The vasa vasorum and the paradox of beta-blocker therapy

The balance between the pro-inflammatory effect of plasma noradrenaline and the anti-inflammatory effect of neuronal noradrenaline determines the peripheral effects of noradrenaline

“…Another cannulation experiment that again confirmed the dilator potency of microcirculatory PNA involved eliminating the presence of tonically released NA in the microcirculation of a CLSV segment by stimulating the segment with reserpine or guanethidine until it ceased to respond to electrical stimulation and then finding that the SO stimulation increased significantly, on one occasion by 91%, from an initial 46 to a subsequent 86 mmHg rise in perfusion pressure [20].…”

“…ISO into a valve sinus on three occasions and finding it caused a 174 mmHg rise in the overall perfusion pressure of the segment on each occasion [20], compared to the 130 mm Hg rise 6.0 µM intraluminal NA would be expected-by extrapolation from a dose response curve [14] -to cause. Given that aggers block ~ 93% of any drug injected into a valve sinus from perfusing its associated microcirculatory module, the difference in sensitivity to NA stimulating a blood vessel through its lumen and through its microcirculation is, in fact, much greater than the figures quoted indicate.…”

“…Normally that level is ~10 ng/min, but in dilator failure it can go as high as 131 ng [89]. That increased efferent activity, in turn, is believed to be evoked by the effect of the increased afferent activity associated with heart 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 pharmacologically, but not physiologically [20], is paradoxically responsive to 1 agonist effect of beta blockers. This constrictor effect is readily duplicated experimentally, using ACh and serotonin [92] [93] instead of NA.…”

“…The effectiveness of the agger in doing that was demonstrated by an experiment where Methylene Blue was injected into the sinuses of cardinal valves at pressures peaking around 200 mmHg and a minimum 92.56 (±3.16) % of the dye was later recovered from the run off of the perfusate within 10 seconds of the injection having been completed[20].…”

Imbalances in the neurotrophic effects of noradrenaline, favouring the positive in the child and the negative in the mother, are the cause of preeclampsia

“…Moreover, unlike its intralumenal dilator effect, which involved the entire length of a constricted segment, the constrictor effect of ISO was stenotic and localised to a short section of the segment upstream of the junction of the injected tributary ( Fig. 1) and upstream, also, of a competent ostial valve in the lumen of the perfused segment [11,18], two facts that ruled out the possibility ISO had acted intralumenally. And because the segment was doubly cannulated that ruled out the possibility ISO had acted through the adventitial surface.…”