Gérard E. Plante

Clinical applications of arterial stiffness; definitions and reference values.

Arterial stiffening is the most important cause of increasing systolic and pulse pressure, and for decreasing diastolic pressure beyond 40 years of age. Stiffening affects predominantly the aorta and proximal elastic arteries, and to a lesser degree the peripheral muscular arteries. While conceptually a Windkessel model is the simplest way to visualize the cushioning function of arteries, this is not useful clinically under changing conditions when effects of wave reflection become prominent. Many measures have been applied to quantify stiffness, but all are approximations only, on account of the nonhomogeneous structure of the arterial wall, its variability in different locations, at different levels of distending pressure, and with changes in smooth muscle tone. This article summarizes the methods and indices used to estimate arterial stiffness, and provides values from a survey of the literature, followed by recommendations of an international group of workers in the field who attended the First Consensus Conference on Arterial Stiffness, which was held in Paris during 2000, under the chairmanship of M.E. Safar and E.D. Frohlich.

Enhancement by endothelin-1 of microvascular permeability via the activation of ETA receptors

1 The objective of the present experiments was to assess the involvement of endothelin‐A (ETA) receptors in mediating the effects of endothelin‐1 on microvascular permeability in conscious rats. 2 Bolus injection of endothelin‐1 (0.1 and 1 nmol kg−1, i.v.) resulted in a dose‐dependent prolonged pressor effect preceded by a transient depressor response. These changes were accompanied by a dose‐dependent loss of plasma volume. Endothelin‐1 (1 nmol kg−1) enhanced the vascular permeability of the upper and lower bronchi, kidney, stomach, duodenum and spleen (up to 270%) as measured by the extravasation of Evans blue dye. 3 Pretreatment of the animals with the selective ETA receptor antagonist, BQ‐123 (1 mg kg−1, i.v.) significantly blunted the pressor response to endothelin‐1 without affecting the depressor response. BQ‐123 inhibited by 87% the endothelin‐1 (1 nmol kg−1)‐induced plasma volume loss. BQ‐123 markedly attenuated protein extravasation elicited by endothelin‐1 in the upper and lower bronchi and kidney, whereas it completely inhibited the permeability effect of endothelin‐1 in the stomach and duodenum. BQ‐123 by itself had no significant effect on the parameters studied. 4 The endothelin‐1 analogue, [Trp(For)21]‐endothelin‐1, in which Trp21 is formylated, was as potent a pressor agent as endothelin‐1, but had no depressor action. Bolus injection of [Trp(For)21]‐endothelin‐l (0.1 and 1 nmol kg−1, i.v.) evoked similar plasma volume losses to those observed following administration of equimolar doses of endothelin‐1. Furthermore, 1 nmol kg−1 [Trp(For)21]‐endothelin‐l evoked increases in protein extravasation similar to endothelin‐1, 1 nmol kg−1. 5 The present findings suggest that endothelin‐1 enhances microvascular permeability, in part, via the activation of ETA receptors.

PAF increases vascular permeability in selected tissues: Effect of BN-52021 and L-655,240

The effect of the potent inflammatory mediator, platelet activating factor (PAF) was studied on the vascular permeability of selected rat tissues using the extravasation of Evans blue dye (EB) as a marker. EB (20 mg/kg) was injected in the caudal vein together with increasing doses of PAF (0.1, 1.0 and 5.0 micrograms/kg). The animals were killed and the dye was extracted in selected organs using formamide (4 ml/g wet weight tissues) and the content was expressed as EB micrograms/g dry weight. Extravasation of EB varied markedly from one tissue to another and increased as a function of time (from 0 to 60 min). PAF (5.0 micrograms/kg) increased the pancreas and duodenum vascular permeability by 15 and 5 fold respectively. At the doses of 0.1 and 1.0 microgram/kg, PAF induced a slight increase (P less than 0.01) of the vascular permeability of the heart 5 min after the injection. The PAF antagonist BN-52021 (2 and 10 mg/kg) produced a dose-dependent inhibition of the PAF effects on the pancreas, heart and duodenum. Maximum inhibition (approximately 100%) was achieved at the dose of 10 mg/kg. This antagonist given in the absence or the presence of PAF reduced the lung plasma extravasation below control levels. A thromboxane antagonist, L-655,240 (1.0 and 5.0 mg/kg) also inhibited PAF-induced increases in vascular permeability in heart, duodenum and pancreas. It also reduced below control levels the EB extravasation in kidneys, spleen and lungs. Maximum inhibition (50% for the duodenum, and 40% for the pancreas) was achieved at the dose of 5.0 mg/kg.

