IMPAIRED NITRIC OXIDE-MEDIATED FLOW-INDUCED DILATION IN ARTERIOLES OF SPONTANEOUSLY HYPERTENSIVE RATS

We tested the hypothesis that impairment of flow-dependent dilator mechanisms of skeletal muscle arterioles is one of the underlying reasons for the increased peripheral resistance in hypertension. Isolated, cannulated arterioles (approximate to 55 mu m) of gracilis muscle of 12-week-old spontaneously hypertensive (SH) and normotensive Wistar (NW) rats were investigated. At a constant perfusion pressure (80 mm Hg), the active diameters of NW and SH arterioles were 57.7+/-1.9 and 51.5+/-3.2 mu m, whereas their passive diameters (Ca2+-free solution) were 113.6+/-2.9 and 101.7+/-2.9 mu m, respectively. Flow-induced dilation was elicited by increases in flow of the perfusion solution from 0 to 25 mu L/min in 5-mu L/min steps. This response was significantly less in arterioles of SH compared with NW rats. For example, at 25-mu L/min flow, the diameter of arterioles of SH rats was approximate to 56% less (P<.05) than those of NW rats. Indomethacin, an inhibitor of prostaglandin synthesis, significantly attenuated the flow-diameter curve in both strains of rats. In contrast, N-Omega-nitro-L-arginine, a nitric oxide synthase inhibitor, significantly shifted the flow-diameter curve to the right in NW rats, but it did not affect the flow-diameter curve in SH rats. Thus, the present findings demonstrate that in gracilis muscle arterioles of normotensive rats in response to increases in flow (shear stress), prostaglandins and nitric oxide are coreleased, resulting in a dilation. In early hypertension, however, there is a reduced arteriolar dilation to increases in flow that is due to the impairment of the nitric oxide-mediated portion of the flow-dependent arteriolar dilation. (Circ Res. 1994;74:416-421.

PROSTAGLANDINS MEDIATE ARTERIOLAR DILATION TO INCREASED BLOOD-FLOW VELOCITY IN SKELETAL-MUSCLE MICROCIRCULATION

In cremaster muscle of pentobarbital-anesthetized rats, temporary occlusion of an arteriole increased red blood cell velocity (mean increase, 8.2 +/- 1.0 mm/sec from a control velocity of 7.9 +/- 0.7 mm/sec) in proximal parallel arteriolar branches (mean control diameter, 19.4 +/- 0.6 microns). Increases in flow velocity were consistently followed by proportional delayed (6-15 seconds) increases in arteriolar diameter (5.8 +/- 0.7 microns). Administration of NG-monomethyl-L-arginine (200 microM), an inhibitor of the synthesis of endothelium-derived relaxing factor that blocked the arteriolar responses to acetylcholine (1 microM) but not to arachidonic acid (10 microM), did not affect the dilation (mean increase, 8.9 +/- 1.1 microns) due to increases in red blood cell velocity (13.4 +/- 1.5 mm/sec). However, the cyclooxygenase inhibitor indomethacin (or meclofenamate), which completely blocked the dilator response to arachidonic acid but did not change the response to acetylcholine, inhibited the arteriolar dilation (mean increase, 0.3 +/- 0.2 micron) due to increases in red blood cell velocity (9.3 +/- 1.0 mm/sec). Inhibition of prostaglandin synthesis also reduced the increase in calculated blood flow by 57% during occlusion. These results suggest that the arterioles are sensitive to increases in blood flow velocity (wall shear stress), in response to which they release prostaglandins, eliciting vasodilation. The existence of this phenomenon in the skeletal muscle microcirculation suggests a new regulatory mechanism that, by modulation of vascular resistance in the microvascular network, has the role of normalizing wall shear stress and providing for substantial increases in tissue blood flow

