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PubMed2003

Pretreatment with phenoxybenzamine attenuates the radial artery's vasoconstrictor response to alpha-adrenergic stimuli.

BACKGROUND: Although the radial artery bypass conduit has excellent intermediate-term patency, it has a proclivity to vasospasm. We tested the hypothesis that brief pretreatment of a radial artery graft with the irreversible adrenergic antagonist phenoxybenzamine attenuates the vasoconstrictor response to the vasopressors phenylephrine and norepinephrine compared with the currently used papaverine/lidocaine. METHODS: Segments of human radial artery grafts were obtained after a 30-minute intraoperative pretreatment with a solution containing 20 mL of heparinized blood, 0.4 mL of papaverine (30 mg/mL), and 1.6 mL of lidocaine (1%). The segments were transported to the laboratory and placed into a bath containing Krebs-Henseleit solution and 10, 100, or 1000 micromol/L phenoxybenzamine or vehicle. The segments were tested in organ chambers for contractile responses to increasing concentrations of phenylephrine and norepinephrine (0.5-15 micromol/L). RESULTS: Contractile responses to 15 micromol/L phenylephrine in control radial artery segments averaged 44.2% +/- 9.1% of the maximal contractile response to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated contraction to 15 micromol/L phenylephrine (32.1% +/- 5.9%; P =.22), but 1000 micromol/L phenoxybenzamine completely abolished radial artery contraction (-7.2% +/- 4.4%; P <.001). The effect of 10 and 100 micromol/L phenoxybenzamine on attenuating vasocontraction was intermediate between 1000 micromol/L phenoxybenzamine and papaverine/lidocaine. Responses to 15 micromol/L norepinephrine in control radial artery segments averaged 54.7% +/- 7.5% of maximal contraction to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated the contraction response of radial artery segments (35.6% +/- 5.1%; P =.04). In contrast, 1000 micromol/L phenoxybenzamine showed the greatest attenuation of norepinephrine-induced contraction (-10.5% +/- 2.0%; P <.001). CONCLUSIONS: A brief pretreatment of the human radial artery bypass conduit with 1000 micromol/L phenoxybenzamine completely attenuates the vasoconstrictor responses to the widely used vasopressors norepinephrine and phenylephrine. Papaverine/lidocaine alone did not block vasoconstriction to these alpha-adrenergic agonists.

Adrenergic alpha-Antagonists↗

PubMed2002

Effect of whole-body and local heating on cutaneous vasoconstrictor responses in humans.

Animal studies suggest that alpha-adrenergic-mediated vasoconstriction is compromised during whole-body heating. The purpose of this study was to identify whether whole-body heating and/or local surface heating reduce cutaneous alpha-adrenergic vasoconstrictor responsiveness in human skin. Protocol I: Six subjects were exposed to neutral skin temperature (i.e., 34 degrees C), whole-body heating, and local heating of forearm skin to increase skin blood flow to the same relative magnitude as that observed during whole-body heating. Protocol II: In eight subjects forearm skin was locally heated to 34, 37, 40, and 42 degrees C. During both protocols, alpha-adrenergic vasoconstrictor responsiveness was assessed by local delivery of norepinephrine (NE) via intradermal microdialysis. Skin blood flow was continuously monitored over each microdialysis membrane via laser-Doppler flowmetry. In protocol I, whole-body and local heating caused similar increases in cutaneous vascular conductance (CVC). The EC50 (log NE dose) of the dose-response curves for both whole body (-4.2 +/- 0.1 M) and local heating (-4.7 +/- 0.4 M) were significantly greater (i.e., high dose required to cause 50% reduction in CVC) relative to neutral skin temperature (- 5.6 +/- 0.0 M; P<0.05 for both). In both local and whole-body heated conditions CVC did not return to pre-heating values even at the highest dose of NE. In protocol II, calculated EC50 for 34, 37, 40, and 42 degrees C local heating was - 5.5 +/- 0.4, -4.6 +/- 0.3, -4.5 +/- 0.3, - 4.2 +/- 0.4 M, respectively. Statistical analyses revealed that the EC50 for 37,40 and 42 degrees C were significantly greater than the EC50 for 34 degrees C. These results indicate that even during administration of high concentrations of NE, alpha-adrenergic vasoconstriction does not fully compensate for local heating and whole-body heating induced vasodilatation in young, healthy subjects. Moreover, these data suggest that elevated local temperatures, above 37 degrees C, and whole-body heating similarly attenuate cutaneous alpha-adrenergic vasoconstriction responsiveness.

