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Biomedical subjects

C J Ferro

Publications and source records attributed to C J Ferro.

9 recordsLinked to original sources
PubMed1999

Impaired cholinergic dilator response of resistance arteries isolated from patients with Raynaud's disease.

AIMS: We examined the effect of cooling on the response to the endothelium-dependent and -independent dilators, acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, in human microvessels in vitro, and compared the responses between Raynaud's disease (RD) patients and controls, in order to assess the pathogenic role of the endothelium in RD. METHODS: Subcutaneous resistance arteries were dissected from gluteal fat biopsies taken from patients with RD (n=18) and from age-and sex-matched control subjects (n=17). Vessels were cannulated in a small vessel arteriograph, in which a pressure of 50 mmHg was maintained across the vessel wall. Cumulative concentration-response curves for ACh (10-10-10-4 m ) and SNP (10-10-10-3 m ) were generated in vessels at either 37 degrees C or 24 degrees C, with endothelium intact for ACh and removed for SNP (n=6 per group). RESULTS: Neither dilator showed significant differences in sensitivity when comparing responses between vessels from RD patients and controls, at either temperature, but the maximal relaxation to ACh was depressed in vessels from RD patients compared with controls at 37 degrees C (Emax=45+/-13 in RD vs 89+/-4 in controls; P=0.004). CONCLUSIONS: These results support the hypothesis that impaired endothelium-dependent vasodilatation is involved in the pathophysiology of RD.

Acetylcholine↗
PubMed1998

Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo.

BACKGROUND: Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1. Systemic inhibition of NEP does not consistently lower blood pressure, even though it increases natriuretic peptide concentrations and causes natriuresis and diuresis. We therefore investigated the direct effects of local inhibition of NEP on forearm resistance vessel tone. METHODS AND RESULTS: Four separate studies were performed, each with 90-minute drug infusions. In the first study, 10 healthy subjects received a brachial artery infusion of the NEP inhibitor candoxatrilat (125 nmol/min), which caused a slowly progressive forearm vasoconstriction (12+/-2%; P=0.001). In a second two-phase study, 6 healthy subjects received, 4 hours after enalapril (20 mg) or placebo, an intra-arterial infusion of the NEP inhibitor thiorphan (30 nmol/min). Thiorphan caused similar degrees of local forearm vasoconstriction (P=0.6) after pretreatment with both placebo (13+/-1%, P=0.006) and enalapril (17+/-6%, P=0.05). In a third three-phase study, 8 healthy subjects received intra-arterial thiorphan (30 nmol/min), the endothelin ETA antagonist BQ-123 (100 nmol/min), and both combined. Thiorphan caused local forearm vasoconstriction (13+/-1%, P=0.0001); BQ-123 caused local vasodilatation (33+/-3%, P=0.0001). Combined thiorphan and BQ-123 caused vasodilatation (32+/-1%, P=0.0001) similar to BQ-123 alone (P=0.98). In a fourth study, 6 hypertensive patients (blood pressure >160/100 mm Hg) received intra-arterial thiorphan (30 nmol/min). Thiorphan caused a slowly progressive forearm vasoconstriction (10+/-2%, P=0.0001). CONCLUSIONS: Inhibition of local NEP causes vasoconstriction in forearm resistance vessels of both healthy volunteers and patients with hypertension. The lack of effect of ACE inhibition on the vasoconstriction produced by thiorphan and its absence during concomitant ETA receptor blockade suggest that it is mediated by endothelin-1 and not angiotensin II. These findings may help to explain the failure of systemic NEP inhibition to lower blood pressure.

Adult↗
PubMed1998

Functional studies in small arteries do not support a primary role for endothelin in the pathogenesis of Raynaud's disease.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of Raynaud's disease (RD). This study examined the effect of cooling on the response to ET-1 in human microvessels. Subcutaneous small arteries were dissected from gluteal fat biopsies taken from patients with RD (n = 20) and from age- and sex-matched control subjects (n = 17) and were cannulated in a small vessel arteriograph. Cumulative concentration-response curves to ET-1 (10(-12) to 3 x 10(-7) M) were obtained in vessels at 37 degrees C and 24 degrees C, with the endothelium either intact or removed (n = 6 per group). There were no significant differences in responses to ET-1 between RD patients and controls in either intact or denuded vessels, at either 37 degrees C or at 24 degrees C. There was, however, a significant endothelium-dependent interaction between the groups when the effect of temperature on the response to ET-1 was examined (p = 0.01; two-way ANOVA). Whereas cooling tended to reduce the sensitivity in RD, the opposite effect was observed in controls. Measurements of plasma ET-1 did not reveal any significant difference between patients with RD and healthy controls. These results suggest that ET-1 does not play a primary pathophysiologic role in RD. ET-1 might be responsible for mediating the prolonged vasospasm in RD, but secondary to another factor(s), such as impaired endothelium-dependent vasodilation.

Adult↗
PubMed1997

The peptide endothelin receptor antagonist, TAK-044, produces sustained inhibition of endothelin-1 mediated arteriolar vasoconstriction.

