Functional Alterations in the Aorta of the Spontaneously Hypertensive Rat: Pharmacological Assessment with Cyclopiazonic Acid

One of the changes in vascular smooth muscle membranes associated with hypertension is an alteration in Ca2+ handling. It has been unclear as to whether changes occurred at the plasma membrane or at the endoplasmic reticulum (ER) or both. Recently, cyclopiazonic acid (CPA) has been reported to inhibit selectively the ER Ca2+ pump. We aimed at determining the effect of ER Ca2+ pump inhibition by CPA on the contractility of aortic smooth muscle from 4- to 5-month-old SHR and age- and weight-matched WKY control rats. The responsiveness of the SHR tissues to phenylephrine or K+ was significantly reduced as compared with controls, although the sensitivity was not altered. Stimulation with phenylephrine (10 mumol/l) in Ca2(2+)-free medium caused a significantly reduced transient contraction in SHR as compared with control tissues. After pretreatment with CPA (30 mumol/l), this contraction was suppressed in SHR and WKY tissues. On the restoration of Ca2+, CPA induced a nifedipine (5 mumol/l) sensitive contraction, significantly larger in SHR than in WKY tissues. The relaxation rate to nifedipine of K(+)-induced contraction in CPA-treated SHR tissue was also reduced. We conclude that the ER Ca2+ pump in SHR aorta is less effective as compared with WKY tissue. The significantly greater CPA-induced contraction together with the reduced relaxation rate in the presence of CPA in SHR tissues as compared with controls suggests that Ca2+ handling was also altered at the plasma membrane.