GsMTx-4 normalizes the exercise pressor reflex evoked by intermittent muscle contraction in early stage type 1 diabetic rats

Abstract

Emerging evidence suggests the exercise pressor reflex is exaggerated in early-stage type 1 diabetes mellitus (T1DM). Piezo channels may play a role in this exaggeration since blocking these channels attenuates the exaggerated pressor response to tendon stretch in T1DM rats. However, tendon stretch constitutes a different mechanical and physiological stimuli than that occurring during muscle contraction. Therefore, the purpose of this study was to determine the contribution of Piezo channels in evoking the pressor reflex during an intermittent muscle contraction in T1DM. In unanaesthetized, decerebrate rats we compared the pressor and cardioaccelerator responses to intermittent muscle contraction before and after locally injecting GsMTx-4 (0.25 µM) into the hindlimb vasculature. Although GsMTx-4 has a high potency for Piezo channels, it has also been suggested to block TRPC channels. We, therefore, performed additional experiments to control for this possibility by also injecting SKF 96365 (10 µM), a TRPC channel blocker. We found that local injection of GsMTx-4, but not SKF 96365, attenuated the exaggerated peak pressor (ΔMAP before: 33±3 mmHg, after: 22±3 mmHg, p=0.007) and pressor index (ΔBPi before: 668±91 mmHg·s, after: 418±81 mmHg·s, p=0.021) response in STZ rats (n=8). GsMTx-4 attenuated the exaggerated early-onset pressor as well as the pressor response over time, which eliminated peak differences as well as those over time between T1DM and healthy controls. These data suggest that Piezo channels are an effective target to normalize the exercise pressor reflex in T1DM.

Altered Cardiovascular Responses to Exercise in Type 1 Diabetes

“…(2) found that T1D patients achieved a higher maximal exercise BP with a similar workload in a cycle ergometer test when compared with control subjects. Previous studies also demonstrated that untreated T1D rats have an exaggerated BP and cardioaccelerator response to static (24) and intermittent (10,11) hindlimb contractions. Determining the underlying mechanisms for an augmented BP response to exercise in T1D is an intriguing area of research, and alterations in the neural control of the cardiovascular system during exercise have been largely implicated.…”

“…The precise mechanism mediating the exaggerated pressor reflex in T1D is not fully understood; however, Piezo channels likely play an important role (9). Of notable interest, studies have shown that GsMTx-4 is able to attenuate the mechanoreflex in rats who are healthy (52), have peripheral artery disease (simulated) (53), or have T1D (9,11). From a translational perspective, however, future research is required to determine the potential role of Piezo channels as a therapeutic target to ameliorate the exaggerated cardiovascular response to muscle contraction in diabetes.…”

“…Overall cardiometabolic benefits of exercise make it a highly recommended treatment strategy in the clinical management of T1D (8). However, previous studies in animals (9)(10)(11)(12) and one study in T1D patients (2) indicate that diabetics may be at a heightened risk of experiencing exaggerated cardiovascular responses to exercise, which in turn, increases the risk of acute cardiovascular events. For example, a population-based followup study suggested that a systolic blood pressure (BP) exceeding 230 mm Hg during exercise is associated with a 2.47-fold greater risk of acute myocardial infarction (13), and an increase of greater than 19.7 mm Hg•min −1 of exercise has a 2.3-fold increased risk of stroke (14).…”

Piezo1 in vascular remodeling of atherosclerosis and pulmonary arterial hypertension: A potential therapeutic target

“…Only a few drugs have been used in pharmacological studies of Piezo1 channel Non-specific inhibitors, broadly classified as Gd3 + , Dooku1, and La3 + in the lanthanide family, gentamicin and streptomycin in the aminoglycoside group, ruthenium red (RR) and the spider venom peptide GsMTx-4 isolated from tarantula toxin (16, 32, 56-60). GsMTx-4 is a cation channelspecific blocker that not only blocks Piezo1 ion channels but also has the effect of inhibiting Piezo1-induced mechanically activated (MA) current generation (61)(62)(63)(64). Mechanistically, GsMTx4 binds to the cell membrane and, by inserting its hydrophobic domain into the lipid bilayer, acts directly on the backbone proteins of the membrane, blocking mechanical force transmission by altering the tension in the membrane and thus achieving a blockade of the Piezo1 ion channel (62,65,66).…”

Sensory neuron inositol 1,4,5-trisphosphate receptors contribute to chronic mechanoreflex sensitization in rats with simulated peripheral artery disease

“…Using this model, we found that the pressor and renal sympathetic nerve activity (RSNA) response to 30 seconds of dynamic muscle stretch was larger when evoked from hindlimb muscles associated with a chronically ligated femoral artery compared to responses evoked from the contralateral hindlimb muscles which were freely perfused (31). Moreover, rat femoral artery ligation was found recently to have no effect on L 4 and L 5 dorsal root ganglia (DRG) protein expression of piezo channels (11), a novel class of MA channel that has been suggested to underlie mechanoreflex activation (10,11,21,22,56). Together, these findings suggest that the exaggerated mechanoreflex in rats with a ligated femoral artery is due, at least in part, to a chronic or persistent sensitization of MA channels located on the sensory endings of thin fiber muscle afferents.…”