Tone Pressure Research Articles

Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening.

Regulation of ductus arteriosus (DA) tension depends on a balance between oxygen-induced constriction and PG and nitric oxide (NO)-mediated relaxation. After birth, increasing Pa(O(2)) produces DA constriction. However, as the full-term ductus constricts, it develops severe tissue hypoxia in its inner vessel wall (oxygen concentration <0.2%). We used isolated rings of fetal lamb DA to determine why the constricted ductus does not relax and reopen as it becomes hypoxic. We used a modification of the 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF5) technique (Clyman RI, Chan CY, Mauray F, Chen YQ, Cox W, Seidner SR, Lord EM, Weiss H, Wale N, Evan SM, and Koch CJ. Pediatr Res 45: 19-29, 1999) to determine mean tissue oxygen concentration. A decrease in the ductus' mean tissue oxygen concentration from 1.4 to 0.1% lowers the isometric tone of the ductus by 15 +/- 10% of its maximal active tension (the maximal tension that can be produced by the ductus). Although decreases in oxygen concentration diminish ductus tension, most of the vasoconstrictor tone in the ductus is independent of ambient oxygen concentration. This oxygen-independent tone is equivalent to 64 +/- 10% of the maximal active tension. At mean tissue oxygen concentrations >0.2%, endogenous PGs and NO inhibit more than 40% of the active tension developed by the ductus. However, when tissue oxygen concentrations drop below 0.2%, the constitutive relaxation of the ductus by endogenous PGs and NO is lost. In the absence of PG and NO production, tension increases to a level normally observed only after treatment of the ductus with indomethacin and nitro-L-arginine methyl ester (inhibitors of PG and NO production). Therefore, under conditions of severe hypoxia (tissue oxygen concentration <0.2% oxygen), the loss of PG- and NO-mediated relaxation more than compensates for the loss of oxygen-induced tension. We hypothesize that this increased ductus tone enables the vessel to remain closed as it undergoes tissue remodeling.

Nifedipine-induced inhibition of parasympathetic-mediated vasodilation in the orofacial areas of the cat.

In anesthetized cats, we 1) compared the effects of antihypertensive agents (nifedipine, clonidine, phentolamine, propranolol, and nitroprusside) on the parasympathetic vasodilations elicited by lingual nerve (LN) stimulation in the lower lip and tongue and 2) investigated the mechanisms underlying the inhibitory effect of nifedipine on parasympathetic lower lip vasodilation. At the doses used, each antihypertensive agent reduced systemic arterial blood pressure by approximately 20 mmHg; however, the parasympathetic vasodilation elicited by LN stimulation was significantly reduced only by nifedipine. This inhibitory effect of nifedipine was not seen when LN was stimulated during ongoing repetitive stimulation of the superior cervical sympathetic trunk at 1-Hz frequency. This suggests that the ability of lip and tongue blood vessels to relax to parasympathetic stimulation is not directly impaired by this calcium channel blocker and that the inhibitory effects of nifedipine seen here probably resulted from an action on postsynaptic sites in vascular smooth muscle that caused a reduction in preexisting sympathetic vasoconstrictor tone (by inhibiting calcium influx into the vascular smooth muscle cell).

Conditions permitting suppression of stretch-induced and vasoconstrictor tone by basal nitric oxide activity in porcine cerebral artery.

This study examined the ability of basal nitric oxide activity to suppress intrinsic and vasoconstrictor tone in isolated rings of porcine cerebral artery. Following stretch of approximately 1 g, N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM) produced a rise in tone in endothelium-containing but not endothelium-denuded rings. Thus, intrinsic tone was present and was powerfully suppressed by basal nitric oxide activity. Nevertheless, when concentration-response curves were constructed to U46619 and 5-hydroxytryptamine (5-HT), no endothelium-dependent depression of vasoconstriction was observed. It therefore appeared that basal nitric oxide activity was able to suppress intrinsic but not vasoconstrictor tone in these vessels. Stretch-tension curves generated following the application of stretch over the range 0 - 5. 5 g on endothelium-denuded rings showed that tension was stretch-induced. Experiments conducted in the presence of L-NAME (100 microM) revealed that the level of tone present in endothelium-containing rings was substantially higher than in endothelium-denuded rings across the entire range of stretch. When endothelium-containing and endothelium-denuded rings were set at similar levels of stretch-induced tone, rather than similar levels of stretch, the presence of the endothelium now depressed significantly vasoconstrictor responses to U46619 and 5-HT. Thus, when endothelium-containing and endothelium-denuded rings of porcine cerebral artery are set at similar points along their respective stretch-tension curves, rather than at similar levels of stretch, basal nitric oxide activity can be seen to inhibit both stretch-induced and vasoconstrictor tone.

