Contrast media-induced nephrotoxicity--questions and answers

The intravascular administration of contrast media (CM) can produce acute haemodynamic changes in the kidney characterized by an increase in renal vascular resistance and a decrease in the glomerular filtration rate (GFR). These changes may lead to clinically significant reduction in renal function in patients with pre-existing risk factors such as diabetic nephropathy, congestive heart failure and dehydration. The pathophysiology of the renal haemodynamic effects of CM involves activation of the tubuloglomerular feedback (TGF) mechanism and the modulation of the intrarenal production of vasoactive mediators such as prostaglandins, nitric oxide, endothelin and adenosine. The TGF response is osmolality-dependent and accounts for about 50% of the acute functional effects of high osmolar CM on the kidney. Reduction in the synthesis of the endogenous vasodilators nitric oxide and prostaglandins increases the nephrotoxicity of CM. Endothelin and adenosine play a crucial role in mediating the acute functional effects of CM. Antagonists of these mediators attenuate the reduction in renal function induced by contrast agents. Vacuolization of the cells of the proximal tubules and necrosis of those of the medullary ascending limbs of loops of Henle are the main structural effects of CM in the kidney. The reduction in renal function induced by CM could be minimized by the use of low osmolar CM and adequate hydration. The prophylactic administration of calcium channel blockers and adenosine antagonists such as theophylline may also offer some protective effect.     

Cytochemical localization of adenylate cyclase in the limb buds of Bufo bufo

Apart from local heterogeneities of myocardial blood flow, the regulation of vascular tone is equally complex. Changes in vascular tone are essential for the adaptation of coronary blood flow to varying metabolic demands. The majority of coronary vascular resistance is found in the microcirculation, that is, in vessels with less than 150-200 microns in diameter; therefore, understanding the regulatory mechanisms that exercise control of the tone of these vessels is paramount to our understanding the control of myocardial perfusion. Recently, it became evident that different regulatory systems such as metabolic, neurohumoral, myogenic, and flow-mediated mechanisms have preferential effects on particular microvascular segments. However, the significance of specific vasoactive mediators is still under investigation. Growth factors, which are synthesized in cells in the surrounding of vessels such as mast cells and cardiac myocytes, have recently been suggested to play a role in the coordination of endothelium-dependent and endothelium-independent vasoactive mechanisms. The aim of this review is, first, to focus on the heterogeneity of the regulation of coronary vascular resistance in general and, second, to discuss recent studies showing a possible role of growth factors, especially fibroblast growth factor (FGF), heparin, and endothelin, as modulators of microvascular tone.     

Nutrition and endothelial cell integrity: implications in atherosclerosis

Loss of functional integrity of the vascular endothelium may be one of the initiating events in the etiology of atherosclerosis. Endothelial cells interact with blood components and the abluminal tissues, thus playing an active role in many aspects of vascular functions, such as permeability and vessel tone regulation. Endothelial cells constantly are exposed to nutrients which can modulate enzymes, receptors, transport molecules and various vasoactive mediators, resulting in significant functional changes of the endothelium and the underlying tissues. Nutrition may play an important role in the atherosclerotic disease process. There is evidence that certain vitamins and minerals prevent some metabolic and physiological perturbations of the vascular endothelium. This review focuses on selected lipids which cause endothelial cell injury or dysfunction and on nutrients which may exhibit antiatherogenic properties by being able to function as antioxidants or membrane stabilizers.     

Voltage-dependent Ca2+ channels in arterial smooth muscle cells

The past years have seen some significant advances in our understanding of the functional and molecular properties of voltage-dependent Ca2+ channels in arterial smooth muscle. Molecular cloning and expression studies together with experiments on native voltage-dependent Ca2+ channels revealed that these channels are built upon a molecular structure with properties appropriate to function as the main source for Ca2+ entry into arterial smooth muscle cells. This Ca2+ entry regulates intracellular free Ca2+, and thereby arterial tone. We summarize several avenues of recent research that should provide significant insights into the functioning of voltage-dependent Ca2+ channels under conditions that occur in arterial smooth muscle. These experiments have identified important features of voltage-dependent Ca2+ channels, including the steep steady-state voltage-dependence of the channel open probability at steady physiological membrane potentials between -60 and -30 mV, and a relatively high permeation rate at physiological Ca2+ concentrations, being about one million Ca2+ ions/s at -50 mV. This calcium permeation rate seems to be a feature of the pore-forming Ca2+ channel alpha1 subunit, since it was identical for native channels and the expressed alpha1 subunit alone. The channel activity is regulated by dihydropyridines, vasoactive hormones and intracellular signaling pathways. While the membrane potential of smooth muscle cells primarily regulates arterial muscle tone through alterations in Ca2+ influx through dihydropyridine-sensitive voltage-dependent ('L-type') Ca2+ channels, the role of these channels in the differentiation and proliferation of vascular smooth muscle cells is less clear. We discuss recent findings suggesting that other Ca2+ permeable ion channels might be important for the control of Ca2+ influx in dedifferentiated vascular smooth muscle cells.     