ENDOTHELIAL DYSFUNCTION AUGMENTS MYOGENIC ARTERIOLAR CONSTRICTION IN HYPERTENSION

To elucidate the underlying reason or reasons for the increased peripheral resistance in hypertension, we investigated the pressure-diameter relation-the myogenic response-of isolated, cannulated arterioles (approximately 50 mu m) of cremaster muscle of 12-week-old Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and normal Wistar (NW) rats. All arterioles constricted in response to step increases in perfusion pressure from 20 to 160 mm Hg. This constriction was, however, significantly enhanced from 60 to 160 mm Hg in arterioles of SHR compared with NW or WKY rats. For example, at 80 and 140 mm Hg, respectively, the normalized diameter (expressed as a percentage of the corresponding passive diameter of arterioles of SHR) was 11.8% and 27.6% (P<.05) less compared with those of WKY rats. Endothelium removal eliminated the enhanced pressure-induced tone in SHR. Similarly, indomethacin (10(-5) mol/L, sufficient to block prostaglandin synthesis) or SQ 29,548 (10(-6) mol/L), a thromboxane A(2)-prostaglandin H-2 receptor blocker that inhibited vasoconstriction to the thromboxane agonist U46619, attenuated the enhanced pressure-diameter curve and reversed the blunted dilation to arachidonic acid in SHR. In contrast, the thromboxane A(2) synthesis inhibitor CGS 13,080 (5x10(-6) mol/L) did not affect the increased pressure-induced tone or the reduced dilation to arachidonic acid in SHR. Thus, the present findings suggest that in early hypertension pressure-induced arteriolar constriction is increased. This seems to be due to an enhanced production of endothelium-derived constrictor factors, primarily prostaglandin H-2

A hemodinamikai erők által aktivált normális éa kóros vaszkuláris mechanizmusok = Haemodynamic forces-activated normal and pathological vascular mechanisms

A hemodinamikai erők által aktivált normális és kóros vaszkuláris mechanizmusok tisztázását tűztük ki célul. Főbb eredmények: 1) A nitrogén-monoxid (NO) befolyásolja a miogén válasz és az érfal mechanikus viselkedése közti kapcsolatot patkány koronária arteriolákban. Továbbá, az NO jelenléte szükséges disztenzibilitás fenntartásához. 2) 2-es típusú diabeteses egerekben az arteriolák tónusa és vérnyomása emelkedett, melyben a COX-2 eredetű konstriktor prosztaglandin fokozott felszabadulása szerepet játszhat. 3) A PECAM-1 mediálja az arteriolák magas fali nyíróerőgrádiens-indukálta NO-függő dilatációját. 4) Izolált ereket oxidatív stressznek kitéve, az Ang II-re adott konstrikciós válaszok fokozódtak. 5) Az asszimetrikus dimetilarginin (ADMA) izolált vázizom arteriolákban nem csak az NO szintézisét csökkenti, hanem szuperoxid termelést is indukál, amelyek módosítják a rezisztencia erek vazomotor működését. Továbbá, a vaszkuláris RAS-t aktiválva fokozza az NAD(P)H oxidáz aktivását, ami oxidatív molekulák felszabadulásához vezet. 6) A magas szorbitol koncentráció jelenlétében az arteriolák vazomotor működése károsodik, részben a NO-mediáció csökkenése, részben a PGH2/TXA2 fokozott termelése révén. 7) A H2O2 fokozza a konstriktor prosztaglandinok termelődését a simaizomban, mely fokozza az arteriolák tónusát 2 típusú diabeteses egerekben. 8) A magas intraluminális nyomás csökkenti az angiotenzinre bekövetkező tachyfilaxia mértékét, azaz a konstrikciók erejének csökkenését. | We aimed to elucidate the physiological and pathological vascular mechanisms that are activated by hemodynamic forces. Main results: 1) Nitric oxide (NO) affects the relation between myogenic response and vessel wall mechanics in coronaries of rats. Also, presence of NO is needed to maintain vascular distensibility. 2) Mice with type 2 DM have increased arteriolar tone and blood pressure, in which an enhanced release of COX-2-derived constrictor prostaglandins can play role. 3) PECAM-mediates the sheer stress gradient-induced NO-mediated dilations of arterioles. 4) After exposing isolated arterial vessels to oxidative stress their constrictions to sequential administration of Ang II increase. 5) Asymmetric dimethylarginine (ADMA) not only reduces NO synthesis in isolated skeletal muscle arterioles, but induces superoxide production, altering the vasomotor function of resistance vessels. ADMA, by activating vascular renin-angiotensin system activates NAD(P)H-oxidase leading to release of oxidative molecules. 6) High sorbitol concentration impairs arteriolar vasomotor function, partly by reducing NO mediation, and partly by increased production of PGH2/TXA2. 7) H2O2 enhances production of constrictor prostaglandins in the smooth muscle, thereby increases arteriolar tone in mice with type 2 DM. 8) High intraluminal pressure diminishes the tachyphylaxis following angiotensin administration that is the rate of reduction in vasoconstriction response