Splanchnic organ blood flow during calcitonin gene-related peptide-induced hypotension with or without propranolol in dogs.

Propranolol has been used to attenuate reflex tachycardia during induced hypotension. The purpose of the current study was to determine whether propranolol can modify splanchnic organ blood flow during calcitonin gene-related peptide (CGRP)-induced hypotension in dogs anesthetized with 1.3% isoflurane in oxygen. After surgical preparation and hemodynamic stabilization, saline as a control, 0.5 mg/kg and 2.0 mg/kg propranolol (n = 10, each) were administered in a bolus injection 20 min before hypotension was induced. Mean arterial pressure was reduced to 60 mm Hg during 60 min of CGRP infusion. Renal blood flow (RBF), hepatic blood flow (HBF), and pancreatic blood flow (PBF) were measured using the hydrogen clearance method. Cardiac index did not change in all three groups, and heart rate in the control group remained unchanged. In the propranolol groups, however, heart rate decreased (P < 0.01). Plasma norepinephrine (NE), but not epinephrine (E), increased (P < 0.05) after propranolol administration. The NE and E increased (P < 0.01) during induced hypotension in all three groups. NE was higher in the 0.5 mg/kg propranolol group than in the control group. RBF in the control group remained unchanged throughout observation. RBF, HBF, and PBF decreased (P < 0.01) after propranolol and remained decreased during and after induced hypotension. The degrees of decreased HBF and PBF in the control group were less than those in the 2.0 mg/kg propranolol group. In conclusion, pretreatment with propranolol decreases splanchnic organ blood flow further during CGRP-induced hypotension, due in part to increased plasma catecholamine concentrations. The reductions in splanchnic organ blood flows during CGRP-induced hypotension with propranolol are due to a reflex augmentation in sympathetic vasoconstrictor tone caused by an increase in plasma catecholamine concentrations. These findings suggest that propranolol may impair splanchnic organ blood flow during CGRP-induced hypotension.

Effect of electroacupuncture on blood pressure and adrenal nerve activity in anesthetized rats

The neural mechanism underlying the effect of electroacupuncture (Ea) on arterial blood pressure (BP) and adrenal nerve activity (ANA) was investigated in anesthetized rats. Tsusanli (St-36) and Hoku (Li-4) were tested with combinations of two different frequencies (3 and 30 Hz) with various stimulation intensities of Ea. At Tsusanli, no effect was found, while at Hoku, an elevation of BP in parallel with ANA was elicited during Ea when the intensity was 5× T or higher. The pattern of the pressor response caused by the low frequency Ea (LFEa, 3 Hz) was a tonic one, while a phasic one was induced by the high frequency Ea (HFEa, 30 Hz). When both Hoku were simultaneously stimulated with the same frequency, the latency to reach the maximal effect was shortened. However, when two different frequencies were used instead, a response characterized by a combination of both phasic and tonic effect was obtained. In bilateral Ea with idential frequency but different onset time, the pressor effect elicited by the latter Ea showed no further increase during the stimulation period, however, when different frequencies were employed, each Ea elicited its own effect independently. The pressor effect elicited by Ea was abolished by regitine but not affected by adrenalectomy. It is concluded that a LFEa and a HFEa at Hoku with appropriate stimulation parameters can increase BP which is mainly due to potentiation of the sympathetic vasoconstrictor tone but via different central mechanisms.

Perioperative heat balance.