AIMS: Endothelin-1 (ET-1) has been implicated in the pathophysiology of a number of cardiovascular diseases for which endothelin receptor antagonists are currently under clinical development. We have previously reported that systemic administration of the combined endothelin A/B receptor antagonist, TAK-044, abolishes the forearm vasoconstriction caused by intrabrachial ET-1 infusion for at least 3 h. In this study we investigated whether TAK-044 can inhibit ET-1 mediated forearm vasoconstriction for longer periods. METHODS: Eighteen subjects were recruited to a randomized, placebo-controlled, single-blind, three-way, crossover study. Subjects were divided into three groups of six. Groups received 25 mg, 50 mg or 100 mg TAK-044 on two separate occasions, 6 and 10 h before the start of a 2 h intrabrachial infusion of ET-1 (5 pmol min(-1)). On a third occasion subjects received only placebo before intra-arterial ET-1 infusion. Forearm vasoconstriction to ET-1 was measured by venous occlusion plethysmography. RESULTS: In the placebo phase, ET-1 caused significant, slowly-progressive local forearm vasoconstriction of approximately 30% (P<0.01) in all three groups. All three doses of TAK-044, administered at both timepoints, tended to blunt the vasoconstriction caused by ET-1. When the responses from all three groups were combined, TAK-044 significantly reduced ET-1 mediated vasoconstriction compared with placebo -9% (95% CI -15 to -3; P=0.01) at 8 h and by -9% (95% CI -17 to -2; P=0.01) 12 h after dosing. CONCLUSIONS: TAK-044 attenuated, but did not abolish, local ET-1 mediated vasoconstriction, for up to 12 h after administration. Vasoconstriction to local intra-arterial administration of ET-1 appears to represent a safe and reproducible pharmacodynamic index of systemic endothelin receptor antagonism in humans.

Adult↗
PubMed1997

Endothelial dysfunction and hypertension.

Vascular endothelial cells play a key role in cardiovascular regulation by producing a number of potent vasoactive agents, including the vasodilator molecule nitric oxide (NO) and the vasoconstrictor peptide endothelin (ET)-1. A dysfunction of the vascular endothelium has been implicated in the pathophysiology of a number of cardiovascular diseases, important among which is essential hypertension. Impairment of NO synthesis, or increased inactivation of NO by superoxide radicals, may account for the increased peripheral vascular tone associated with hypertension, as well as contribute to the clinical consequences of this condition, which include vascular hypertrophy, increased platelet and monocyte adhesion to the endothelium, atherosclerosis, myocardial infarction and stroke. Similarly, increased ET-1 synthesis, or increased smooth muscle sensitivity to ET-1, could account for many of the features of hypertension, including increased peripheral vascular tone and vascular hypertrophy. Modulation of endothelial function is, therefore, an attractive therapeutic option in the treatment of hypertension. Calcium antagonists have been shown to enhance the effects of NO, and inhibit those of ET-1, on vascular smooth muscle cells. In addition, calcium antagonists have antiatherogenic and antioxidant properties and could, therefore, prove to be useful therapeutic agents in preventing some of the important complications of hypertension. The long term effects on cardiovascular morbidity and mortality of the long-acting nifedipine gastrointestinal therapeutic system (nifedipine GITS) used in the treatment of essential hypertension are currently being investigated in the first multinational outcome study (INSIGHT) of an antihypertensive agent since the major studies of beta-adrenoceptor blockers or thiazide diuretics. The results of this study are awaited with considerable interest.

Calcium Channel Blockers↗
PubMed1996

Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans.

BACKGROUND: Although local inhibition of the generation or actions of endothelin-1 has been shown to cause forearm vasodilatation, the systemic effects of endothelin receptor blockade in healthy humans are unknown. We therefore investigated the cardiovascular effects of a potent peptide endothelin ETA/B receptor antagonist, TAK-044, in healthy men. METHODS AND RESULTS: Two randomized, placebo-controlled, crossover studies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension. Four hours after infusion of the highest dose (1000 mg), there were decreases in mean arterial pressure of 18 mm Hg and total peripheral resistance of 665 AU and increases in heart rate of 8 bpm and cardiac index of 0.9 L x min(-1) x m(-2) compared with placebo. TAK-044 caused a rapid, dose-dependent increase in plasma immunoreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1. Brachial artery infusion of TAK-044 caused local forearm vasodilation. CONCLUSIONS: The endothelin ETA/B receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstriction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodilator properties of endothelin receptor antagonists may prove valuable therapeutically.

Adult↗
PubMed1996

The increase in human plasma immunoreactive endothelin but not big endothelin-1 or its C-terminal fragment induced by systemic administration of the endothelin antagonist TAK-044.

1. We examined the effects of systemic infusion, in healthy human volunteers, of the endothelin antagonist TAK-044 on the plasma concentrations of mature endothelin, big endothelin-1 and the C-terminal fragment of big endothelin-1, by selective solid-phase extraction and specific radioimmunoassays. 2. Unlabelled TAK-044 competed with specific [125I]-endothelin-1 binding to human left ventricle tissue in a biphasic manner giving KD values of 0.11 nM and 26.8 nM at the ETA and ETB receptor subtypes, respectively, indicating a 244 fold selectivity for the ETA receptor subtype. 3. A 15 min intravenous infusion of placebo or 30 mg TAK-044 (giving a serum concentration of 2 nM, calculated to block > 95% of ETA but < 5% ETB receptors) had no effect on the immunoreactive plasma concentrations of the three peptides. 4. At the higher dose of 750 mg TAK-044 (giving a serum concentration of 80 nM, calculated to block > 99% of ETA and > 75% ETB receptors), the immunoreactive plasma endothelin concentrations were increased 3.3 fold over basal levels (P < 0.01). The concentrations of big endothelin-1 or C-terminal fragment of big endothelin-1 were unchanged. 5. At both doses of TAK-044, there were significant decreases in diastolic blood pressure, and peripheral vascular resistance, with corresponding increases in cardiac index and stroke index. There were no changes in systolic or mean arterial blood pressures or heart rate. 6. Since only the concentrations of the mature peptide were increased, we conclude that the most likely sources of endothelin contributing to the observed rise were displacement of receptor-bound peptide and reduction in plasma clearance rather than peptide synthesis.

Adult↗
PubMed1996

The clinical potential of endothelin receptor antagonists in cardiovascular medicine.

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.

Amino Acid Sequence↗