The peripheral circulation

The ratio \(Ca^{2+}\text{-Calmodulin-MLCK} : \text{MLCP}\) determines force of contraction

Smooth muscle lacks troponin.

Instead, contraction is initiated when the light chain of myosin is phosphorylated.

Intracellular calcium binds with calmodulin and then to myosin light chain kinase. This \(Ca^{2+}\text{-Calmodulin-MLCK}\) complex phosphorylates myosin light chain.

Myosin light chain phosophotase dephosphorylates myosin light chain.

Because both enzymes are acting, the total force of contraction is determined by the ratio of their activities.

\(\alpha_1\): IP3 (from phospholipase C, e.g. from alpha-1 receptors) liberates intracellular calcium from the sarcoplasmic reticulum, which increases \(Ca^{2+}\text{-Calmodulin-MLCK}\) \(\to\) constriction.

\(\beta_2\) or prostatcyclin receptor: cAMP, via PKA, increases MLCP \(\to\) relaxation.

NO: cGMP, via PKG, increases MLCP \(\to\) relaxation.

More positive membrane voltage increases calcium influx and decreases calcium efflux by modulating L-type Ca channels and Na/Ca exchanger. Membrane voltage is controlled by \(K^+\) channels which, when open, hyperpolarize the cell.

Increased shear stress is translated to the glycocalyx, and from there to the endothelium, which release prostatcyclin and NO.

Diffusion is, as always, governed by Fick's law:

$$D \propto \frac{\text{SA}\cdot \text{Solubility} \cdot \Delta C}{\text{Thickness}\cdot\sqrt{\text{Molar mass}}}$$

But lipid-insoluble molecules have to diffuse through endothelial pores. Molecules >60kD simply can't fit.

The rate of delivery of highly permiable substances (H2O, urea, glucose) is delivery: they are flow limited. The rate of diffusion of larger stuff is diffusion limited. Diffusion limitation can occur in oedema when the capillary-cell distance is embiggened by fluid.

Large molecules have to use pinocytosis to get across the endothelium.

Flux of fluid through the capillary membrane is proportional to the pressure difference over the membrane, and also to other things:

$$Q_fluid \propto K_t \Delta P$$

where \(\K_t\) is the filtration constant for a given tissue.

$$\Delta P = [(P_{Hc} - P_{Hi}) - \sigma (P_{\pi c} - P_{\pi i})]$$

$$P_H = \begin{cases} 32 \text{ arterial systemic capillary} \\ 15 \text{ venous systemic capillary} \\ 10 \text{ pulmonary capillary} 0 \text{ interstitium} \end{cases}$$

$$P_{\pi} = iCRT \approx 25\text{mmHg}$$

Note that the oncotic pressure of albumin is augmented by the Gibbs-Donnan effect (chloride is pulled into the capillary by a concentration difference, and then sodium by the negative charge on both albumin and chloride).

Effect of a fall in cardiac output

The arterial blood pressure falls. Through myogenic and adrenergic mechanisms, precapillary arterioles constrict. The CVP falls because the MSFP falls. All of this drops the \(P_{Hc}\), causing absorbtion to dominate filtration. This causes fluid to shift from the interstitium to the vascular space, expanding plasma volume and increasing preload, restoring cardiac output. As a consequence, the haemoglobin concentration is diluted.

Effect of dehydration

The plasma proteins get concerntrated. \(P_{\pi c}\) rises. Fluid moves from interstitium to vascular space, restoring normal osmolality.

These are thin-walled, blind-ended vessels that resemble veins histologically. They allow diffusion of interstitial fluid and - importantly - protein. They are the only way albumin can get back into the vascular space (it can't move up its concentration gradient).

One whole circulating volume, and half of circulating protein, is returned as lymph every 24 hours.

Flow is maintained at a constant level over a wide range of blood pressures, because increases in driving pressure cause arteriolar vasospasm, and falls in driving pressure cause arteriolar vasodilation, by four mechanisms.

Myogenic mechanism

Increased intraluminal pressure causes increased depolarization and intracellular calcium flux in vascular smooth muscle (independant of endothelium). $$\uparrow Ca^{2+}-\text{-Calmodulin-MLCK activity} \to \text{dilation} \to \text{normalization of flow}$$

Flow-mediated endothelial response

Higher shear stress from higher flow rates is tranduced by glycocalyx to endothelium, which releases NO and prostacyclin. $$NO \to cGMP \to PKG \to \uparrow MLCP$$ $$\text{Prostacyclin receptor} \to cAMP \to PKA \to \uparrow MLCP$$

It also causes upstream vasodilation in response to arteriolar vasodilation (because distal resistance falls and flow increases).

Metabolic control

$$\downarrow DO_2:VO_2 \to \uparrow \uparrow P_aCO_2 / [K^+] / [\text{Lactate}^-] /\text{Adenosine}$$

Unclear which of these substances produces vasodilation, or how.

Conducted responses

Vascular smooth muscles have gap junctions. Intracellular calcium (and therefore vasodilation / constriction) propagates along vessels.

Only a small part of the vascular tree (mostly splanchnic vessels) are innervated by parasympathetic nerves. The sympathetic nervous system is doing all the heavy lifting.

Sensors

Baroreceptors: Carotid sinus (more sensitive) and aortic arch (less sensitive)

Controller

Pressor region (dorsal-lateral medulla)

Depressor region (dorsal-medial medulla)

Effectors

Descending fibres \(\to\) T1-L2 lateral horns \(\to\) sympathetic chain \(to\) resistance vessels \(\to\) noradrenaline release.

This causes \(\alpha_1 \text{ agonism} \to IP_3 + DAG \to \ \uparrow [Ca^{2+}]_{\text{intracellular}} \to \text{constriction}\)