Hypothermia during general anesthesia develops with a characteristic three-phase pattern. The initial rapid reduction in core temperature after induction of anesthesia results from an internal redistribution of body heat. Redistribution results because anesthetics inhibit the tonic vasoconstriction that normally maintains a large core-to-peripheral temperature gradient. Core temperature then decreases linearly at a rate determined by the difference between heat loss and production. However, when surgical patients become sufficiently hypothermic, they again trigger thermoregulatory vasoconstriction, which restricts core-to-peripheral flow of heat. Constraint of metabolic heat, in turn, maintains a core temperature plateau (despite continued systemic heat loss) and eventually reestablishes the normal core-to-peripheral temperature gradient. Together, these mechanisms indicate that alterations in the distribution of body heat contribute more to changes in core temperature than to systemic heat imbalance in most patients. Just as with general anesthesia, redistribution of body heat is the major initial cause of hypothermia in patients administered spinal or epidural anesthesia. However, redistribution during neuraxial anesthesia is typically restricted to the legs. Consequently, redistribution decreases core temperature about half as much during major conduction anesthesia. As during general anesthesia, core temperature subsequently decreases linearly at a rate determined by the inequality between heat loss and production. The major difference, however, is that the linear hypothermia phase is not discontinued by reemergence of thermoregulatory vasoconstriction because constriction in the legs is blocked peripherally. As a result, in patients undergoing large operations with neuraxial anesthesia, there is the potential of development of serious hypothermia. Hypothermic cardiopulmonary bypass is associated with enormous changes in body heat content. Furthermore, rapid cooling and rewarming produces large core-to-peripheral, longitudinal, and radial tissue temperature gradients. Inadequate rewarming of peripheral tissues typically produces a considerable core-to-peripheral gradient at the end of bypass. Subsequently, redistribution of heat from the core to the cooler arms and legs produces an afterdrop. Afterdrop magnitude can be reduced by prolonging rewarming, pharmacologic vasodilation, or peripheral warming. Postoperative return to normothermia occurs when brain anesthetic concentration decreases sufficiently to again trigger normal thermoregulatory defenses. However, residual anesthesia and opioids given for treatment of postoperative pain decreases the effectiveness of these responses. Consequently, return to normothermia often needs 2-5 h, depending on the degree of hypothermia and the age of the patient.

Effects of color temperature of fluorescent lamps on body temperature regulation in a moderately cold environment.

A study on the effects of different color temperatures of fluorescent lamps on skin and rectal temperatures in a moderately cold environment involving (i) changes in skin temperature of 7 male subjects exposed to an ambient temperature ranging from 28 degrees C to 18 degrees C (experiment I) and (ii) changes in skin and rectal temperatures and metabolic heat production of 11 male subjects exposed to ambient temperature of 15 degrees C for 90 min (Experiment II) was conducted. In Experiment I, the reduction of mean skin temperature from the control value was significantly greater under 3000 K than under 5000 K or 7500 K lighting. In Experiment II, the reductions in mean skin temperature and rectal temperature were respectively greater and smaller under 3000 K than those under 5000 K or 7500 K lighting. However, metabolic heat production was not affected by color temperature conditions. The relationships between morphological and physiological parameters revealed that no significant relation of rectal temperature to body surface area per unit body weight was found only under 3000 K. Furthermore, while the mean skin temperature was independent on the mean skinfold thickness under 3000 K, a significant negative correlation between the rectal and mean skin temperatures was observed. Therefore, body heat loss might be suppressed effectively by increasing the vasoconstrictor tone under a color temperature of 3000 K, and the body shell was dependent only on morphological factors under 5000 K and 7500 K lighting.

Stretch induces mitogen-activated protein kinase activation and myogenic tone through 2 distinct pathways.