Endothelin-1 enhances vascular permeability in conscious rats: role of thromboxane A2

The purpose of the present experiments was to study the effects of endothelin-1 (ET-1) on vascular permeability and the involvement of the cyclooxygenase metabolites in the vascular responses to ET-1. Bolus intravenous injection of ET-1 (0.1-1.0 nmol/kg) into conscious rats induced immediate hypotension lasting for 30 s followed by sustained dose-dependent hypertension. A low dose of ET-1 (0.1 nmol/kg) did not modify the hematocrit value but the 1.0-nmol/kg dose increased the hematocrit value from 39.7 to 44.4%. Pretreatment of the animals with BM-13505 (1 mg/kg), a thromboxane A2 (TxA2) receptor antagonist, prolonged the duration of the hypotensive response to ET-1 (1.0 nmol/kg) but had no effect on the pressor response. Pretreatment with OKY-046 (10 mg/kg), a TxA2 synthesis inhibitor, or indomethacin (10 mg/kg), a cyclooxygenase inhibitor, had no significant effect on ET-1-induced changes in blood pressure. Evans blue dye extravasation, a marker of vascular permeability, increased up to 235% over control levels in specific vascular beds including the upper and lower bronchi, stomach, duodenum and kidney of ET-1 (1.0 nmol/kg)-treated animals. Pretreatment of the animals with BM-13505, OKY-046 or indomethacin reduced by 60-100% the Evans blue extravasation in these tissues. These results suggest that the effect of ET-1 on vascular permeability is partly mediated and/or modulated by the secondary release of TxA2, whereas its action on arterial blood pressure appears to be independent from prostanoid release in conscious rats.

Role of eicosanoids in PAF‐induced increases of the vascular permeability in rat airways

1 Platelet activating factor (PAF; 1.0 and 5.0 μg kg−1) injected in the tail vein of unanaesthetized rats dose‐dependently increased the vascular permeability of the trachea, upper and lower bronchi (up to 400%) as measured by the extravasation of Evans blue dye. The permeability of the parenchyma was not affected by PAF treatment. 2 Pretreatment of the animals with an intravenous injection of the PAF antagonist BN‐52021 (10 mg kg−1) abolished almost totally the vascular permeability changes elicited by PAF injection (5.0 μg kg−1). 3 Pretreatment of the animals with intravenous injections of inhibitors of thromboxane formation, indomethacin (10 mg kg−1) and compound OKY‐046 (10 mg kg−1), and thromboxane antagonist, compound L‐655,240 (5 mg kg−1), partially reduced PAF effects in the airways (from 28 to 69%). The thromboxane mimic U‐44069 (5.0 μg kg−1) did not modify the vascular permeability of rat airways. The effect of a low dose of PAF (0.1 μg kg−1) on the vascular permeability of the trachea and bronchi (but not of the parenchyma) was potentiated by compound U‐44069 (5.0 μg kg−1) or noradrenaline (400 ng kg−1) whereas the effect of a high dose of PAF (5.0 μg kg−1) was not affected. 4 Neither the peptidoleukotriene antagonist MK‐571 (10 mg kg−1) nor the 5‐lipoxygenase inhibitor, L‐663,536 (10 mg kg−1) given before the injection of PAF (5.0 μg kg−1) affected the protein extravasation in rat lung tissues. 5 These data suggest that the effect of PAF on rat vascular permeability is partly modulated by thromboxane formation although thromboxanes have no direct effect on the permeability. Thromboxane may act via a vasoconstriction that increases hydrostatic pressure and potentiates the extravasation elicited by PAF effect on endothelial cells. 6 Leukotrienes do not appear to be involved in the changes of rat airway permeability induced by PAF.

