocardial metabolism regulation. Cholinergic blockade by atropine++ increases heat production and limits negative ino- and chronotropic components of cardiac adrenergic reactions. That increase is completely eliminated by subsequent obsidan blockade of beta-adrenoreceptors.     

The mechanism of beta-adrenergic receptor blockade-induced elevation of arterial blood pressure in rats

Beta-adrenergic blockade increases peripheral vascular resistances acutely and paradoxically lowers arterial blood pressure in most species but not in the rat. In this study the hypothesis has been tested of a significant participation of unopposed alpha-adrenergic mediated vasoconstriction following beta-adrenergic blockade in blood pressure regulation of conscious rats. Alpha-adrenergic blockade in propranolol-pretreated rats significantly decreased mean arterial blood pressure by 22%, heart rate by 20%, and total peripheral resistance by 14% when compared to rats treated only with propranolol, whereas cardiac output was similar in the two groups. A significant 28% reduction of coronary blood flow in rats treated with alpha- and beta-adrenergic blockers, when compared to rats treated only with propranolol, is most likely related to phentolamine's indirect effects on the coronary vasculature. Cerebrovascular and renovascular resistances were similar in these groups. All changes reported were significant at the 95% confidence level. It is concluded that the mechanism of increased blood pressure following beta-adrenergic blockade in rats is related at least in part to unmasking of unopposed alpha-receptor tone, which, however, is minimal in the coronary, cerebral and renal circulations.     

Influence of alpha and beta adrenergic receptors blockade on the adrenolytic effect of muscular work

The changes in the response of adrenergic receptors alpha and beta in the blood vessels in the working muscles in a hindlimb in cats were studied after intra-arterial administration of noradrenaline, isoprenaline and during electric stimulation of the sympathetic trunk. The experiments were carried out during alpha-adrenergic receptors blockade with dihydroergotamine (0.3 mg/kg) beta-adrenergic receptors blockade with propranolol (1 mg/kg) and blockade of acetylcholine M receptors with atropine (0.5 mg/kg). The investigations were performed at rest, during exercise (electric stimulation of the sciatic nerve) and after the exercise. The following results deserve attention: 1) beta-adrenergic receptors blockade reduced significantly the alpha-adrenolytic effect of exercise restoring the ability of blood vessel to constriction in response to noradrenaline; 2) the vasodilator effect of isoprenaline evident in resting state and maintained to some extent during exercise was abolished completely by preceding alpha-adrenergic blockade. The changes in the reactivity of resistance vessels in working skeletal muscles to noradrenaline, with abolition of its vasoconstrictor effect, have been shown by Rein [7] and others authors [2, 5]. Similarly, it is well known that the resistance vessels contain two types of adrenergic receptors alpha and beta, and that the response of the vessels to stimulation of these receptors are different [1]. In view of the recently published observations of Jarhult and Lundvall suggesting that the beta-adrenergic receptors play an important physiological role [6] in the arterial part of the microcirculation [6] and in view of the hypothesis put forward by Kunos and Szentivanyj that alpha and beta receptors can be transformed depending on the intensity of tissue metabolism [8] it seemed worth while to study more systematically the changes of the reactivity of alpha and beta adrenergic receptors in the vascular bed of the skeletal muscles during and after muscle exercise.     

Specificity of autonomic influences on cardiac responses during myocardial ischemia.

A possible role of the autonomic nervous system in the left ventricular response to acute regional myocardial ischemia was sought in conscious dogs instrumented for measurement of left ventricular pressure, internal diameter, and aortic flow. Ischemia produced by occluding the left circumflex coronary artery caused tachycardia and reduced contractility. Changes during control occlusions were compared with those during occlusion.s after beta-adrenergic blockade, parasympathetic blockade, and combined sympathetic and parasymphatetic blockade. Beta-blockade did reduce the tachycardia and slightly reduced left ventricular diameter changes in response to coronary occlusion. Results obtained in animals following surgical cardiac sympathectomy indicated reduced tachycardia and no effects on other parameters. The principal effect of parasympathetic blockade was to augment the increase in end diastolic diameter during occlusion Right atrial pacing indicated this change was due to higher initial heart rates. Combined parasympathetic and sympathetic blockade did not alter inotropic responses to coronary occlusion. Results indicated that inotropic support due to changes in activity in autonomic nerves is not increased during acute occlusion of the left circumflex coronary artery.     