The aim of this study was to evaluate the involvement of the mitogen-activated protein kinase (ERK1/2) pathway in response to stretch in a blood vessel developing myogenic tone on stretch. Indeed, in resistance arteries and veins, the main effect of pressure is to induce a maintained vasoconstrictor (myogenic) tone. Isolated segments of rabbit facial vein were mounted in organ baths and submitted to isometric stretch. In this experimental model, myogenic tone was absent when the bath temperature was 33 degrees C. ERK1/2 activity was determined in each isolated segment by an in-gel kinase assay. Wall tension and ERK1/2 activity were measured in the same samples in the presence (39 degrees C) or in the absence of myogenic tone (33 degrees C). At 39 degrees C, a 5-mN wall tension induced myogenic tone (5.7+/-1.8 mN) and an increase in ERK1/2 activity (282+/-52% versus unstretched vessels, P<0.05). At 33 degrees C, in the absence of myogenic tone, ERK1/2 activity was similarly increased by stretch (254+/-35% versus unstretched vessels). The calcium-dependent and -independent protein kinase C (PKC) blocker Ro-31-8220 (5 x 10(-7) mol/L), but not the calcium-dependent PKC blocker Go-6976 (10(-6) mol/L), inhibited myogenic tone. However, ERK1/2 activity was not affected by either PKC blocker. Genistein (10(-7) mol/L), a general tyrosine kinase inhibitor, but not herbimycin A (5 x 10(-7) mol/L), a cSrc-family tyrosine kinase inhibitor, suppressed stretch-induced ERK1/2 activation (P<0.05) without affecting myogenic tone. Nifedipine (10(-6) mol/L), a voltage-dependent calcium entry inhibitor, and ryanodine (10(-6) mol/L), which depletes calcium stores, both inhibited ERK1/2 activity (113+/-12% and 121+/-7%, respectively; P<0. 05) without affecting myogenic tone. The mitogen-activated protein kinase kinase inhibitor PD 98059 (5 x 10(-6) mol/L) also inhibited ERK1/2 activation without affecting myogenic tone. The present results suggest that stretching the rabbit facial vein induced 2 distinct pathways, one leading to myogenic tone (via a non-calcium-dependent PKC activation) and one leading to ERK1/2 activation through a calcium-dependent pathway involving tyrosine kinase.

Effects of sympathectomy and nitric oxide synthase inhibition on vascular actions of insulin in humans.

Insulin exerts cardiovascular actions by stimulating nitric oxide (NO) release and sympathetic neural outflow. It is unclear, however, whether insulin stimulates muscle blood flow (and NO release) by a direct action at the vasculature and/or by stimulating neural vasodilator mechanisms. In these studies we used patients with regional sympathectomy to examine the vascular actions of insulin in the presence and absence of sympathetic vasoconstrictor and vasodilator innervation. A 2-hour insulin (6 pmol/kg per minute)/glucose clamp increased muscle blood flow in both innervated and denervated limbs by roughly 40% (P<0.01 versus baseline for both limbs). The vasodilation reached its maximum within the first 30 to 45 minutes of insulin/glucose infusion in sympathetically denervated limbs, but only at the end of the infusion in innervated limbs (P<0. 01, denervated versus innervated limb). Infusion of a NO synthase inhibitor (N(G)-monomethyl-L-arginine [L-NMMA]) increased baseline arterial pressure, abolished the vasodilation in the denervated limb, and led to a significant additional increase in arterial pressure during the clamp, but did not alter whole body glucose uptake. Our data indicate that insulin stimulates blood flow in sympathectomized limbs by a direct action at the vasculature. This effect is mediated by stimulation of NO release and appears to be masked by the sympathetic vasoconstrictor tone in innervated limbs.

The Pseudomonas aeruginosa quorum-sensing signal molecule, N-(3-oxododecanoyl)-L-homoserine lactone, inhibits porcine arterial smooth muscle contraction.

The Pseudomonas aeruginosa quorum sensing molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) has been shown to suppress cytokine production in macrophages. We have examined the effect of OdDHL and related compounds on constrictor tone of porcine blood vessels. OdDHL (1-30 microM) caused a concentration-dependent inhibition of U46619-induced contractions of the coronary artery through a largely endothelium-independent mechanism, but was markedly less effective in the pulmonary artery. Quantitively similar effects to those produced by OdDHL were observed with N-(3-oxododecanoyl)-L-homocysteine thiolactone, a thiolactone derivative, while N-3-oxododecanamide, a lactone-free acyl analogue, possessed 1/3rd the potency as a vasorelaxant. Neither N-butanoyl-L-homoserine lactone nor L-homoserine lactone (up to 30 microM) were active. Our findings indicate that OdDHL inhibits vasoconstrictor tone of both pulmonary and coronary blood vessels from the pig. The vasorelaxant action of OdDHL appears to be primarily determined by the N-acyl chain length, with a minor contribution by the homoserine lactone moiety.