Adult↗

PubMed1991

The effects of intra-arterial vasoconstrictors on the distribution of a radiolabelled low molecular weight marker in an experimental model of liver tumour.

Regional chemotherapy for colorectal liver metastases has not demonstrated a convincing survival benefit over systemic chemotherapy. This may be due to poor delivery of chemotherapeutic drugs to hypovascular liver tumour. Since vasoactive agents may influence hepatic blood flow this study investigated the effects of systemic and regional vasoconstrictors on the delivery of a regionally delivered marker in an experimental model of liver tumour. Systemic administration of angiotensin II caused a significant retention of marker in normal liver, but not in tumour compared to controls. Regional delivery of angiotensin II and phenylephrine caused significantly greater retention of marker in tumour than liver with an overall 4-fold increased retention of marker one minute after its injection. Ninety minutes after injection there was still significant retention of marker compared to control animals. Regional delivery of hepatic artery vasoconstrictors increase delivery of marker and may increase delivery of chemotherapeutic drug to liver tumour.

Angiotensin II↗

PubMed1992

Effects of tumour cells on angiogenesis and vasoconstrictor responses in sponge implants in mice.

The effects of tumour cells (Colon 26) on the development and response of new blood vessels to different vasoconstrictors (platelet activating factor; PAF, endothelin-1, angiotensin II, adrenalin and 5-hydroxytryptamine) have been investigated. Sponge implants in mice were used to host tumour cells while washout of 133Xe was employed to assess local blood flow in the implanted sponges. By 14 days after implantation the response of vessels in tumour-bearing implants to the various vasoconstrictors generally was decreased compared to that obtained in control sponge implants or adjacent normal skin. Thus at this time point the t1/2 for 133Xe washout from control sponges treated with adrenalin (0.5 micrograms) was 30 +/- 4 min whereas in tumour-bearing sponges it was 5 +/- 1 min. This decreased sensitivity in tumour vessels was probably not due to a complete lack of contractile elements since actin was demonstrated by immunohistochemistry around blood vessels in both types of implant. The results of the present study have shown that the pharmacological responses of blood vessels in a growing tumour, Colon 26, differed from the responses of vessels of a similar age in non-neoplastic tissue. These results appear to suggest that the different angiogenic stimuli released from tumour tissue may markedly influence pharmacological reactivity of newly formed blood vessels.

Adenocarcinoma↗

PubMed1976

Contribution of prostaglandins to the renal vascular supersensitivity to vasoconstrictor agents exhibited by New Zealand genetic hypertensive rats.

1. Studies were made of the effects on responses to vasoconstrictor agents of prostaglandins released from Krebs perfused isolated kidneys of genetic hypertensive and normotensive rats. 2. Prostaglandin E-like activity, detected by bioassay, was released from kidneys of both groups of rats during the vasoconstriction produced by noradrenaline, angiotensin or prostaglandin F2alpha. 3. In preparations obtained from hypertensive rats, responses to higher doses of noradrenaline or angiotensin were initially greater than those from normotensive rats and these were then reduced to a greater extent by infusion of indomethacin, which abolished release of prostaglandin E-like activity. Thereafter, in kidneys of either group, vasoconstriction to noradrenaline was potentiated by infusion of prostaglandin E2. 4. We conclude that, in rats, renal prostaglandins released in response to vasoconstrictor agents could augment the effect of such agents and in genetic hypertensive rats release of renal prostaglandins could contribute to the disease.

Animals↗

PubMed1997

A prospective, double-blind, randomized study on the use of a topical anesthetic, vasoconstrictor, and placebo during transnasal flexible fiberoptic endoscopy.

The purpose of the present study was to compare patient comfort levels following administration of a topical anesthetic, vasoconstrictor, placebo, or nothing to the nasal mucosa prior to flexible fiberoptic transnasal endoscopy. Using a prospective, double-blind, randomized design, 152 consecutive patients were randomly assigned to receive a topical anesthetic (N = 54), vasoconstrictor (N = 50), or placebo (N = 48). No significant differences were found among the three variables. An additional 50 consecutive patients had endoscopy performed without administration of any substance to the nares, and no significant differences were found among the four variables (N = 202). It was concluded that speech-language pathologists can perform independent and comfortable transnasal endoscopy without administration of any substance to the nasal mucosa. Flexible fiberoptic endoscopy, however, should be performed by experienced clinicians with care taken to examine visually the patency of both nares for ease and comfort of scope insertion.