Constriction to hypoxia-reoxygenation in isolated mouse coronary arteries: role of endothelium and superoxide.

The aim of the present study was to determine the role of endothelium and superoxide in the responses of isolated mouse coronary arteries to hypoxia-reoxygenation. Isolated mouse coronary artery was cannulated, pressurized at 60 mmHg, and constantly superfused with recirculating Krebs-Ringer bicarbonate solution for continuous measurement of intraluminal diameter (ID) by video microscopy. Under a no-flow condition, hypoxia (0% O(2), 30 min) caused vasoconstriction. Reoxygenation caused a further vasoconstriction (ID change from 111.4 +/- 11.1 to 91 +/- 16.5 microm) that was significantly reduced by removal of endothelium (ID change from 105.4 +/- 27 to 109.9 +/- 23.4 microm). Cu/Zn superoxide dismutase (150 U/ml) did not alter the hypoxic vasoconstriction but abolished the reoxygenation-caused endothelium-dependent vasoconstriction. Hypoxia-reoxygenation markedly enhanced the generation of superoxide that was significantly reduced by either removing the endothelium or treated these endothelium-intact vessels with superoxide dismutase. These results suggest that, in isolated mouse coronary arteries, hypoxia causes vasoconstriction that is independent of endothelium, whereas reoxygenation causes vasoconstriction that is mediated by enhanced generation of superoxide from endothelium.     

17beta-Estradiol modulates vasoconstriction induced by endothelin-1 following trauma-hemorrhage

Although endothelin-1 (ET-1) induces vasoconstriction, it remains unknown whether 17beta-estradiol (E(2)) treatment following trauma-hemorrhage alters these ET-1-induced vasoconstrictive effects. In addition, the role of the specific estrogen receptor (ER) subtypes (ER-alpha and ER-beta) and the endothelium-localized downstream mechanisms of actions of E(2) remain unclear. We hypothesized that E(2) attenuates increased ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-beta-mediated pathway. To study this, aortic rings were isolated from male Sprague-Dawley rats following trauma-hemorrhage with or without E(2) treatment, and alterations in tension were determined in vitro. Dose-response curves to ET-1 were determined, and the vasoactive properties of E(2), propylpyrazole triol (PPT, ER-alpha agonist), and diarylpropionitrile (DPN, ER-beta agonist) were determined. The results showed that trauma-hemorrhage significantly increased ET-1-induced vasoconstriction; however, administration of E(2) normalized ET-1-induced vasoconstriction in trauma-hemorrhage vessels to the sham-operated control level. The ER-beta agonist DPN counteracted ET-1-induced vasoconstriction, whereas the ER-alpha agonist PPT was ineffective. Moreover, the vasorelaxing effects of E(2) were not observed in endothelium-denuded aortic rings or by pretreatment of the rings with a nitric oxide (NO) synthase inhibitor. Cyclooxygenase inhibition with indomethacin had no effect on the action of E(2). Thus, E(2) administration attenuates ET-1-induced vasoconstriction following trauma-hemorrhage via an ER-beta-mediated pathway that is dependent on endothelium-derived NO synthesis.     

Vagal inhibitory effects on peripheral circulation in acute coronary occlusion.

The reflex adjustments of the peripheral circulation in response to acute coronary occlusion were studied in anesthetized dogs with isolated vascular beds perfused at constant flow. Coronary occlusion caused significant increases in perfusion pressure which averaged 27 +/- 4 mmHg in the hindlimb, 19 +/- 8 mmHg in skeletal muscle, and 13 + 5 mmHg in the mesenteric artery. These responses were less than half those caused by a similar decrease in aortic pressure obtained with hemorrhage. Coronary occlusion caused no significant changes in renal and paw circulations, while marked vasoconstriction resulted from hemorrhage. When aortic pressure was maintained constant throughout the duration of coronary occlusion, there was a significant vasodilatation in all beds studied. After vagotomy, coronary occlusion caused a constrictor response similar in magnitude to that caused by hemorrhage in each vascular bed and the dilator responses to occlusion at constant aortic pressure were abolished. Both constrictor and dilator changes were prevented by alpha-adrenergic blockade. Mechanical distension of the left ventricle in four dogs with carotid sinus nerves cut caused a significant reflexdilatation in the hindlimb. Thus, coronary occlusion initiates an inhibitory reflex mediated by vagal afferents which opposes peripheral vasoconstriction most effectively in the renal and paw circulations.