Impact of kinins in the treatment of cardiovascular diseases

In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikrein-kinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs.

Consequences of alteration in capillary permeability

In this review paper, three aspects related to alteration in capillary permeability, based on a series of recent observations from this laboratory, are examined. Firstly, the determinants of capillary extravasation, which include pre- and post-capillary resistances in different microcirculation networks, as well as endothelial permeability per se, are described with particular reference to the heterogeneous character of both regulatory components, reported by this and other groups. Secondly, the endothelium-interstitium relationship, responsible in part for the maintenance of the interstitial compartment physicochemical characteristics, is introduced as an important factor in regulating the traffic of vital nutrients delivered to the cell mass, and the removal of waste products from the cellular compartment to the microcirculation, for ultimate excretion. Examined in this manner, it appears that modulation of capillary permeability is essential for the maintenance of cellular life, yet the neurohumoral mechanisms involved in the control of microcirculation networks are just starting to be identified. A number of morbid conditions characterized by multiorgan involvement exhibit a common pathophysiological denominator which involves endothelium-interstitium relationships, as illustrated in experimental animal models of arterial hypertension, diabetes mellitus, heart failure, and degenerative renal diseases. Enhanced capillary permeability associated with local interstitial edema in specific organs, such as the heart and the kidney, in arterial hypertension and diabetes mellitus, as well as decreased permeability in peripheral tissues, such as the skeletal muscle and the skin, in congenital cardiomyopathy, have been documented. It is likely that alteration in the characteristics of interstitial matrix composition contributes to target organ damage in these examples of systemic disorders from different etiologies. Thirdly, the recent identification of autocoids and hormones involved in the direct and indirect control of capillary permeability has led to the development of pharmacological tools capable of modulating pre- and post-capillary vascular tonus, as well as endothelial permeability. Angiotensin II antagonism, bradykinin B1-receptor inhibition, and modulation of eicosanoid production, in particular thromboxane A2, are associated in some of the above-described disorders, with normalization of capillary permeability defects, and occasionally with improvement in organ function. The eventual development of agents capable of directly controlling the physicochemical characteristics of the interstitial matrix should be of interest, not only for preventing the development of irreversible matrix structural alterations but also for facilitating the traffic of metabolites between capillaries and the cell mass of vital organs.

Arterial Stiffness, Pulse Pressure, and the Kidney

Classical studies indicate that the contribution of kidneys to hypertension is almost exclusively related to the association between mean arterial pressure (MAP) and vascular resistance. Recent reports including estimates of glomerular filtration rate (GFR) have shown that pulse pressure (PP) and pulse wave velocity, 2 major indices of arterial stiffness, now emerge as significant predictors of cardiovascular risk and age-associated decline in GFR. Such findings are mainly observed in patients with hypertension and renal failure and in atherosclerotic subjects undergoing coronary angiography. In such patients, amplification of PP between ascending and terminal aorta at the renal site is constantly increased over 10mm Hg (P < 0.001), whereas MAP level remains continuously unmodified. This PP amplification is significantly associated with presence of proteinuria. Furthermore, increases in plasma creatinine and aortic stiffness are independently and positively correlated (P < 0.001) both in cross-sectional and longitudinal studies. All these relationships associating PP, arterial stiffness, and renal function are mainly observed in patients 60 years of age or older. Furthermore, in renal transplant patients and their donors, subjects have been recruited for evaluations of arterial stiffness and posttransplant decline in GFR. Determinants of GFR decline were evaluated 1 and 9 years after transplantation. The first year GFR decline was related to smoking and acute rejection, whereas the later was significantly and exclusively associated with donor age and aortic stiffness. Thus, in hypertensive humans, the observed association between PP and GFR suggests that the 2 parameters are substantially mediated by arterial stiffness, not exclusively by vascular resistance.

