With thanks to ace Tweep @tony_breu, this is an important topic to be considered in the light of steady-state Starling physiology. Indeed I am not aware of any up-to-date review in the literature, so if one or two of you want to use this as a basis for such a review and get it peer-reviewed, I’d be happy to help.
Let’s visit the topic in the way Tony develops his tweetorial thread.
By decreasing intracellular [Ca], calcium channel blockers (CCBs) lead to arterial vasodilation.
CCBs don’t increase plasma volume. If anything, they cause natriuresis.
As arterioles dilate, mean capillary hydrostatic pressure (Pc) increases.
As arterioles constrict, Pc decreases.
At this point I must say that we could KNOW this is true rather than rely on a theoretical treatment from 1948 if we pressed industry to deliver us the technology of co-extensive bioimpedance plethysmography which so far they have resolutely denied us. Then we could KNOW arteriolar pressure – volume characteristics and KNOW the mean capillary pressure and appreciate that even more relevant to this matter is the venular filling pressure. But I am whistling in the wind on that one…
Tony says “CCBs dilate precapillary arterioles (i.e., they decrease arteriolar resistance a lot) and may not dilate postcapillary venules (i.e., they don’t change Rv).” Now while I understand the concept of resistance affecting pressure on the arterial side, I find it harder to conceptualise venous-side resistance. Venoconstriction predominantly causes volume change rather than pressure change. But that doesn’t matter, because we are agreed that arteriolar smooth muscle relaxation increases capillary pressure. Tony leaps to the conclusion that oedema results, but there are other factors that have to come into play if oedema is to manifest, as we shall explore.
“Another mechanism of CCB mediated edema is the loss of reflex vasoconstriction that occurs with standing. In particular, CCBs may block the myogenic response (i.e., arteriolar vasoconstriction in response to increased transmural pressure).vasoconstriction that occurs with standing. In particular, CCBs may block the myogenic response (i.e., arteriolar vasoconstriction in response to increased transmural pressure). https://www.ncbi.nlm.nih.gov/pubmed/11464254 “
“Because CCBs preferentially dilate precapillary arterioles, they should increase GFR. There is evidence suggesting exactly this. This study found more afferent than efferent dilation with L-type CCBs. Result: ↑renal plasma flow and ↑GFR. https://www.ncbi.nlm.nih.gov/pubmed/12840599 “
I am less convinced than Tony that change in efferent vessel diameter reflects myogenic constriction rather than the reduced flow we expect there after glomerular filtration, but hey I’m not the Nephrologist. Even so, I agree that afferent arteriolar dilation increases blood flow and glomerular filtration rate.
“… warm temperatures lead to arteriolar vasodilation. And, as noted above, arteriolar vasodilation leads to edema.” I’m so delighted to see my friends Rodney Levick and Charles Michel cited here, and hope their later work developing the steady-state Starling principle and the Michel-Weinbaum model (as named by Levick) is also familiar to today’s physicians.
“Because the edema of CCBs is not mediated by sodium retention (see tweet 4), pre-treatment with diuretics may not mitigate this side effect. At least one study supports this. https://www.ncbi.nlm.nih.gov/pubmed/15076203 “
“ACE inhibitors, on the other hand, produce vasodilation in the pre AND post-capillary vessels. As a result, they are able to mitigate the increase in Pc seen with CCBs. Result: edema is less common when ACE inhibitors are given alongside CCBs. https://www.ncbi.nlm.nih.gov/pubmed/11090788 “
@sripalbangalore contributed “ACEi or ARBs reduce incidence of CCB induced pedal edema by ~50%. https://www.amjmed.com/article/S0002-9343(10)00745-X/pdf …“
At which point Lars @LMSaxhaug pointed out that the lymphatic regulation of interstitial fluid volume has also to fail if oedema is to occur: “My first thought was that reduction in lymphatic contractility could play an important role. This study shows CCB certainly decreases it in vitro, but that it’s probably counterbalanced by increased lymphatic preload from increased filtration in vivo https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2014.276683 …
Well done, Lars. In my next blog I’ll explore the lymphatic side of drug-associated oedema further.