A study of the calcium regulatory mechanisms involved in maintained agonist-induced vascular smooth muscle tone

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)



First Committee Member

Cornelis van Breemen - Committee Chair


Isometric tension was measured in parallel with $\sp{45}$Ca influx in rabbit aorta or simultaneously with (Ca$\sp{2+}$) $\sb{\rm i}$ in rabbit inferior vena cava loaded with fura-2. In the presence of external Ca$\sp{2+}$, phenylephrine, norepinephrine and high K$\sp+$ caused a maintained increase in tension, $\sp{45}$Ca influx and (Ca$\sp{2+}$) $\sb{\rm i}$ which were markedly inhibited in the absence of extracellular Ca$\sp{2+}$. In (Ca$\sp{2+}$) $\sb{\rm i}$ vs force curves, the norepinephrine curve was shifted to the left of that of high K$\sp+$. The protein kinase C activator TPA induced a slow increase in tension and shifted the (K$\sp+$) $\sb{\rm e}$-force relationship to the left without any change in (Ca$\sp{2+}$) $\sb{\rm i}$. TPA alone did not maintain the contraction initiated by high K$\sp+$. The protein kinase C inhibitor H-7 completely inhibited the contraction induced by TPA but only partially inhibited the phenylephrine-, norepinephrine- and high K$\sp+$-induced contraction without changing $\sp{45}$Ca influx or (Ca$\sp{2+}$) $\sb{\rm i}$. In the presence of external Ca$\sp{2+}$, ryanodine caused a maintained increase in (Ca$\sp{2+}$) $\sb{\rm i}$ which was not inhibited by diltiazem, but completely abolished by La$\sp{3+}$ or in Ca$\sp{2+}$-free solution. Ryanodine caused a small increase in tension and transient decrease in the caffeine-releasable Ca$\sp{2+}$. Ryanodine did not enhance the high K$\sp+$-induced force, $\sp{45}$Ca influx and (Ca$\sp{2+}$) $\sb{\rm i}$. It is concluded that the maintained agonist-induced vascular tone is due to (1) Ca$\sp{2+}$ influx from the extracellular space, (2) increased myofilament force sensitivity probably due to activation of protein kinase C, and (3) inhibition of Ca$\sp{2+}$ buffering by the sarcoplasmic reticulum.


Health Sciences, Pharmacology

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