Administration, Topical↗

PubMed1997

Long-lasting coronary vasoconstrictor effects and myocardial uptake of endothelin-1 in humans.

The effect of intravenous administration of the endothelium derived vasoconstrictor peptide endothelin-1 (ET-1 0.2. 1 and 8 pmol kg-1 min-1) on coronary blood flow in relation to plasma ET-1 as well as blood lactate and glucose levels were investigated in six healthy volunteers. Coronary sinus blood flow was measured by thermodilution. Administration of ET-1 elevated arterial plasma ET 35-fold, dose-dependently increased mean arterial blood pressure from 95 +/- 5 mmHg to 110 +/- 6 mmHg (P < 0.01) and reduced heart rate from 64 +/- 4 beats min-1 to 58 +/- 4 beats min-1 (P < 0.05) at 8 pmol kg-1 min-1. Coronary sinus blood flow was reduced maximally by 23 +/- 4% (P < 0.01) and coronary vascular resistance increased by 48 +/- 11% (P < 0.01). Coronary sinus oxygen saturation decreased from 35 +/- 1% to 22 +/- 2% at 2 min after the infusion (P < 0.01). A coronary constrictor response was observed at a 4-fold elevation in plasma ET. The reduction is coronary sinus blood flow lasted 20 min and coronary sinus oxygen saturation was still reduced 60 min after the infusion. Myocardial oxygen uptake or arterial oxygen saturation were not affected by ET-1. Myocardial lactate net uptake decreased by 40% whereas glucose uptake was unaffected. At the highest infusion rate there was a net removal of plasma ET by 24 +/- 3% over the myocardium (P < 0.05). The results show that ET-1 induces long-lasting reduction in coronary sinus blood flow via a direct coronary vasoconstrictor effect in healthy humans observable at a 4-fold elevation in plasma ET-1. Furthermore, there is a net removal of circulating ET-1 by the myocardium.

Adult↗

PubMed2000

Diversity of responses of renal cortical and medullary blood flow to vasoconstrictors in conscious rabbits.

The medullary microcirculation receives only about 10% of total renal blood flow, but plays a critical role in long-term arterial pressure regulation, so we need to better understand its regulation. Although there is evidence that circulating and locally acting hormones can differentially affect cortical and medullary blood flow in anaesthetized animals, there is little information from studies in conscious animals. This study is aimed (i) to develop a method for chronic measurement of cortical and medullary blood flow in conscious rabbits, and (ii) to test whether renal cortical and medullary blood flow can be differentially affected by intravenous (i.v.) infusions of various vasoconstrictor hormones in conscious rabbits. At preliminary operations, rabbits were equipped with single-fibre laser-Doppler flowprobes in the (left) renal cortex and medulla, and Transonic flowprobes for measuring cardiac output and renal blood flow. Intravenous angiotensin II (300 ng kg(-1) min(-1)), [Phe2,Ile3,Orn8]-vasopressin (30 ng kg(-1) min(-1)), noradrenaline (300 ng kg(-1) min(-1)), endothelin-1 (20 ng kg(-1) min(-1)) and N G-nitro-L-arginine (10 mg kg(-1)) increased mean arterial pressure (by 10-45% of baseline) and reduced heart rate (by 16-35%) and cardiac output (by 16-45%). Consistent with previous observations in anaesthetized rabbits, all treatments except [Phe2,Ile3, Orn8]-vasopressin reduced renal blood flow (13-63%) and cortical blood flow (16-47%), but medullary blood flow was significantly reduced only by [Phe2,Ile3,Orn8]-vasopressin (41%) and N G-nitro-L-arginine (42%). The diversity of these responses of cortical and medullary blood flow to i.v. infusions of vasoconstrictors provides further evidence for physiological roles of circulating and local hormones in the differential regulation of regional kidney blood flow.

Animals↗

PubMed1998

Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors.

