Vascular Tone In Man Research Articles

Functional and immunocytochemical evidence for a role of ghrelin and des-octanoyl ghrelin in the regulation of vascular tone in man

Ghrelin is the recently identified endogenous ligand for the ghrelin receptor GHS-R1a and known to regulate growth hormone secretion and appetite. Ghrelin also is a potent vasodilator and improves cardiac performance after systemic administration. Generally, the octanoyl modification on Ser3 has been considered essential for biological activity. Recently however, cardiovascular actions of des-octanoyl ghrelin have been reported in rodents. Our aim was to investigate if ghrelin and ghrelin receptor protein are expressed within the human vasculature, to determine if des-octanoyl ghrelin, like ghrelin, is a vasodilator in human artery and to test the acute effect of ghrelin peptides on cardiac contractility. Distribution of ghrelin and ghrelin receptor was determined using standard immunocytochemistry and confocal microscopy. Ghrelin peptides were tested for vasodilator actions in human isolated arteries and their effect on cardiac contractility was investigated in human isolated paced atria. Immunoreactive ghrelin was detected in endothelial cells of human arteries and veins where it localized to intracellular vesicles but not to the Weibel-Palade bodies of the regulated pathway, suggesting constitutive ghrelin production. Specific antisera detected ghrelin receptor on vascular smooth muscle cells and cardiomyocytes. Ghrelin (pD2=8.60+/-0.1, Emax=55.8+/-8.9, mean+/-standard error of the mean) and des-octanoyl ghrelin (pD2=8.8+/-0.2, Emax=54.7+/-5.3) showed comparable (P>0.05) endothelium independent vasodilator potency and efficacy in reversing endothelin-1 induced constriction in human artery. Neither ghrelin nor des-octanoyl ghrelin had effects on contractile force in paced atria. We show widespread expression of ghrelin and its cognate receptor in the human cardiovascular system with functional evidence suggesting a role for both ghrelin and the more abundant endogenous form des-octanoyl ghrelin in the paracrine regulation of vascular tone in man.

Selective increase of the contractile response to endothelin-1 in subcutaneous arteries from patients with essential hypertension.

Endothelin-1 has been shown to contribute to basal vascular tone in man. Since endothelin-1 is a potent vasoconstrictor putatively involved in hypertension, we have compared the contractile responses of endothelin-1 and noradrenaline in relation to potassium chloride in subcutaneous resistance arteries from subjects with established essential hypertension with matched controls. Furthermore, with RT-PCR, the occurrence of mRNA for the ETA and ET(B) receptors was shown in the tunica media layer of subcutaneous arteries in controls and hypertensives. The maximum contractile response to endothelin-1 was significantly higher in the subcutaneous arteries of the hypertensives (by 88% with no change in potency) as compared to controls. The responses to noradrenaline, acetylcholine and potassium chloride did not differ between the groups. This selective increase in the contractile response to endothelin-1 might contribute to the development of essential hypertension.

Selective Increase of the Contractile Response to Endothelin-1 in Subcutaneous Arteries from Patients with Essential Hypertension

Endothelin-1 has been shown to contribute to basal vascular tone in man. Since endothelin-1 is a potent vasoconstrictor putatively involved in hypertension, we have compared the contractile responses of endothelin-1 and noradrenaline in relation to potassium chloride in subcutaneous resistance arteries from subjects with established essential hypertension with matched controls. Furthermore, with RT-PCR, the occurrence of mRNA for the ETA and ETB receptors was shown in the tunica media layer of subcutaneous arteries in controls and hypertensives. The maximum contractile response to endothelin-1 was significantly higher in the subcutaneous arteries of the hypertensives (by 88% with no change in potency) as compared to controls. The responses to noradrenaline, acetylcholine and potassium chloride did not differ between the groups. This selective increase in the contractile response to endothelin-1 might contribute to the development of essential hypertension.

Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome.

