Lymphatic contractile function: a comprehensive review of drug effects and potential clinical application

Abstract

The lymphatic system and the cardiovascular (CV) system work together to maintain body fluid homeostasis. Despite that, the lymphatic system has been relatively neglected as a potential drug target and a source of adverse effects from CV drugs. Like the heart, the lymphatic vessels undergo phasic contractions to promote lymph flow against a pressure gradient. Dysfunction or failure of the lymphatic pump results in fluid imbalance and tissue oedema. While this can be due to drug effects, it is also a feature of breast cancer-associated lymphoedema, chronic venous insufficiency, congestive heart failure, and acute systemic inflammation. There are currently no specific drug treatments for lymphatic pump dysfunction in clinical use despite the wealth of data from pre-clinical studies. The aim of this study was to identify (i) drugs with direct effects on lymphatic tonic and phasic contractions with potential for clinical application, and (ii) drugs in current clinical use that have a positive or negative side effect on lymphatic function. We comprehensively reviewed all studies that tested the direct effect of a drug on the contractile function of lymphatic vessels. Of the 208 drugs identified from 193 studies, about a quarter had only stimulatory effects on lymphatic tone, contraction frequency, and/or contraction amplitude. Of Food and Drug Administration-approved drugs, there were 14 that increased lymphatic phasic contractile function. The most frequently used class of drugs with inhibitory effects on lymphatic pump function were the calcium channels blockers. This review highlights the opportunity for specific drug treatments of lymphatic dysfunction in various disease states and for avoiding adverse drug effects on lymphatic contractile function.

Intestinal Lymphatic Dysfunction in Kidney Disease

“…A recent review of >200 drugs with potential lymphatic vessel effects found that the most frequently used drug with inhibitory effects on lymphatic pumping was the calcium channel blocker. 197 Notably, most of the identified drugs dampen lymphatic contractile functions. 197 These observations highlight the possibility that adverse consequences such as refractory edema with diuretic use may be linked to effects on lymphatics.…”

“…197 Notably, most of the identified drugs dampen lymphatic contractile functions. 197 These observations highlight the possibility that adverse consequences such as refractory edema with diuretic use may be linked to effects on lymphatics. We found that NKCC1 inhibition by the diuretic furosemide decreased both lymphatic vessel tone and contractility.…”

Lymphatic Collecting Vessel: New Perspectives on Mechanisms of Contractile Regulation and Potential Lymphatic Contractile Pathways to Target in Obesity and Metabolic Diseases

“…The mechanisms by which obesity may interact with the gene pathways critical to lymphangiogenesis and lymphatic endothelial maintenance have been recently described ( Norden and Kume, 2021 ; Ho and Srinivasan, 2020 ; Kataru et al, 2020 ). An examination of the effects of vasoactive molecules on lymphatic function and their respective pharmacological implications has also been recently discussed in the exhaustive review ( Russell et al, 2021 ). In this article, we will review: 1) an introduction describing the links between obesity and metabolic syndrome with lymphatic dysfunction and lymphedema 2) a brief synopsis of the lymphatic vasculature to introduce the lymphatic collecting vessels; 3) our understanding of the necessity of the lymphatic pump in physiology; 4) ionic and molecular mechanisms underlying lymphatic contractions; 5) the role of eNOS in lymphatic collecting vessel function and dysfunction; 6) contractile dysfunction in metabolic disease; 7) potential pharmacological targets.…”

“…Lymphatic collecting vessels exhibit rhythmic, fast phasic contractions that drive lymph flow largely as a consequence of generating the pressure stimuli necessary to open the downstream valve and expel the lymph into the next lymphangion. Additionally, lymphatic collecting vessels display lymphatic tonic contraction, and in some cases myogenic constriction ( Zawieja et al, 2018 ), which can also be modulated by lymph flow associated with local, neural, and humoral factors, including α-adrenergic agonist, prostaglandins, bradykinin, substance p ( Bridenbaugh et al, 2003 ; von der Weid and Zawieja, 2004 ; Muthuchamy and Zawieja, 2008 ; Russell et al, 2021 ). These factors modulate lymphatic collecting vessel tone and thus alter resistance to lymph flow to promote or impede lymph flow from the upstream lymphatic bed ( Davis et al, 2008 ; Dougherty et al, 2008 ; Muthuchamy and Zawieja, 2008 ; von der Weid and Muthuchamy, 2010 ; Davis et al, 2012 ).…”

“…In this role, potassium channels regulate activation of voltage gated calcium channels and arterial contraction ( Tykocki et al, 2017 ). Five major classes of potassium channels have been identified in vascular muscle cells and there is evidence that at least four of these classes represented in LMCs across multiple species ( Telinius et al, 2014a ; Russell et al, 2021 ). These include calcium-activated potassium channels (BK Ca , Ik Ca , Sk Ca ), inward rectifiers (K ir and K ATP ), and voltage gated potassium channels (K V ).…”