AIMS: We compared the vasoconstrictor effects of 5-HT with those of the selective 5-HT1B/1D-receptor agonists sumatriptan and rizatriptan in human isolated cranial (middle meningeal) arteries. In addition selective 5-HT1B- or 5-HT1D-receptor antibodies were used in combination with semiquantitative immunohistochemical techniques to compare the levels of expression of these receptors in human middle meningeal and coronary arteries. METHODS: Middle meningeal and coronary arteries were obtained (with consent) from either neurosurgical patients or donor hearts, respectively. Segments of middle meningeal artery were mounted in organ baths for isometric recording and cumulative concentration-effect curves to 5-HT, rizatriptan and sumatriptan were obtained. Frozen fresh sections of middle meningeal and coronary arteries were subjected to standard immunohistochemical techniques using specific 5-HT1B- or 5-HT1D-receptor primary antibodies and a radiolabelled secondary antibody. Data were subjected to analysis of variance (ANOVA) and nonlinear regression analysis. RESULTS: 5-HT, rizatriptan and sumatriptan were potent vasoconstrictors in human isolated middle meningeal artery (EC50 values=32, 90 and 71 nM, respectively). A significantly higher level of 5-HT1B-receptor immunoreactivity was detected in middle meningeal artery compared with coronary artery (ANOVA, F=7.95, DF=1,4, P<0.05). CONCLUSIONS: Rizatriptan and sumatriptan act selectively to cause vasoconstriction in human isolated middle meningeal artery and are 10-fold more potent than in human coronary artery. The higher level of expression of 5-HT1B-receptors in middle meningeal compared with coronary artery provides a pharmacological basis for the craniovascular selectively of both rizatriptan and sumatriptan.

Adult↗

PubMed1998

Pharmacological reactivity of neoplastic and non-neoplastic associated neovasculature to vasoconstrictors.

Angiogenesis and the pharmacological responses of the tumour and non-tumour associated neovasculature have been investigated. Cannulated sponge discs in mice were used to host the angiogenic stimulators, while 133Xe washout was employed to assess local blood flow. Enhancement of blood flow was detected in implants bearing B16 cells, 3T3 cells and angiotensin II (AII)-treated at day 7. The responses of non-neoplastic associated neovasculature at day 14 post sponge implantation to the vasoconstrictors used endothelin-1 (Et-1), AII, platelet activating factor (PAF) and 5-hydroxytryptamine (5-HT) were dose-dependent. By contrast, the newly formed blood vessels induced by tumour cells were markedly insensitive to the vasoconstrictors agonists Et-1 and AII, while fully responsive to PAF and 5-HT. The vessels resulting from neoplastic stimulus exhibited altered pharmacological reactivity, suggesting that the characteristics of the neovasculature are dependent on the nature of the angiogenic stimuli.

Animals↗

PubMed1998

Endothelial vasoconstrictor prostanoids, vascular reactivity, and acute renal failure.

The interaction of endothelium-derived vasoconstrictor prostaglandins, the angiotensins (Ang), and the sympathetic nervous system in acute renal failure still remains to be determined. In this study, acute renal failure (ARF) was induced in male Wistar Kyoto rats (N = 7) in a 2K/2C model of 30-minute clamping. Contractions to Ang I and II and norepinephrine (NE) were studied in isolated aortic and renal artery rings 24 hours after clamp release. Sham-operated animals served as controls (N = 7). In ARF, contractions to NE were increased in the aorta and even further enhanced in the renal artery (P < 0.05 to 0.001), whereas contractions to Ang I and II were blunted (P < 0.05). Contractions were inhibited by SQ 30741, a thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist. We conclude that ARF is characterized by abnormal vascular reactivity both in the renal as well as the systemic vasculature that is in part mediated by endothelium-derived vasoconstrictor prostaglandins.

Acute Kidney Injury↗

PubMed2001

Latanoprost is a vasoconstrictor in isolated porcine ciliary arteries.

PURPOSE: The purpose of this study was to assess the vasoconstrictor effect of the prostaglandin F2 alpha analog latanoprost in isolated porcine ciliary arteries. MATERIAL AND METHODS: With a myograph system to measure isometric forces, porcine ciliary arteries were exposed, in a cumulative manner, to increasing concentrations of latanoprost (0.1 nM-0.1 mM). Experiments were conducted in quiescent vessels as well as in vessels precontracted with potassium chloride (KCl; 40 mM) or endothelin-1 (10 nM). Contractions were expressed in percent of 100 mM KCl-induced contraction. RESULTS: In a concentration dependent manner latanoprost induced significant (p < 0.001) contractions in quiescent vessels (maximum: 68 +/- 3%, n = 5; PD50: 5.7 +/- 0.1). In KCl or in endothelin-1 precontracted vessels latanoprost did not evoke any relaxation but in contrast significant (p < 0.001) contractions (maximum: 33 +/- 4%, n = 5 and 26 +/- 6%, n = 8, respectively). CONCLUSIONS: Latanoprost has a vasoconstrictor effect in isolated porcine ciliary arteries. No relaxation could be observed. The clinical relevance of this finding requires further evaluation.