The hypoxaemia of hepatopulmonary syndrome, seen in severe chronic liver dysfunction, occurs as a result of precapillary pulmonary arterial dilatation and arteriovenous communications. These abnormalities contribute to the mismatch between ventilation and perfusion, and the right to left blood flow shunting. Nitric oxide (NO) is a powerful vasodilator concerned with the regulation of pulmonary vascular tone in man. Using a chemiluminescence analyser, we have measured endogenously produced NO in the exhaled air of three patients with the hepatopulmonary syndrome, six normoxaemic cirrhotic patients and six healthy volunteers. The subjects breathed NO-free air throughout the measurements. The molar rate of production of exhaled NO was raised almost threefold in the patients with hepatopulmonary syndrome compared with normal volunteers and with normoxaemic cirrhotic patients. Hypoxia per se, achieved in the normal volunteers by breathing a hypoxic gas mixture, reduced rather than increased the exhaled NO. One hepatopulmonary syndrome patient received an orthotopic liver transplant and achieved normoxaemia after 3 months. The exhaled NO also returned to normal. Increased pulmonary production of NO could contribute to the development of the hepatopulmonary syndrome.

Endothelins as Regulators of Vascular Tone in Man

1. The vascular pharmacology, physiological relevance and pathophysiological roles of the endothelium-derived vasoconstrictor peptide endothelin-1 have been unclear. These issues were investigated, in vivo in man, using infusion of drugs into the brachial artery or dorsal hand vein, with responses measured by forearm plethysmography and the hand vein displacement technique respectively. 2. Endothelin-1 is a potent and sustained constrictor of resistance and capacitance vessels in vivo in man, acting through both subtypes (ETA and ETB) of endothelin receptors. Endothelin-1 stimulates generation of vasodilator prostaglandins, but not of nitric oxide, that act to oppose its direct constrictor actions. Venoconstriction to endothelin-1 is blocked more effectively by K(+)-channel openers than by Ca(2+)-channel antagonists, suggesting a novel cellular mechanism of action for this peptide. 3. The forearm vasculature is able to convert the precursor big endothelin-1 to the mature peptide, endothelin-1, thus demonstrating the local presence of 'endothelin-converting enzyme' in man. Local inhibition of this enzyme, or blockade of ETA receptors, causes slow-onset forearm vasodilatation, suggesting that endogenously generated endothelin-1 contributes to basal resistance vessel tone in man. 4. Venoconstriction to endothelin-1 is selectively enhanced in patients with untreated essential hypertension. Endothelin-1 also potentiates sympathetically mediated vasoconstriction, but only in hypertensive subjects. 5. Endogenous generation of endothelin-1 plays a fundamental physiological role in the maintenance of basal vascular tone. Endothlin-converting enzyme inhibitors and endothelin receptor antagonists possess novel vasodilator properties and should represent a major therapeutic advance in cardiovascular disease.

Endothelins as Regulators of Vascular Tone in Man

Endothelins as Regulators of Vascular Tone in Man

What is the Effect of Arginine Vasopressin on Coronary and Systemic Vascular Tone in Man?

Conference Abstract| December 01 1989 What is the Effect of Arginine Vasopressin on Coronary and Systemic Vascular Tone in Man? J J Glazier; J J Glazier 1Boston University Medical Centre, Massachusetts, USA Introduced by Dr D. R. Hackett Search for other works by this author on: This Site PubMed Google Scholar H Gavras; H Gavras 1Boston University Medical Centre, Massachusetts, USA Introduced by Dr D. R. Hackett Search for other works by this author on: This Site PubMed Google Scholar R M Mills; R M Mills 1Boston University Medical Centre, Massachusetts, USA Introduced by Dr D. R. Hackett Search for other works by this author on: This Site PubMed Google Scholar M Bresnahan; M Bresnahan 1Boston University Medical Centre, Massachusetts, USA Introduced by Dr D. R. Hackett Search for other works by this author on: This Site PubMed Google Scholar T J Ryan; T J Ryan 1Boston University Medical Centre, Massachusetts, USA Introduced by Dr D. R. Hackett Search for other works by this author on: This Site PubMed Google Scholar D P Faxon D P Faxon 1Boston University Medical Centre, Massachusetts, USA Introduced by Dr D. R. Hackett Search for other works by this author on: This Site PubMed Google Scholar Clin Sci (Lond) (1989) 77 (s21): 34P. https://doi.org/10.1042/cs077034Pa Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation J J Glazier, H Gavras, R M Mills, M Bresnahan, T J Ryan, D P Faxon; What is the Effect of Arginine Vasopressin on Coronary and Systemic Vascular Tone in Man?. Clin Sci (Lond) 1 December 1989; 77 (s21): 34P. doi: https://doi.org/10.1042/cs077034Pa Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsClinical Science Search Advanced Search This content is only available as a PDF. © 1989 The Biochemical Society and the Medical Research Society1989 Article PDF first page preview Close Modal You do not currently have access to this content.