Sympathectomy potentiates the vasoconstrictor response to nitric oxide synthase inhibition in humans.

Nitric oxide exerts its cardiovascular actions at least in part by modulation of the sympathetic vasoconstrictor tone. There is increasing evidence that nitric oxide inhibits central neural sympathetic outflow, and preliminary evidence suggests that it may also modulate peripheral sympathetic vasoconstrictor tone. To test this latter concept, in six subjects having undergone thoracic sympathectomy for hyperhydrosis, we compared the vascular responses to systemic L-NMMA infusion (1 mg/kg/min over 10 min) in the innervated and the denervated limb. We also studied vascular responses to the infusion of the non-nitric-oxide-dependent vasoconstrictor phenylephrine. L-NMMA infusion evoked a roughly 3-fold larger increase in vascular resistance in the denervated forearm than in the innervated calf. In the denervated forearm, vascular resistance increased by 58 +/- 10 percent (mean +/- SE), whereas in the innervated calf it increased only by 21 +/- 6 percent (P < 0.01, forearm vs. calf). This augmented vasoconstrictor response was specific for L-NMMA, and not related to augmented non-specific vasoconstrictor responsiveness secondary to sympathectomy, because phenylephrine infusion increased vascular resistance similarly in the denervated forearm and the innervated calf (by 24 +/- 7, and 29 +/- 8 percent, respectively). The augmented vasoconstrictor response was related specifically to denervation, because in control subjects, the vasoconstrictor responses to L-NMMA were comparable in the forearm and the calf. These findings indicate that in the absence of sympathetic innervation, the vasoconstrictor responses to nitric oxide synthase inhibition are augmented.

Frequency response characteristics of sympathetic transmission to skin vascular smooth muscles in rats.

Sympathetic modulation of cutaneous vasomotor waves in humans is most effective at frequencies up to 0.1 Hz. In contrast, sympathetic modulation of mesenteric vasomotor waves in rats is strongest in the frequency band between 0.2 and 0.75 Hz. Therefore, we addressed the question as to whether these different frequency response characteristics are due to species- or organ-specific disparities. Eleven Sprague-Dawley rats were instrumented with catheters in the carotid artery and in the jugular vein, together with electrodes on the centrally sectioned left lumbar sympathetic trunk (LST) and laser Doppler flow probes directed to the plantar surface of the skin of the left and right hind paws. In anesthetized rats, the LST was electrically stimulated at eight different stimulation frequencies, and the responses in laser Doppler blood flow were recorded in the skin of the ipsilateral and contralateral paw. At stimulation frequencies <0.2 Hz, LST stimulation induced corresponding oscillations in skin blood flow in the ipsilateral, but not in the contralateral, paw. These dynamic responses to LST stimulation in the ipsilateral paw were strongest at 0.05 and 0.075 Hz. At higher stimulation frequencies a tonic vasoconstriction was observed. It is concluded that organ-specific disparities exist in sympathetic transmission to vascular smooth muscles, whereas no species-specific differences are apparent in sympathetic transmission to cutaneous blood vessels of humans and rats.

Review of Evidence for a Novel Model of Cocaine-Induced Cardiovascular Toxicity

Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.

Clinical Pharmacology of α1-Adrenoceptor Antagonists

Benign prostatic hyperplasia (BPH) is the most prevalent condition to affect men beyong middle age. α₁-adrenoceptor blockers have been used in the treatment of BPH for more than 20 years and their effect on the lower urinary tract is now well established. These agents as a class have produced consistent improvements in both symptom scores and urinary flow rates in around 60–70% of patients treated. This efficacy is balanced against a small, but significant, incidence of side-effects, that consist of headaches, dizziness, nasal stuffiness, tiredness and very occasionally postural hypotension. There are important other effects of α₁-adrenoceptor blockers; for example in men with hypertension, these agents generally produce a clinically significant reduction in both systolic and diastolic blood pressures. There is also well documented evidence of a reduction in LDL cholesterol levels as well as serum triglycerides. A new and interesting observation is that patients receiving certain α₁-adrenoceptor blockers notice improvement in their sexual function and in particular in the quality of their erectile response. This effect has been attributed to decreased sympathetic vasoconstrictor tone to the helicine arteries supplying the lacunar spaces of the corpora cavernosa in the penis. In summary α₁-adrenoceptor blockers produce significant improvements in symptoms and flow rates in patients with bladder outflow obstruction due to benign prostatic hyperplasia. This is balanced against a small but significant incidence of side-effects, but some of these side-effects, such as a reduction in blood pressure in hypertensive patients, improvement in lipid profile and improvement in erectile function could be construed as beneficial.

