Abstract
Transient receptor potential (TRP) C1 and C3 (TRPC1 and TRPC3) are expressed in vascular smooth muscle cells and are thought to be involved in vascular contractility. In the present study, we determined the effect of systemic hypertension on TRPC1/TRPC3 channel expression and vascular contractility in rat carotid artery (CA). CA were studied from male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY), and Long Evans (LE) rats. TRPC1/3 expression was determined by RT-PCR and Western blot. TRP channel function was evaluated by whole-cell patch clamp, using UTP (60 μM) to stimulate TRPC1/3 channels. Contractions of endothelium-denuded CA segments to UTP (1–300 μM) and phenylephrine (Phe; 0.1 nM–10 μM) were measured in an isometric tension bath. TRPC1 and TRPC3 mRNA was present in CA of both WKY and SHR. Western blot demonstrated 3.1 ± 1.2 times greater TRPC3 expression and 0.5 ± 0.2 times TRPC1 in SHR versus WKY CA. Isolated CA showed potentiated contraction to UTP in the SHR versus WKY. Activation of voltage-dependent Ca2+ channels (VDCC) in UTP-mediated constriction only occurred in SHR CA. Contraction to Phe was unaltered between WKY and SHR CA and involved equal significant VDCC activation in both groups. Patch clamp demonstrated that the UTP-stimulated current (Iutp) was greater in SHR compared to the normotensive WKY and LE rats with peak Iutp (at −110 mV) of −63 ± 24 pA compared to −25 ± 4 pA, respectively. We demonstrate that UTP-mediated but not Phe-mediated constrictions are potentiated in the CA during hypertension. Expression of TRPC1 is decreased whereas TRPC3 is increased in SHR CA. Interestingly, VDCC activation only contributes to UTP-mediated contraction of SHR CAs whereas it contributes substantially and equally in Phe-mediated contraction. We speculate that the alteration of TRPC channel expression in hypertension leads to greater smooth muscle depolarization, VDCC activation, and vascular contractility in the UTP (but not Phe) signaling pathway.
Highlights
Hypertension is associated with profound alteration in smooth muscle cell calcium homeostasis and proliferation (Sugiyama et al, 1990; Bendhack et al, 1992; Touyz and Schiffrin, 1997)
Protein expression for TRPC1 and TRPC3 was detected by Western blot in spontaneously hypertensive rats (SHR) and WKY carotid artery (CA) (Figure 1B)
Densitometric analysis of the blots (Figure 1C) revealed that TRPC3 was increased by 3.1 ± 1.2 times (P = 0.002; n = 6 each) in SHR compared to WKY, whereas TRPC1 expression was slightly decreased to 0.5 ± 0.2 times WKY expression (P = 0.014; n = 7 each)
Summary
Hypertension is associated with profound alteration in smooth muscle cell calcium homeostasis and proliferation (Sugiyama et al, 1990; Bendhack et al, 1992; Touyz and Schiffrin, 1997). The TRPC channels comprise a seven member family (TRPC1–7) of nonselective cation channels with varying Na+ and Ca2+ permeability (Clapham et al, 2005; Ramsey et al, 2006). They are activated by a variety of vasoconstrictors such as ATP, UTP, endothelin, and Angiotensin II (Hurst et al, 1998; Reading et al, 2005; Peppiatt-Wildman et al, 2007; Alvarez et al, 2008; Abramowitz and Birnbaumer, 2009). In addition to a potential direct contribution to calcium influx, the TRPC channels are thought to promote calcium entry by providing the depolarizing stimulus (Na+ and Ca2+ current) for VDCC activation and subsequent smooth muscle contraction (Welsh et al, 2002; Gudermann et al, 2004)
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