Animals↗

PubMed2003

Influence of plasma insulin levels on antinatriuretic and vasoconstrictor actions of angiotensin-II.

The objective of the present study is to investigate whether plasma insulin levels play a role in the antinatriuretic and vasoconstrictor actions of angiotensin-II (Ang-II). We evaluated antinatriuretic function of endogenous Ang-II using an AT1 receptor antagonist, candesartan in anesthetized Sprague-Dawley rats. In control rats, candesartan produced significant increases in natriuresis and diuresis and these effects were abolished in streptozocin (STZ, 55 mg/kg i.p.) treated rats. Replacement of insulin restored these renal effects of candesartan. In a separate group of rats pretreated with an autonomic ganglionic blocker, pressor responses to Ang-II and norepinephrine (NE) before or after L-NNA, a nitric oxide synthase inhibitor were not affected by STZ treatment. However, insulin replacement greatly augmented these responses. These data provide evidence in vivo showing that insulin can enhance both antinatriuretic and vasoconstrictor actions of Ang-II. Hence exaggerated renal and vascular effects of Ang-II in the obese Zucker rats observed in our previous studies may be related to hyperinsulimemia and this phenomena could contribute to salt-sensitivity and development of sustained hypertension.

Angiotensin II↗

PubMed2004

Free radical activity depends on underlying vasoconstrictors in renal microcirculation.

We examined the role of free radicals in renal microvascular tone induced by various vasoactive stimuli. Isolated perfused rat hydronephrotic kidneys were used for direct visualization of renal microcirculation. The effect of tempol on angiotensin II-, norepinephrine-, KCl-, and pressure-induced afferent arteriolar constriction was evaluated. Under angiotensin II-induced constriction, tempol (3 mmol/L) caused 57 +/- 8% dilation of afferent arterioles. In contrast, tempol elicited only 38 +/- 8% and 26 +/- 9% dilation of norepinephrine- and KCl-induced constriction. Similarly, myogenic response induced by elevating renal arterial pressure from 80 to 180 mmHg was resistant to the vasodilator action of tempol (22 +/- 7% inhibition). Furthermore, tempol failed to reverse nitro-L-arginine methylester-induced afferent constriction, nor had vasodilator effect on the angiotensin II-induced constriction in the presence of nitro-L-arginine methylester. In contrast, nitroprusside elicited marked vasodilation of angiotensin II- (97 +/- 5% reversal) and norepinephrine-induced afferent constriction (89 +/- 6% reversal), but had less effect on KCl- (46 +/- 8% reversal) and pressure-induced constriction (26 +/- 9% reversal). These different actions were also observed when polyethylene-glycolated superoxide dismutase was used as an antioxidant. In conclusion, the role of free radicals in afferent arteriolar tone varies, depending on the underlying vasoconstrictor stimuli, with greater contribution of free radicals to angiotensin II-induced constriction. The heterogeneity in the responsiveness to free radical scavengers is attributed to both magnitude of free radicals produced and sensitivity of the underlying vasoconstrictors to nitric oxide.

Angiotensin II↗

PubMed1996

Vasoconstrictors inhibit ATP-sensitive K+ channels in arterial smooth muscle through protein kinase C.

The effects of vasoconstrictor-receptor (neuropeptide Y, alpha-adrenergic, serotonergic, histaminergic) stimulation on currents through ATP-sensitive potassium (KATP) channels in arterial smooth muscle cells were examined. Whole-cell KATP currents, activated by the synthetic KATP channel opener pinacidil or by the endogenous vasodilator, calcitonin gene-related peptide, which acts through protein kinase A, were measured in smooth muscle cells isolated from mesenteric arteries of rabbit. Stimulation of NPY-, alpha 1-, serotonin (5-HT2)-, and histamine (H1)-receptors inhibited KATP currents by 40-56%. The signal transduction pathway that links these receptors to KATP channels was investigated. An inhibitor of phospholipase C (D609) and of protein kinase C (GF 109203X) reduced the inhibitory effect of these vasoconstrictors on KATP currents from 40-56% to 11-23%. Activators of protein kinase C, a diacylglycerol analogue and phorbol 12-myristate 13-acetate (PMA), inhibited KATP currents by 87.3 and 84.2%, respectively. KATP currents, activated by calcitonin gene-related peptide, were also inhibited (47-87%) by serotonin, phenylephrine, and PMA. We propose that KATP channels in these arterial myocytes are subject to dual modulation by protein kinase C (inhibition) and protein kinase A (activation).