Effect of ceramide on KCa channel activity and vascular tone in coronary arteries.

A sphingomyelin metabolite, ceramide, serves as a second messenger in a variety of mammalian cells. Little is known regarding the production and actions of this novel intracellular signaling lipid molecule in the vasculature. The present study was designed to test the hypothesis that a ceramide-mediated signaling pathway is present in coronary arterial smooth muscle and that ceramide serves as an inhibitor of the large-conductance Ca2+-activated potassium (KCa) channels and mediates vasoconstriction in coronary circulation. We found that C2-ceramide produced a concentration-dependent decrease in KCa channel activity in vascular smooth muscle cells from small bovine coronary arteries. The average channel activity of the KCa channels in cell-attached patches decreased from 0.046+/-0.01 to 0. 008+/-0.001 at a C2-ceramide concentration of 10 micromol/L. In inside-out patches, C2-ceramide (1 micromol/L) reduced the average channel activity of the KCa channels from 0.06+/-0.007 to 0.016+/-0. 004. Dithiothreitol, an inhibitor of acidic sphingomyelinase (1 mmol/L), increased the average channel activity of the KCa channels in cell-attached patches from 0.05+/-0.02 of control to 0.26+/-0.04, a 5-fold increase that was reversed by addition of 1 micromol/L ceramide. Glutathione, an inhibitor of neutral sphingomyelinase, was without effect. C2-ceramide significantly reduced the diameter of isolated perfused small coronary arteries in a concentration-dependent manner. Addition of 1 micromol/L C2-ceramide decreased average arterial diameter by 28%. When 14C-sphingomyelin was incubated with coronary arterial homogenates at pH 7.4 and pH 5. 0, 14C-choline phosphate and ceramide were produced. The conversion rates of 14C-sphingomyelin into 14C-choline phosphate and ceramide were 65.1+/-1.0 fmol/min per milligram protein at pH 7.4 and 114. 6+/-8.3 fmol/min per milligram protein at pH 5.0. We conclude that both acidic and neutral sphingomyelinases are present in the bovine coronary arteries and that ceramide inactivates the KCa channel in arterial smooth muscle cells and hence exerts a tonic vasoconstrictor action in coronary microcirculation.

Adrenergic and vasopressinergic contributions to the cardiovascular response to acute hypoxaemia in the llama fetus.

1. The effects of fetal intravenous treatment with phentolamine or a vasopressinergic V1-receptor antagonist on the fetal cardiovascular responses to acute hypoxaemia in the llama were investigated. 2. Six llama fetuses were surgically prepared between 60 and 70 % of gestation under general halothane anaesthesia with vascular catheters and transit-time ultrasonic flow probes around a carotid artery and a femoral artery. At least 4 days after surgery all fetuses were subjected to a 3 h experiment: 1 h of normoxia, 1 h of hypoxaemia and 1 h of recovery while on slow i.v. infusion with saline. On separate days this experiment was repeated with fetal i.v. treatment with either phentolamine or a V1-receptor antagonist dissolved in saline. 3. During saline infusion all llama fetuses responded to acute hypoxaemia with intense femoral vasoconstriction. Phentolamine during normoxia produced hypotension, tachycardia and vasodilatation in both the carotid and the femoral circulations. During hypoxaemia, fetuses treated with phentolamine did not elicit the pronounced femoral vasoconstriction and all died within 20 min of the onset of hypoxaemia. A V1-receptor antagonist produced a femoral vasodilatation during normoxia but did not affect the fetal cardiovascular responses to acute hypoxaemia. 4. In conclusion, alpha-adrenergic and V1-vasopressinergic mechanisms contribute to a basal vasoconstrictor tone in the femoral circulation in the llama fetus. The enhanced femoral vasoconstriction during acute hypoxaemia in the llama fetus is not mediated by stimulation of V1-vasopressin receptors, but is dependent on alpha-adrenergic receptor stimulation. Such alpha-adrenergic efferent mechanisms are indispensable to fetal survival during hypoxaemia in the llama since their abolition leads to cardiovascular collapse and death.

