Pharmacological characterisation of calcium channels in vascular smooth muscle from hypertensive and normotensive animals

Patel, Ashwinkumar (1986) Pharmacological characterisation of calcium channels in vascular smooth muscle from hypertensive and normotensive animals. Masters thesis, Memorial University of Newfoundland.

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Abstract

A consistent feature of hypertension is an increase in peripheral vascular tone which is ultimately controlled by intracellular calcium levels. Over the past decade, evidence has emerged indicating an abnormality in ion handling by vascular smooth muscle as a possible cause of the elevated vascular tone. Various lines of evidence have led to the suggestion that there is an increased calcium influx in hypertension. The present work attempted to characterise calcium influx through receptor operated (ROC) and potential operated channels (POC) in tail artery from SHR and WKY rats, using nifedipine, a calcium antagonist, as a probe. -- Potassium induced responses, were significantly more sensitive to nifedipine than norepinephrine responses in both SHR and WKY. However there was no difference in sensitivity to nifedipine, of either potassium or norepinephrine responses, between SHR and WKY at both ED₁₀₀ or ED₅₀ levels of stimulation. These results suggest a normal role for POC and ROC function in SHR animals. -- The calcium sensitivity of the vessels was higher in SH rats when activated by ED₅₀ levels of norepinephrine but not potassium, suggesting ROC alteration. The study also suggest that submaximal (ED₅₀) levels of agonists should be used, in addition to ED₁₀₀ doses of agonists. Low concentrations of nifedipine (0.05nM) significantly reduced calcium sensitivity in potassium (ED₁₀₀) activated arteries from SH, but not WKY rats. Higher concentrations of nifedipine were required to significantly reduce calcium sensitivity in norepinephrine activated vessels from both SHR and WKY. Maximal calcium responses in norepinephrine (ED₁₀₀) activated SHR vessels were more resistant to nifedipine than WKY vessels. These results suggest alterations in POCs and ROCs. -- No differential sensitivity to nifedipine was found in young 'prehypertensive' (5 week old) animals. At the 10-12 week age group, SH rats were more sensitive, compared to WKY, at high doses of nifedipine. Wistar normotensive rats were more insensitive to nifedipine than WKY rats. Surprisingly the differential sensitivity, to nifedipine, between SHR and WKY was reduced at the 20 week age group. These results suggest that enhanced calcium influx may not precede development of high blood pressure. As blood pressure increases calcium influx may sustain the high vascular tone, although direct evidence is still lacking. -- Collectively the results presented provide further indirect, evidence for altered calcium channel function in hypertension.

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