Affiliation:
1. From the Department of Physiology, University of Tennessee Health Science Center, Memphis.
Abstract
Vasoconstrictors that bind to phospholipase C–coupled receptors elevate inositol-1,4,5-trisphosphate (IP
3
). IP
3
is generally considered to elevate intracellular Ca
2+
concentration ([Ca
2+
]
i
) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP
3
receptors, leading to intracellular Ca
2+
release. We show that IP
3
also stimulates vasoconstriction via a SR Ca
2+
release–independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca
2+
was depleted to abolish Ca
2+
release (measured using D1ER, a fluorescence resonance energy transfer–based SR Ca
2+
indicator), IP
3
activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (
I
Cat
) caused by Na
+
influx, induced membrane depolarization, elevated [Ca
2+
]
i
, and stimulated vasoconstriction. The IP
3
-induced
I
Cat
and [Ca
2+
]
i
elevation were attenuated by cation channel (Gd
3+
, 2-APB) and IP
3
receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca
2+
channel blockers, reduced the SR Ca
2+
release–independent, IP
3
-induced [Ca
2+
]
i
elevation and vasoconstriction. In pressurized arteries, SR Ca
2+
depletion did not alter IP
3
-induced constriction at 20 mm Hg but reduced IP
3
-induced constriction by ≈39% at 60 mm Hg. [Ca
2+
]
i
elevations and constrictions induced by endothelin-1, a phospholipase C–coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca
2+
-depleted arteries. In summary, we describe a novel mechanism of IP
3
-induced vasoconstriction that does not occur as a result of SR Ca
2+
release but because of IP
3
receptor–dependent
I
Cat
activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca
2+
channels, leading to a myocyte [Ca
2+
]
i
elevation, and vasoconstriction.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
103 articles.
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