The small arteries (prearteriolar vessels with lumen diameter less than approximately 500 microns) contribute importantly to and participate actively in the regulation of the peripheral resistance. New techniques, building on the classic histological and hemodynamic techniques, have enabled detailed in vitro investigation of small arteries. At present, research in small arteries is in its infancy, and our understanding of the heterogeneity of small arteries within vascular beds, between vascular beds, and between species is extremely limited. This review attempts to describe the current status of the field. New techniques, based primarily on a wire myograph (where the vessels are mounted as ring preparations) and a pressure myograph (where vessels are cannulated and pressure-lumen relations are determined), have allowed in vitro investigations of small arteries. The more physiological arrangement of the pressure myograph allows, for example, investigation of the vasoconstrictor response to raised intravascular pressure (the Bayliss response), whereas the less-sophisticated wire myograph is similar to use and may be more useful in certain situations where particular mechanisms are being investigated. Both techniques allow simultaneous measurements of vessel tone and a variety of parameters (e.g., membrane potential and intracellular ion activities) and thus allow precise determination of the relation between small artery structure and function. The vessels appear to remain fully viable with regard to the contractility of their smooth muscle cells as well as to the function of their perivascular nerves and their endothelium. The evidence suggests that the monovalent transport mechanisms in the plasma membrane, in particular potassium channels, play an important role in the determination of the membrane potential in small arteries, although the relation is more complex than indicated by the Goldman equation. Confirmation of these findings requires, however, simultaneous determinations of ion transport and vascular tone under conditions where vessels are subjected to mechanical loading. The membrane potential, through its effect on potential-dependent calcium channels, plays an important role in the determination of vascular tone. With regard to calcium homeostasis, current knowledge is hampered by the lack of direct measurements of the relation between cytoplasmic calcium and vascular tone. The evidence, however, suggests that besides potential-dependent calcium channels, receptor-operated calcium channels are present in the plasma membrane, although this still requires confirmation. The role of the sarcoplasmic reticulum is not clarified.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract-Vasomotion is the regular variation in tone of arteries. In our study, we suggest a model for the initiation of vasomotion. We suggest that intermittent release of Ca 2ϩ from the sarcoplasmic reticulum (SR, cytosolic oscillator), which is initially unsynchronized between the vascular smooth muscle cells, becomes synchronized to initiate vasomotion. The synchronization is achieved by an ion current over the cell membrane, which is activated by the oscillating Ca 2ϩ release. This current results in an oscillating membrane potential, which synchronizes the SR in the vessel wall and starts vasomotion. Therefore, the pacemaker of the vascular wall can be envisaged as a diffuse array of individual cytosolic oscillators that become entrained by a reciprocal interaction with the cell membrane. The model is supported by experimental data. Confocal [Ca 2ϩ ] i imaging and isometric force development in isolated rat resistance arteries showed that low norepinephrine concentrations induced SR-dependent unsynchronized waves of Ca 2ϩ in the vascular smooth muscle. In the presence of the endothelium, the waves converted to global synchronized oscillations of [Ca 2ϩ ] i after some time, and vasomotion appeared. Synchronization was also seen in the absence of endothelium if 8-bromo-cGMP was added to the bath. Using the patch-clamp technique and microelectrodes, we showed that Ca 2ϩ release can activate an inward current in isolated smooth muscle cells from the arteries and cause depolarization. These electrophysiological effects of Ca 2ϩ release were cGMP dependent, which is consistent with the possibility that they are important for the cGMP-dependent synchronization. Further support for the model is the observation that a short-lasting current pulse can initiate vasomotion in an unsynchronized artery as expected from the model.

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The mechanical and morphological properties of segments of certain precisely defined resistance vessels (approximately 150 micrometer lumen diameter) in the mesenteric bed of spontaneously hypertensive (SHR) and normotensive (WKY) rats have been compared in vitro under carefully controlled conditions and also after fixation. At a given transmural pressure, the relaxed SHR vessels (compared with the WKY vessels) would have had a 16% smaller lumen diameter (P less than 0.01) and a 49% thicker media (P less than 0.005), so that the media volume per unit segment length was 31% greater (P less than 0.05). The smooth muscle cells were arranged circumferentially in about four layers in the SHR vessels and in about three layers in the WKY vessels. The SHR active wall tension in response to potassium was 53% greater (P less than 0.02) and to norepinephrine was 50% greater (P less than 0.01) than for WKY. However, the ED50 values for the norepinephrine dose-response curves were similar (approximately 5 micrometer). Activation with potassium plus norepinephrine gave greater responses in both vessel types, than with either agent alone, but the SHR responses were on average only 19% greater than the WKY (P less than 0.10). However, under these conditions, the SHR vessels would have been able to contract against 45% greater transmural pressures (P less than 0.001) because of their smaller lumen. On maximal activation, the mean force developed by each cell (approximately 3.85 micro N) was the same in both vessel types, even though on average (P = 0.10) the SHR cells had a 21% greater cross-sectional area. The results support the Folkow hypothesis that in genetic hypertension the increased peripheral resistance is associated with structural changes in the resistance vessels.

Two electroneutral, Na+-driven HCO3- transporters, the Na+-driven Cl-/HCO3- exchanger and the electroneutral Na+/HCO3- cotransporter, have crucial roles in regulating intracellular pH in a variety of cells, including cardiac myocytes, vascular smooth-muscle, neurons and fibroblasts; however, it is difficult to distinguish their Cl- dependence in mammalian cells. Here we report the cloning of three variants of an electroneutral Na+/HCO3- cotransporter, NBCn1, from rat smooth muscle. They are 89-92% identical to a human skeletal muscle clone, 55-57% identical to the electrogenic NBCs and 33-43% identical to the anion exchangers. When expressed in Xenopus oocytes, NBCn1-B (which encodes 1,218 amino acids) is electroneutral, Na+-dependent and HCO3(-)-dependent, but not Cl(-)-dependent. Oocytes injected with low levels of NBCn1-B complementary RNA exhibit a Na+ conductance that 4,4-diisothiocyanatostilbene-2,2'-disulphonate stimulates slowly and irreversibly.

That smooth muscles dilate and contract rhythmically has been known for a long time and the phenomenon has been studied for nearly as long. However, the causes and effects of smooth muscle oscillation (termed vasomotion) are far from clear. It is thought that vasomotion aids the delivery of oxygen to tissues surrounding capillary beds. On the other hand, unregulated vasomotion might participate in the development and maintenance of pathophysiological states. Nilsson and Aalkjaer review what is known about vasomotion and its consequences.

Background-Disturbances in pH affect artery function, but the mechanistic background remains controversial. We investigated whether Na ϩ ,HCO 3 Ϫ cotransporter NBCn1, by regulating intracellular pH (pH i ), influences artery function and blood pressure regulation. Methods and Results-Knockout of NBCn1 in mice eliminated Na ϩ ,HCO 3 Ϫ cotransport and caused a lower steady-state pH i in mesenteric artery smooth muscle and endothelial cells in situ evaluated by fluorescence microscopy. Using myography, arteries from NBCn1 knockout mice showed reduced acetylcholine-induced NO-mediated relaxations and lower rho-kinase-dependent norepinephrine-stimulated smooth muscle Ca 2ϩ sensitivity. Acetylcholine-stimulated NO levels (electrode measurements) and N-nitro-L-arginine methyl ester-sensitive L-arginine conversion (radioisotope measurements) were reduced in arteries from NBCn1 knockout mice, whereas relaxation to NO-donor S-nitroso-Nacetylpenicillamine, acetylcholine-induced endothelial Ca 2ϩ responses (fluorescence microscopy), and total and Ser-1177 phosphorylated endothelial NO-synthase expression (Western blot analyses) were unaffected. Reduced NO-mediated relaxations in arteries from NBCn1 knockout mice were not rescued by superoxide scavenging. Phosphorylation of myosin phosphatase targeting subunit at Thr-850 was reduced in arteries from NBCn1 knockout mice. Evaluated by an in vitro assay, rho-kinase activity was reduced at low pH. Without CO 2 /HCO 3 Ϫ , no differences in pH i , contraction or relaxation were observed between arteries from NBCn1 knockout and wild-type mice. Based on radiotelemetry and tail-cuff measurements, NBCn1 knockout mice were mildly hypertensive at rest, displayed attenuated blood pressure responses to NO-synthase and rho-kinase inhibition and were resistant to developing hypertension during angiotensin-II infusion. Conclusions-Intracellular acidification of smooth muscle and endothelial cells after knockout of NBCn1 inhibits NO-mediated and rho-kinase-dependent signaling in isolated arteries and perturbs blood pressure regulation. (Circulation. 2011;124:1819-1829.)Key Words: pH Ⅲ hypertension Ⅲ blood pressure Ⅲ nitric oxide Ⅲ rho-kinase B lood pressure dysregulation is a major cause of human disease. Hypertension is a risk factor for development of coronary heart disease, stroke, and peripheral vascular disease 1-3 whereas hypotension is related to syncope and falls. 4,5 Both hyper-and hypotension increase overall mortality. 6 -8 Editorial see p 1806 Clinical Perspective on p 1829Arterial tone regulation is important for blood pressure control and is modulated by local and systemic factors. Sustained changes in intracellular pH (pH i ) of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) occur physiologically and pathologically, but have been difficult to investigate experimentally, and little is known about their vascular effects. 9 It has, however, been proposed that endothelial enzymes (eg, endothelial nitric oxide synthase [eNOS] 10 and endothelin converting...

This minireview discusses vasomotion, which is the oscillation in tone of blood vessels leading to flowmotion. We will briefly discuss the prevalence of vasomotion and its potential physiological and pathophysiological relevance. We will also discuss the models that have been suggested to explain how a coordinated oscillatory activity of the smooth muscle tone can occur and emphasize the role of the endothelium, the handling of intracellular Ca(2+) and the role of smooth muscle cell ion conductances. It is concluded that vasomotion is likely to enhance tissue dialysis, although this concept still requires more experimental verification, and that an understanding at the molecular level for the pathways leading to vasomotion is beginning to emerge.