Phosphoramidon blocks big‐endothelin‐1 but not endothelin‐1 enhancement of vascular permeability in the rat

1 Changes in vascular permeability following intravenous injections of human big‐endothelin‐1 (big‐ET‐1) and endothelin‐1 (ET‐1) were measured by extravasation of Evans blue dye (EB, 20 mg kg−1) in selected tissues. 2 A low dose of big‐ET‐1 (40 pmol kg−1) failed to alter vascular permeability but a dose of 400 pmol kg−1 increased EB extravasation in the trachea, upper and lower bronchi, and lung parenchyma by 55 to 69% (P < 0.05). Vascular permeability was also enhanced in the liver, spleen, kidney, heart, and diaphragm by 20, 14, 41, 25, and 67%, respectively (P < 0.05). 3 Upon injection of ET‐1 (400 pmol kg−1), EB extravasation increased in the upper and lower bronchi, lung parenchyma, liver, pancreas, kidney, heart, and diaphragm. 4 Administration of ET‐1 and big‐ET‐1 was not associated with significant systemic responses. 5 Pretreatment with phosphoramidon (PA) blocked the response to big‐ET‐1 in all tissues examined but this inhibitor failed to alter the response to ET‐1. 6 We conclude from these results that the dose‐dependent increase in vascular permeability induced by big‐ET‐1 in various tissues follows its conversion to ET‐1 by the endothelin converting enzyme, a PA‐sensitive process.

Hemodynamic effects of PAF-Acether on the dog kidney

PAF-Acether (PAF) is a potent vasodilator produced in several organs, including the kidney. In the present study, the effect of intra-femoral PAF (0.78 micrograms/kg) in control dogs (Group 1) or indomethacin (3 mg/kg) treated animals (Group 2) was examined. In Group 1, systemic blood pressure dropped from 108 +/- 8 to 47 +/- 7 mmHg following PAF and hematocrit rose from 42 +/- 2 to 56 +/- 2%. These changes were associated with a reduction in both urine flow, urinary sodium (from 69 +/- 9 to 25 +/- 6 muEq/min), glomerular filtration and renal plasma flow (from 28 +/- 2 to 11 +/- 1 and 52 +/- 5 to 26 +/- 4 ml/min, respectively). All parameters returned to normalcy during the following 50 minutes. In Group 2, the systemic effects of PAF were abolished by indomethacin. However, indomethacin failed to prevent the renal abnormalities which were altered as in Group 1. In additional experiments (Group 3) the influence of BN-52021, a specific antagonist of PAF receptors, was examined. The dose of PAF utilized in this group was 0.78 micrograms/kg, whereas BN-52021 was administered 30 minutes before PAF injections in increasing doses (1.0, 2.5, 5.0 and 25.0 micrograms). This antagonist blocked the effect of PAF on blood pressure and renal parameters in a dose-related manner. Finally, the effect of intrarenal PAF was studied (Group 4: increasing continuous infusions of 2, 5, 10, and 20 ng/kg/min; Group 5: single bolus of 0.15 and 0.30 micrograms/kg). In these two groups, the systemic effects of PAF were abolished as expected. In Group 4, a dose related reduction of urinary sodium was observed during the continuous infusion of PAF. Only at higher doses, was an effect on glomerular filtration and renal plasma flow observed. In Group 5, a marked reduction of urinary sodium (from 110 +/- 15 to 22 +/- 5 muEq/min) occurred while glomerular filtration and renal plasma flow decreased by approximately 50%. These data support a direct influence of PAF on urinary sodium excretion and renal hemodynamics. The peripheral effects of this compound are mediated by vasodilatory prostaglandins, as shown in Group 2. Finally, the actions of this powerful vasodilator on the kidney do not require the intervention of systemic influences, as clearly demonstrated in Groups 4 and 5.