The Same but Different

Individual segments along the cerebrovascular tree serve unique functions in the overall coordination of cerebral blood flow. Consequently, after pathologic conditions, we must understand how each segment of the cerebrovascular tree is affected in order to fully comprehend the net effect on cerebral blood flow. In this issue, Cipolla et al. ¹ studied parenchymal arterioles (PAs), a final control point before capillaries in the cerebral cortex, early into the reperfusion phase after an ischemic event. Reperfusion is the beginning of a pathologic cascade that amplifies tissue damage. The PAs, which penetrated into the cortex from a branch of the middle cerebral artery, were isolated and pressurized to study the development of spontaneous tone, an intrinsic property of arteries and arterioles where the vessels constrict to pressures across the vessel wall. ² PAs that were isolated 30 minutes into reperfusion developed the same amount of tone as PAs from naive rats over intraluminal pressures ranging from 40 to 80 mm Hg. Thus, without further investigations, PAs after ischemia/reperfusion (I/R) might be considered ‘the same’ as those without insult. However, after further probing, the investigator discovered that after I/R, PAs maintained ‘the same’ tone as naive PAs but did so using ‘different’ mechanisms for achieving this tone.

First, there was an enhanced dilator response through enhanced endothelial-dependent hyperpolarization (EDH), a process where hyperpolarizations of the endothelium by small and intermediate conductance calcium-activated potassium channels are passed to the vascular smooth muscle (VSM) through gap junctions. ³ Hyperpolarizations of the VSM, in turn, close voltage-operated calcium channels to dilate the arteriole. With this enhanced dilator process, another mechanism(s) must be present to constrict PAs in an equal and opposite manner to EDH. Although the authors cannot definitively state what underlies this constrictors process, they did show constrictor responses with activation of the endothelin receptor type B (ET_BR) only after I/R. As message for ET_BR was not found in VSM of the PAs, the ET_BR-related constriction must have involved the endothelium. ET_BR on endothelium are known to activate endothelial nitric oxide (NO) synthase.^4–6 The investigators speculated that reactive oxygen species associated with I/R reacted with newly synthesized NO after ET_BR stimulation to produce peroxynitrite. Peroxynitrite was demonstrated in this study to constrict PAs through an unknown mechanism. Although the investigators provided interesting and provocative circumstantial evidence for an ET_BR constrictor response to offset the EDH dilatory effect, more studies will be required for a definitive conclusion. While, there are many questions remaining as to what is controlling the tone of PAs after I/R, the fact remains that the tone is the ‘same’ as naive PAs but the mechanisms regulating this tone are ‘different’.