Role of endothelin in the increased vascular tone of patients with essential hypertension.

We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ETA) (BQ-123) and endothelin-B (ETB) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (P=0.78 and P=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33+/-7% (P<0.001 versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63+/-12%; P=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17+/-5%; P=0.004 versus baseline) in control subjects and transient vasodilation (15+/-7% after 20 minutes) in hypertensive patients (P<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (P=0.04) in hypertensive patients (46+/-4%) than in control subjects (32+/-4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ETA and ETB blockade seems to produce a greater vasodilator effect than selective ETA blockade.

Acute effects of transcendental meditation on hemodynamic functioning in middle-aged adults.

Increased peripheral vasoconstriction (ie, total peripheral resistance, or TPR) has been implicated as playing an important role in the early development of essential hypertension. Some studies have demonstrated that Transcendental Meditation (TM) reduces high blood pressure, but the hemodynamic adjustments behind these blood pressure reductions have not been elucidated. The aim of this study was to provide a preliminary investigation of the acute effects of TM on TPR. Subjects were 32 healthy adults (16 women and 16 men; 30 white and two African American; mean age, 46.4 +/- 3.9 years). Subjects were divided into a TM group of long-term TM practitioners (eight white women, nine white men, and one African American man; mean years of twice-daily TM practice, 22.4 +/- 6.7) and a control group (eight white women, five white men, and one African American man). Hemodynamic functioning was assessed immediately before and during three conditions: 20 minutes of rest with eyes open (all subjects), 20 minutes of TM (TM group), and 20 minutes of eyes-closed relaxation (control group). During eyes-open rest, the TM group had decreases in systolic blood pressure (SBP) and TPR, compared with increases in the control group (SBP: -2.5 vs. +2.4 mm Hg, p < .01; TPR: -0.7 vs. +0.5 mm Hg/liter per minute, p < .004). During TM, there was a greater decrease in SBP due to a concomitantly greater decrease in TPR compared with the control group during eyes-closed relaxation (SBP: -3.0 vs. +2.1 mm Hg, p < .04; TPR: -1.0 vs. +0.3 mm Hg/liter per minute, p < .03). TPR decreased significantly during TM. Decreases in vasoconstrictive tone during TM may be the hemodynamic mechanism responsible for reduction of high blood pressure over time. The results of this study provide a preliminary contribution to the understanding of the underlying hemodynamic mechanisms responsible for the beneficial influence of TM on cardiovascular risk factors.

Endothelin in heart failure.

Congestive heart failure is a complex disease that results from pumping failure of the cardiac muscle and adaptational processes of the cardiovascular system to correct for the reduced blood supply to the organism. It is associated with increased vasoconstriction and impaired vasodilation in response to physical activity. The elevated vasoconstrictor tone is caused by the activation of compensatory mechanisms including the sympathetic nervous system and stimulation of the release of neurohormones like angiotensin II, catecholamines, and vasopressin. Furthermore, the vascular endothelium is importantly involved in the regulation of vascular tone as it releases a variety of vasoactive substances that act locally and systemically. In congestive heart failure, there is a marked imbalance between the diminished release or the increased inactivation of vasodilators on the one hand, ie, nitric oxide, and the elevated production, release, or reduced inactivation of vasoconstrictors such as endothelin-1 on the other hand. In addition to its very potent vasoconstrictor effects, endothelin-1 possesses antinatriuretic and mitogenic properties that are a common feature of substances that are involved in development of the deleterious consequences that render congestive heart failure a lethal disease. The spectrum of action of the endothelin system and the advent of specific antagonists for its receptors have made this system a very interesting target for clinical research and possibly for future therapeutic approaches.

Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease

Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease. In a double-blind, placebo-controlled randomized study, we investigated the effects of the ETA/ETB endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (P<0. 05), whereas heart rate increased slightly (P<0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (P<0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (P<0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated. Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ETA/ETB endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease.