Reduction of norepinephrine-induced tonic contraction and phosphoinositide turnover in arteries of spontaneously hypertensive rats. A possible role for protein kinase C.
Experiments were conducted to determine whether a difference in receptor-induced phosphatidylinositol hydrolysis occurred in aorta from spontaneously hypertensive rats (SHR) v Wistar-Kyoto (WKY) rats, and whether such a difference was correlated with contractile response. Basal incorporation of 32P into phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol diphosphate (PIP2) and phosphatidic-acid (PA) was not different between SHR and WKY groups. However, after five minutes of norepinephrine (NE; 10 mumol) exposure, increases in 32P labeling were markedly lower in SHR arteries. The percentage decrease amounted to 45% for PI, 68% for PIP, 100% for PIP2 and 58% for PA. Basal incorporation of 3H-myo-inositol into inositol monophosphate (IP) was similar for SHR and WKY groups. However, after 30 minutes of NE (10 mumol), SHR arteries failed to show an increase in 3H-IP levels, whereas labeling was increased 219% in WKY arteries. The contractile response of SHR arteries to 10 mumol NE showed a marked reduction in the rate of development of the tonic phase that has previously been shown to be supported by activity of protein kinase C. Higher Ca2+ levels failed to augment the SHR response, whereas WKY responses were significantly increased. Contractions in the presence of the phorbol ester tetradecanoylphorbolacetate exhibited a similar reduction in NE-induced tonic phase tension. These results indicate an impairment in SHR arteries at the level of receptor-induced formation of inositol cycle second messengers, possibly due to elevated basal levels of protein kinase C. These differences may be important in explaining altered vascular responses in primary hypertension.
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Section of Pharmacology, Northeastern University, Boston, Massachusetts.
Campbell
M D
MD
Deth
R C
RC
Gowraganahalli
J
J
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D010716:Phosphatidylinositols; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine