Altered phospholipase activities related to alpha 1-adrenergic receptor supersensitivity of aortas from aldosterone-salt hypertensive rats.
Many of the concepts presented in this paper are summarized in Fig. 7. Some aspects are well supported while others are speculative. The operation of PLC in VSM is well established, and in some hypertensive models (AHR, SHRSP) PLC assays exhibited altered activation. Currently this pathway leading to the production of IP3 and DAG is considered to be the major regulator of Ca release from sarcoplasmic reticulum (SR) and Ca entry by channels (CaC). Regulation of PKC by [Ca]i and DAG is thought to play a major role in controlling Ca entry. PKC has also been proposed to regulate PLA2 as well as PLD in conjunction with elevated [Ca]i. An important issue to be resolved is whether receptor regulation of other lipases occurs independently of the PLC-[Ca]i-PKC axis. Currently information supporting receptor regulation is lacking for VSM, but few studies have been conducted. Our observation that NE stimulation of PLD activity occurs in VSM indicates that the control of VSM by biochemical messengers is much more complicated than previously proposed. This seemingly redundant pathway may allow VSM to use alternate substrates for producing PA and DAG than are readily available to PLC. It also allows PA to be produced directly without phosphorylation of DAG. Although the role of PA in the regulation of Ca entry was proposed earlier, definitive studies establishing this linkage are still required. Any PLD activity on PIP2 would produce biochemical messengers (PA, DAG) which could stimulate Ca entry without producing the messenger, IP3, associated with Ca release (inactive IP2 would be produced). If PLC and PLD were independently regulated by receptor-guanine nucleotide-regulatory protein (G-protein) complexes, this would offer the potential for some agonists to excite VSM by Ca release and Ca entry mechanisms while others may excite by Ca entry alone. This system would also circumvent the problem of limited substrate for cellular regulation of [Ca]i if PIP2 were the primary substrate. This limitation does not exist with other phospholipids such as phosphatidylcholine which is a preferred substrate for PLD. The presence of multiple phospholipases under separate receptor regulation allows for a wider range of tissue responses to various agonists, than a system which is linked only through the PLC-[Ca]i-PKC axis. The presence of a PLD pathway also reopens the interpretation of previous studies which demonstrated a resetting between receptor occupancy and production of second messengers by PLC.(ABSTRACT TRUNCATED AT 400 WORDS)
Jones
A W
AW
Department of Physiology, University of Missouri, Columbia 65212.
Shukla
S D
SD
Geisbuhler
B B
BB
Jones
S B
SB
Smith
J M
JM
D000450:Aldosterone; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010740:Phospholipases / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D012965:Sodium Chloride
D011942:Receptors, Adrenergic, alpha; D012965:Sodium Chloride; D000450:Aldosterone; D010740:Phospholipases; D011188:Potassium; D009638:Norepinephrine