A review of the actions and control of intracellular pH in vascular smooth muscle

OBJECTIVE: This review is an account of the physiological issues involved in the effects of pH on vascular smooth muscle tone. The following criteria were considered when reviewing the literature: (i) the type of smooth muscle, i.e. either tonic or phasic, (ii) the source of the smooth muscle i.e. pulmonary, systemic, large artery, resistance artery, vein or cell line, (iii) the effects of changing intracellular or extracellular pH alone, (iv) the acute or chronic effects of altered pH (v) the influence of extracellular pH on intracellular pH and (vi) the influence of altered intracellular pH on basal or agonist induced tone. Studies of the effects of pH on the individual intracellular components of vascular tone, specifically sarcoplasmic reticulum and contractile proteins function are considered. Finally, the pH sensitivity of molecular components that contribute to smooth muscle cell tone are reviewed. CONCLUSIONS: There appear to be distinct differences in the response of large arteries and resistance arteries to altered intracellular pH which may be based on the different properties of the smooth muscle within the wall of each blood vessel. Similarly, systemic and pulmonary vessels may respond differently, but no systematic study exists to allow a more definitive conclusion. Factors controlling intracellular pH such as intracellular buffering power and sarcolemmal pH regulating mechanisms may differ across the vascular bed and may contribute to some of the differences observed in response to altered extracellular pH. Finally, few studies have examined the pH sensitivity the intracellular processes involved in basal tone and pharmaco-mechanical coupling in vascular smooth muscle. More information concerning these latter aspects of smooth muscle function is required to progress the understanding of the modulator action on pH on vascular tone.     

Glomerulonephritis in autopsy cases with hepatitis C virus infection

1. The inducible isoform of nitric oxide synthase (iNOS) is expressed in human and experimental cardiac allografts and is localized to infiltrating macrophages, cardiac myocytes, endothelial cells and smooth muscle cells. A recent clinical report proposes a causal link between myocardial expression of iNOS and ventricular contractile dysfunction, a potentially graft- and life-threatening post-transplant complication. 2. Coronary blood flow is elevated in human graft recipients with biopsy proven cellular rejection, indicating that vasodilation accompanies graft rejection. In Lewis-to-F-344 coronary resistance vessels, which show intimal expression of iNOS, pressure-induced myogenic tone is significantly inhibited. Selective iNOS inhibition partially reverses the inhibition of myogenic tone, confirming that iNOS produces vasoactive nitric oxide (NO) and may mediate the rejection-induced vasodilation seen clinically. 3. Endothelial dysfunction, identified as loss of endothelium-dependent dilation, has tremendous prognostic significance in vascular diseases of multiple aetiologies. In transplantation, endothelial dysfunction predicts early cardiac allograft vasculopathy and poor clinical outcome. Lewis-to-F-344 coronary vessels develop endothelial dysfunction at 1 week post-transplantation, but this is preceded by a transient state of endothelial cell hyperfunction, with enhanced endothelial production of NO. 4. The normal interaction between endothelial and smooth muscle cells in coronary resistance vessels is critical for the regulation of coronary blood flow and the maintenance of fluid homeostasis. With allospecific expression of iNOS, the inhibition of vascular tone predicts greatly enhanced intravascular pressure in precapillary arterioles and capillaries; this would be expected to cause a net movement of fluid from the intravascular compartment into the myocardial interstitium, resulting in ventricular oedema, non-compliance and poor contractile performance.     

Dopexamine hydrochloride in septic shock: effects on oxygen delivery and oxygenation of gut, liver, and muscle

It has been suggested that septic shock is a disorder of microvascular autoregulation. Tissue blood flow is modulated by the state of activation of upstream endothelial receptors controlling the vascular smooth muscle tone. Because vascular receptor populations vary between organs, it should be expected that vasoactive drugs affect tissue oxygenation differently in different organs. We studied the effects of dopexamine HCl (a novel inotrope) and septic shock on oxygen delivery as well as tissue Po2 in gut, liver, and skeletal muscle in anesthetized rabbits. Employing the thermodilution technique, cardiac output was measured across the pulmonary bed and used to calculate oxygen delivery. Three eight-channel Mehrdraht Dortmund Oberfl?che oxygen electrodes were placed on gut serosa, liver, and skeletal muscle surfaces, respectively, and sufficient readings were obtained to calculate tissue Po2 distributions. During septic shock mean arterial pressure, cardiac output, oxygen delivery, and mean tissue Po2 decreased in all organs. Our results suggest that the observed changes in tissue oxygenation during septic shock were caused by defective regulation of microvascular blood flow. In conclusion, during baseline conditions dopexamine HCl caused no statistically significant changes in tissue oxygenation in any organ, except in skeletal muscle at 10 micrograms/kg/min when tissue Po2 increased. During septic shock, however, dopexamine HCl improved oxygenation in all three organs in a dose-dependent manner.     

Hyperventilation alters colonic motor and sensory function: effects and mechanisms in humans

BACKGROUND & AIMS. Hyperventilation-induced hypocapnia affects hemodynamic function and enhances colonic motility. The aims of this study were to determine the effects of hypocapnic hyperventilation on colonic motility and sensation in health and to explore the putative neurohumoral mechanisms. METHODS: In experiment 1, colonic tone, sensation, plasma levels of cortisol, beta-endorphin, selected gut neuropeptides, norepinephrine, epinephrine, and splanchnic blood volume were measured during two sequences of hypocapnic hyperventilation. In experiment 2, colonic tone and sensation were assessed during eucapnic hyperventilation and abdominal compression. RESULTS: Hypocapnic hyperventilation, but not eucapnic hyperventilation or abdominal compression, significantly increased colonic tone and sensitivity to balloon distention (P = 0.017) without altering humoral mediators or splanchnic blood volume. Plasma norepinephrine level increased (P = 0.017) and splanchnic blood volume decreased (P = 0.028) during 5 minutes after hyperventilation, consistent with homeostatic responses. CONCLUSIONS: Increased colonic tone and sensation during hypocapnic hyperventilation are not caused by colonic compression. These effects of hyperventilation are not mediated humorally but may result from direct metabolic effects of hypocapnia on colonic muscle or from changes in central autonomic control of colonic smooth muscle.     

Nitric oxide and regulation of vascular tone: pharmacological and physiological considerations

The endothelial cells of the vascular system are responsible for many biological activities that maintain vascular homeostasis. Responding to a variety of chemical and physical stimuli, the endothelium elaborates a host of vasoactive agents. One of these agents, endothelium-derived relaxing factor, now accepted as nitric oxide, influences both cellular constituents of the blood and vascular smooth muscle. A principal intracellular target for nitric oxide is guanylate cyclase, which, when activated, increases the intracellular concentration of cyclic guanosine monophosphate, which in turn activates protein kinase G. Acting by this pathway, nitric oxide induces relaxation of vascular smooth muscle and inhibits platelet activation and aggregation. Derangements in endothelial production of nitric oxide are implicated as both cause and consequence of vascular diseases, including hypertension, atherosclerosis, and coronary artery disease.     

Vascular endothelial cells and renin-angiotensin system

The vascular renin-angiotensin system (RAS) is regulated independently from circulating RAS and plays a role in the local regulation of vascular tone, the modulation of sympathetic activity and vascular remodeling. Endothelial cells are a major source of angiotensin converting enzyme (ACE), which produces angiotensin II and degrades bradykinin, in normal arteries. Mechanical stress such as transmural pressure, stretch stress and shear stress appear to contribute to the regulation of endothelial ACE activity. In contrast, vessels with intimal proliferation such as atheromatous plaque and neointima following balloon injury show expression of ACE in smooth muscle cells and macrophages in the intimal lesions. Activation of ACE in intimal SMC may relate to a phenotypic change of SMC from the contracting type of the synthetic type. Activation of ACE in macrophages is also related to the transformation of macrophages from monocytes. Concerning the role of the activated RAS, elevated blood pressure and vascular tonus by angiotensin II are candidates of vascular injury and plaque rupture. Angiotensin II stimulates migration and proliferation of smooth muscle cells and production of extracellular matrix. Furthermore, angiotensin II increases oxidized-LDL which may be related to the forming of macrophages. These evidence suggest that activation of vascular RAS following endothelial dysfunction/injury play an important role in the pathogenesis of vascular remodeling and atherosclerosis.     