Effect of arginine vasopressin on coronary and systemic hemodynamics in man

Arginine vasopressin is a potent constrictor of isolated arterial segments in vitro. However, it is disputed whether, in vivo, arginine vasopressin acts as either a systemic or coronary vasoconstrictor. The purpose of this study was to determine the effect of arginine vasopressin on coronary and systemic vascular tone in man. Six patients undergoing routine diagnostic cardiac catheterization were studied. At angiography, all patients were found to have severe coronary artery disease. Cardiac and systemic pressures and coronary blood flow as well as serum arginine vasopressin and osmolality levels were measured before and after administration of hypertonic contrast dye and then following intravenous injection of an analog inhibitor of arginine vasopressin. At baseline, serum arginine vasopressin levels were within the normal range in all patients, but, following infusion of contrast dye, rose above physiological levels in 5 patients. In these latter patients, there were no significant changes in coronary and systemic hemodynamics between baseline (condition 1), following administration of contrast dye (condition 2) and 10 minutes after injection of arginine vasopressin inhibitor (condition 3). Mean coronary sinus blood flow (ml/min) and mean coronary vascular resistance (dyne·sec·cm −5) were 184±49 and 41,235±8275 during condition 1, 204±62 and 39,442±8781 during condition 2, and 192±75 and 44,930±11455 during condition 3. Mean arterial pressure (mm Hg) and mean systemic vascular resistance (dyne·sec·cm −5) during conditions 1, 2 and 3 were 105 ± 12 and 1454 ± 174, 114 ± 21 and 1432 ± 210, and 114 ± 15 and 1436 ± 147, respectively. These data suggest that arginine vasopressin has no effect on coronary or systemic vascular tone in patients with coronary artery disease.

Non-prostanoid endothelium-derived vasoactive factors.

Endothelium-derived relaxing factor (EDRF) and endothelium-derived contracting factor (EDCF) are released by endothelial cells following stimulation by a wide range of chemical agonists acting on specific endothelial membrane receptors and by physical factors such as shear stress on the vascular wall. It has now been firmly established that EDRF is nitric oxide, whereas EDCF has been recently identified as a 21-residue peptide, endothelin. Circumstantial evidence, however, suggests that there may be more than one EDRF and/or EDCF. EDRF induces relaxation of the underlying vascular smooth muscle by enhancing intracellular cyclic GMP levels. This action is comparable to that of nitrovasodilators, and nitric oxide can, therefore, be regarded as an endogenous nitrovasodilator. The mechanism of action of endothelin is uncertain, but depends on influx of extracellular calcium. The respective roles of EDRF and EDCF in disease are still hypothetical. It is preferable to think in terms of balance (or imbalance) between these two factors which, probably, have a fundamental role, and very likely interact with each other in maintaining and regulating vascular tone in man.

Human calcitonin gene related peptide: a potent endogenous vasodilator in man.

In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 +/- 5 to 55 +/- 7 mmHg (P less than 0.05), the heart rate to increase from 61 +/- 7 to 87 +/- 5 beats/min (P less than 0.05) and the skin temperature to increase from 33.7 +/- 0.9 to 34.9 +/- 0.5 degrees C. Plasma noradrenaline increased from 481 +/- 126 to 835 +/- 65 pg/ml (P less than 0.05) and plasma adrenaline from 57 +/- 17 to 82 +/- 12 pg/ml (P less than 0.05). There were no significant changes in the albumin-corrected plasma calcium. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.