Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation.

(1) Background: Traumatic brain injury (TBI) frequently occurs worldwide, resulting in high morbidity and mortality. Here, we hypothesized that TBI impairs an autoregulatory mechanism, namely the flow-induced constriction of isolated rat middle cerebral arteries (MCAs). (2) Methods: TBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure-flow chamber. The internal diameter was measured by a video-microscopy. (3) Results: In MCAs from intact rats, increases in flow and pressure + flow elicited constrictions (-26 ± 1.9 µm and -52 ± 2.8 µm, p < 0.05), which were significantly reduced after TBI or in the presence of thromboxane-prostanoid (TP receptor) antagonist SQ 29,548. Flow-induced constrictions were significantly reduced by HET0016, inhibitor of cytochrome P450 4A (CYP450 4A). Arachidonic acid, (AA, 10-7 M), and CYP-450 4A metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) elicited constrictions of intact MCA (-26 ± 2.3% and -31 ± 3.6%), which were significantly reduced after TBI (to 11 ± 1.3% and -16 ±2.5%). The TP receptor agonist U46619 (10-7 M) elicited substantial constrictions of MCA from intact rats (-21 ± 3.3%), which were also significantly reduced, after TBI (to -16 ± 2.4%). (4) Conclusions: Flow-induced constrictor response of MCA is impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins and the mitigated sensitivity of thromboxane-prostanoid receptors.

Coronary Microvascular and Cardiac Dysfunction Due to Homocysteine Pathometabolism; A Complex Therapeutic Design.

In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 µM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFα, NFκbeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments.

Remodeling of Wall Mechanics and the Myogenic Mechanism of Rat Intramural Coronary Arterioles in Response to a Short-Term Daily Exercise Program: Role of Endothelial Factors.

PURPOSE: Exercise elicits early adaptation of coronary vessels enabling the coronary circulation to respond adequately to higher flow demands. We hypothesized that short-term daily exercise induces biomechanical and functional remodeling of the coronary resistance arteries related to pressure. METHODS: Male rats were subjected to a progressively increasing 4-week treadmill exercise program (over 60 min/day, 1 mph in the final step). In vitro pressure-diameter measurements were performed on coronary segments (119 ± 5 µm in diameter at 50 mm Hg) with microarteriography. The magnitude of the myogenic response and contribution of endogenous nitric oxide and prostanoid production to the wall mechanics and pressure-diameter relationship were assessed. RESULTS: Arterioles isolated from exercised ani mals - compared to the sedentary group - had thicker walls, increased distensibility, and a decreased elastic modulus as a result of reduced wall stress in the low pressure range. The arterioles of exercised rats exhibited a more powerful myogenic response and less endogenous vasoconstrictor prostanoid modulation at higher pressures, while vasodilator nitric oxide modulation of diameter was augmented at low pressures (< 60 mm Hg). CONCLUSIONS: A short-term daily exercise program induces remodeling of rat intramural coronary arterioles, likely resulting in a greater range of coronary autoregulatory function (constrictor and dilator reserves) and more effective protection against great changes in intraluminal pressure, contributing thereby to the optimization of coronary blood flow during exercise.

[Regulation of vasomotor tone of small skeletal muscle veins by intrinsic mechanisms]. / Vázizomkisvénák vazomotortónusának intrinszik szabályozómechanizmusai.

In many developed countries the prevalence of venous disorders and its consequences are higher than that of arterial diseases. Thus it is very important to understand the exact physiological and pathophysiological function of small veins and their control mechanisms. Small veins and venules have an important role in the regulation of capillary fluid exchange, as well as return of the venous blood into the heart. However, there is only limited knowledge available regarding the role of local mechanisms controlling the vasomotor tone and diameter of small veins. In the last decade the authors focused on the elucidation of these mechanisms in isolated skeletal muscle venules of rats. Their results suggest that the tone of small veins is controlled by the integration of several mechanisms, activated by the intraluminal pressure and flow/wall shear stress, in addition to numerous local mediators synthesized and released from the smooth muscle and endothelium. These mechanisms are involved - in a complex manner - in the control of postcapillary resistance, thus regulation of tissue blood supply, venous return and consequently in the modulation of the cardiac output, as well.