Platelets inhibit the induction of nitric oxide synthesis by interleukin-1 beta in vascular smooth muscle cells

We have investigated the role of platelets in regulating the hemostatic and vasomotor properties of vascular smooth muscle. Experiments were performed to examine the effect of the releasate from activated platelets on the production of nitric oxide from interleukin-1 beta (IL-1 beta)-treated cultured rat aortic smooth muscle cells. Treatment of vascular smooth muscle cells with IL-1 beta resulted in significant accumulation of nitrite in the culture media and in marked elevation of intracellular cyclic guanosine monophosphate (GMP) levels. The releasate from collagen-aggregated platelets blocked the IL-1 beta-mediated production of nitrite and the accumulation of cyclic GMP in smooth muscle cells in a platelet number-dependent manner. In functional assays, the perfusates from columns containing IL-1 beta-treated smooth muscle cells relaxed detector blood vessels without endothelium and the addition of IL-1 beta-treated smooth muscle cells to suspensions of platelets inhibited their thrombin-induced aggregation. The simultaneous treatment of smooth muscle cells with IL-1 beta and the platelet releasate abolished both the vasorelaxing activities of the perfusates and the inhibition of platelet aggregation. Platelet releasates treated with a neutralizing antibody to platelet-derived growth factor (PDGF) failed to block IL-1 beta-induced nitric oxide production by the smooth muscle cells, as measured by both biochemical and functional assays. The platelet releasate from a patient with gray platelet syndrome likewise failed to block IL-1 beta-induced nitrite release by smooth muscle cells. These results demonstrate that platelets downregulate the production of nitric oxide by IL-1 beta-treated vascular smooth muscle cells through the release of PDGF. This effect may represent a novel mechanism by which platelets regulate vasomotor tone and thrombus formation at sites of vascular injury.     

Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) are perisinusoidal cells believed to participate in the regulation of hepatic blood flow because of their contractile properties and presence of receptors for several vasoactive factors. It is unknown whether HSCs have receptors for vasopressin, one of the most potent endogenous vasoconstrictors. This study investigated the existence of receptors for and the effects of arginine vasopressin (AVP) on cultured human HSCs. METHODS: intracellular calcium concentration ([Ca2+]i) and cell contraction were measured in individual cells loaded with fura-2 using a morphometric method with an epifluorescence microscope coupled to a CCD imaging system (Photometrics, Tucson, AZ). AVP-specific binding was measured with [3H]AVP. Mitogen-activated protein kinase (MAPk) activity and DNA synthesis were measured by in vitro phosphorylation of myelin basic protein and [3H]thymidine incorporation, respectively. Parallel experiments were performed in vascular smooth muscle cells. RESULTS: AVP elicited a dose-dependent increase in [Ca2+]i and contraction of HSCs. Moreover, AVP increased MAPk activity, DNA synthesis, and cell number. These effects were similar to those observed in vascular smooth muscle cells and were blocked by a V1 receptor antagonist. The existence of V1 receptors was further confirmed by binding studies. CONCLUSIONS: Human HSCs have V1-vasopressin receptors that induce effects similar to those observed in vascular smooth muscle cells. AVP may play a role in the regulation of HSC function.     

Epoxyeicosatrienoic acid metabolism in arterial smooth muscle cells

Epoxyeicosatrienoic acids (EETs) are eicosanoids synthesized from arachidonic acid by the cytochrome P450 eposygenase pathway. The present studies demonstrate that 8,9-, 11,12-, and 14,15-EET are rapidly taken up by porcine aortic smooth muscle cells. About half of the uptake is incorporated into phospholipids, and saponification indicates that most of this remains in the form of EET. The EETs also are converted to the corresponding dihydroxyeicosatrienoic acids (DHETs) and during prolonged incubations, additional metabolites that do not retain the EET carboxyl group are formed. Most of these products are released into the medium. However, some DHET and metabolites less polar than EET are incorporated into the phospholipids, and a small amount of unesterified EET is also present in the cells. The incorporation of 14,15-EET and its conversion to DHET did not approach saturation until the concentration exceeded 10-20 microM, indicating that vascular smooth muscle has a large capacity to utilize this EET. These findings suggest that certain vasoactive effects of EETs may be due to their incorporation by smooth muscle cells. Furthermore, through conversion to DHET and other oxidized metabolites, smooth muscle apparently has the capacity to inactivate EETs that are either formed in or penetrate into the vascular wall.     