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. Orv. Hetil., 2016, 157(21), 805-812

A szívizom intracelluláris kalcium homeosztázisának szabályozása diabéteszes kardiomiopátiában = Intracellular calcium handling of the heart in diabetic cardiomyopathy

A diabétesz mellitusz (DM) egyik súlyos szövődménye a csökkent szívizom funkció, kardiomiopátia. Ennek hátterében a szívizomsejtek Ca2+i homeosztázisának zavara állhat. Pályázatunk fő célkitűzése a 2. típusú diabétesz mellitusz során kialakuló szívizom Ca2+i homeosztázis zavarok vizsgálata volt különböző perfundált patkány és egér szív modellekben. Kísérleti rendszerünkben az aktuális szívpumpa funkció hemodinamikai paramétereit és a Ca2+i homeosztázist jellemző, ún. Ca2+i-tranzienst egyidejűleg vizsgáltuk, ezáltal a kontrakciós tevékenység változásait a háttérben álló Ca2+i fluxusok ismeretében értelmeztük. Eredményeink szerint a csökkent szívfunkció hátterében a szarkoplazmatikus retikulum (SR) Ca2+ raktározó és felszabadító működésének károsodása állhat. Továbbá, a manifeszt kardiális diszfunkciót megelőzően már sérül az SR Ca2+ pumpájának (SERCA2a) működése. Ennek a diszfunkciónak a mechanizmusa lehet a SERCA2a posztranszlációs modifikációja vagy a membránkörnyezet kedvezőtlen változása. A funkciózavar ellensúlyozására a diabéteszes szívekben a SERCA2a fehérje fokozott expressziója következik be. A hipoxiás tűrőképességet vizsgálva megállapítottuk, hogy a diabéteszes szívben a SERCA2a diszfunkció miatt csökkent Ca2+i szekvesztráció hipoxiára fokozottan érzékeny, amely oxigénhiányos állapotokban a Ca2+i szint túlzott mértékű emelkedését okozhatja. Eredményeink hozzájárulhatnak a diabéteszes kardiomiopátia patomechanizmusának részletesebb megértéséhez. | One of the serious complications of diabetes mellitus (DM) is decreased myocardial function, cardiomyopathy, which is probably underlined by disturbances of Ca2+i homeostasis of the cardiomyocytes. The main goal of this project was to delineate pathological changes of myocardial Ca2+i handling in type 2 DM using different isolated, perfused rat and mouse heart models. Our experimental setup enabled the concomitant measurement of the hemodynamic parameters of actual heart pump function and the Ca2+i-transient characterizing myocardial Ca2+i homeostasis. This way disturbances in contractile activities of the heart could be assessed in view of background Ca2+i fluxes. Our results show that disturbances of Ca2+ sequestration and release by the sarcoplasmic reticulum (SR) underlie contractile abnormalities of the heart. Furthermore, the normal operation of the Ca2+ pump of the SR (SERCA2a) progressively deteriorates prior to manifestation of cardiac dysfunction the mechanism of which could be related to posttranslational modifications of SERCA2a or unfavorable alterations in the surrounding membrane composition. SERCA2a protein expression increases to counteract functional disturbances. Decreased Ca2+ sequestration by SERCA2a dysfunction in the diabetic heart has augmented sensitivity to hypoxia. This enhanced sensitivity could lead to Ca2+i overload when O2 is in short supply. These results may lead to the better understanding of the pathomechanisms of diabetic cardiomyopathy

The Beta-1-Receptor Blocker Nebivolol Elicits Dilation of Cerebral Arteries by Reducing Smooth Muscle [Ca2+]i

K