Adenosine Triphosphate↗

PubMed1990

The cellular mechanism of action by vasoconstrictor hormones in cultured rat vascular smooth muscle cells.

The effects of angiotensin (Ang) II, arginine vasopressin (AVP), and serotonin (5-HT) on inositol trisphosphate (IP3) production, cytosolic Ca2+ concentration [( Ca2+]i), and the phosphorylation of 20 kilodalton myosin light chain (MLC) were examined in cultured rat vascular smooth muscle cells (VSMC). These vasoconstrictors immediately induced dose-dependent and concomitant increases in IP3 production, [Ca2+]i, and phosphorylation of 20 kDa MLC. The agonist-induced increases in IP3 production, [Ca2+]i, and phosphorylation of 20 kDa MLC in VSMC were completely blocked by pretreatment with the receptor antagonists for Ang II, V1, and 5-HT2, respectively. These data suggest that receptor-mediated increases in IP3 production, [Ca2+]i, and phosphorylation of 20 kDa MLC by these vasoconstrictors are closely interrelated.

Angiotensin II↗

PubMed1988

Neuropeptide Y is a vasoconstrictor of human coronary arteries.

Neuropeptide Y (NPY) is a 36-amino-acid polypeptide which coexists with catecholamines in many adrenergic and noradrenergic neurons. It has been demonstrated to exert pressor effects in the perfused guinea pig heart and to constrict large cerebral and coronary blood vessels in animal studies. To determine if NPY might be a human coronary vasoconstrictor, the authors studied its effect on postmortem human coronary arteries. Proximal epicardial coronary rings were studied in a superfusion apparatus in Krebs-Ringer bicarbonate buffer (37 degrees C, pH 7.4) presaturated with 95% O2-5% CO2. Concentration-response curves were obtained using NPY in 0.1% bovine serum albumin in buffer and the responses were compared to those obtained in the presence of alpha 1, beta, and cyclooxygenase antagonists. A dose-related constrictor effect was obtained with NPY, which was significantly more potent than noradrenaline, constriction often being seen at 10(-12) M concentration. A vasorelaxant effect was seen in nonatherosclerotic vessels at higher concentrations. The vasoconstriction produced by noradrenaline was potentiated by subthreshold concentrations of NPY. The vasoconstrictor effect of NPY was not inhibited by prazosin (10(-6) M), and the vasodilatory effect was not inhibited by propranolol (10(-5) M). Indomethacin (3 X 10(-6) M) did not alter either vasoconstriction or vasorelaxation. The authors conclude that NPY is a potent constrictor of the human coronary artery at concentrations that may be achievable in vivo; it may thus be a contributor to sympathetic enhancement of coronary artery tone.

Coronary Vessels↗

PubMed1988

A novel peptide vasoconstrictor, endothelin, is produced by vascular endothelium and modulates smooth muscle Ca2+ channels.

Since the discovery of endothelium-dependent vasodilation, vascular endothelium has been recognized as an important functional unit contributing to the regulation of vascular tonus. Recent purification, structure determination and molecular cloning of a novel peptidergic vasoconstrictor, endothelin, from the culture supernatant of porcine aortic endothelial cells has further substantiated this concept. Starting from a large quantity of serum-fee endothelial cell-conditioned medium, endothelin was purified to homogeneity after three steps of high performance liquid chromatography by collecting active fractions and constricting porcine coronary artery strips. A peptide sequence analysis showed that endothelin was a previously unknown 21-residue peptide with two intrachain disulphide bonds. The EC50 of endothelin for contraction of porcine coronary artery was 4.0 x 10(-10) mol/l, indicating that endothelin is one of the most potent vasoconstrictors known. The pharmacological and structural properties of endothelin suggest that the peptide acts by activating voltage-dependent Ca2+ channels in vascular smooth muscle cells. Cloning and sequence analysis of complementary (c)DNA encoding porcine and human endothelin precursors showed that endothelin was produced de novo in endothelial cells from an approximately 200-residue prepropeptide through an unusual proteolytic processing by a putative 'endothelin-converting enzyme'. Northern blot analysis showed that preproendothelin messenger (m)RNA was expressed not only in cultured endothelial cells but also in fresh intimal tissue from porcine aorta, and that mRNA can be induced markedly in response to several vasoactive agents in cultured endothelial cells, suggesting the existence of a novel endothelium-mediated cardiovascular control system.

Animals↗