Cell membrane receptors and intracellular signalling. Characterization in cultivated, contractile and endothelial cells

Numerous hormones and mediators develop their effect via one or several specific receptors/subtypes. In glomerular endothelial cells (GEC), for example, the action of adenosine triphosphate is mediated by a novel nucleotide receptor. Since the latter is not found in large vessels, it is expected to play an important role in the regulation of the microcirculation. Substances with a very similar structure, such as vasopressin and oxytocin, can bind to the same receptor in vascular smooth muscle cells (VMC), although only the true agonist produces a maximum response. Following the binding of vasopressin to its specific V1-VP receptor, the ligand/receptor complex is internalized and processed within the cell. The freed receptor is then recycled to the cell membrane. This mechanism is responsible for the transient nature of vasopressin action. In VMC and the functionally similar contractile glomerular mesangial cells, vasopressin triggers intracellular signals, resulting in contraction. These signals may be enhanced or attenuated by numerous hormonal factors or mediators.     

K+ channel modulation in arterial smooth muscle

Potassium channels play an essential role in the membrane potential of arterial smooth muscle, and also in regulating contractile tone. Four types of K+ channel have been described in vascular smooth muscle: Voltage-activated K+ channels (Kv) are encoded by the Kv gene family, Ca(2+)-activated K+ channels (BKCa) are encoded by the slo gene, inward rectifiers (KIR) by Kir2.0, and ATP-sensitive K+ channels (KATP) by Kir6.0 and sulphonylurea receptor genes. In smooth muscle, the channel subunit genes reported to be expressed are: Kv1.0, Kv1.2, Kv1.4-1.6, Kv2.1, Kv9.3, Kv beta 1-beta 4, slo alpha and beta, Kir2.1, Kir6.2, and SUR1 and SUR2. Arterial K+ channels are modulated by physiological vasodilators, which increase K+ channel activity, and vasoconstrictors, which decrease it. Several vasodilators acting at receptors linked to cAMP-dependent protein kinase activate KATP channels. These include adenosine, calcitonin gene-related peptide, and beta-adrenoceptor agonists. beta-adrenoceptors can also activate BKCa and Kv channels. Several vasoconstrictors that activate protein kinase C inhibit KATP channels, and inhibition of BKCa and Kv channels through PKC has also been described. Activators of cGMP-dependent protein kinase, in particular NO, activate BKCa channels, and possibly KATP channels. Hypoxia leads to activation of KATP channels, and activation of BKCa channels has also been reported. Hypoxic pulmonary vasoconstriction involves inhibition of Kv channels. Vasodilation to increased external K+ involves KIR channels. Endothelium-derived hyperpolarizing factor activates K+ channels that are not yet clearly defined. Such K+ channel modulations, through their effects on membrane potential and contractile tone, make important contributions to the regulation of blood flow.     

Vasoactive effects of basic and acidic fibroblast growth factors in hamster cheek pouch arterioles

Fibroblasts growth factors (FGFs) exhibit well-known angiogenic actions, but there is some controversy about whether they have vasoactive effects on blood vessels which might contribute to angiogenesis per se. To clarify this, changes in arteriolar diameter were recorded during observation by videomicroscopy of 3rd- and 4th (terminal)-order arterioles (resting diameters 22.5 +/- 0.5 microns and 14.4 +/- 0.3 microns, respectively) in the hamster cheek pouch in response to FGF application. Recombinant human bFGF (basic) and aFGF (acidic) were applied from micropipettes positioned 5-10 microns from the adventitial surface of vessels. Maximum vasodilator effects of adenosine (10(-4) M) applied in a similar way were also observed. Adenosine increased the diameters of 4th-order arterioles by 37.2 +/- 3.8% and those of 3rd-order arterioles by 38.7 +/- 2.7. bFGF produced vasodilatation (threshold dose 0.1 ng ml-1) in both classes of arterioles, while aFGF produced dose-dependent constriction (threshold dose 0.01 ng ml-1). A maximal dilator effect in 4th-order arterioles was obtained with 100 ng ml-1 bFGF, when diameters reached 82.6 +/- 2.4% of those with adenosine. Maximal constrictor effect (-48.2 +/- 5.6% of resting diameter) occurred with a dose of 100 ng ml-1 aFGF. Vehicle alone (MOPS or bicarbonate buffer used as solvents for FGFs) had no effect. As vasoconstrictors are known to stimulate growth of smooth muscle cells while dilators stimulate growth of endothelial cells, it is possible that the opposing vasoactivities demonstrated for aFGF and bFGF are linked with their selective mitogenicity for smooth muscle and endothelial cells, respectively, and contribute to their angiogenic actions.