ABNORMALITY OF THE ATP-SENSITIVE POTASSIUM CHANNEL IN HYPERTENSION

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Evidence that the ATP-sensitive K+(KATP) channel is the specific site of action of the antihypertensive K+ channel activators has focussed a great deal of attention on the role of this channel in vascular smooth muscle function. Investigation and elucidation of these characteristics in a variety of blood vessel types may provide insight into the role of these channels in norm,al smooth muscle function. In hypertension, the ATP sensitivity of this channel appears to be decreased. The studies proposed in this grant are designed to test the following hypotheses: 1) the altered sensitivity to ATP of the KATP channel of vascular smooth muscle cells in hypertension is part of the adaptive response to the vascular hypertrophy associated with high blood pressure; 2) the altered sensitivity to ATP is indicative of the genetic expression of a different from this channel. Specific aims: 1) To characterize the effects of specific agonists and antagonists of the KATP channel on basal and agonist-stimulated contractile responses in vascular smooth muscle from hypertensive and normotensive rats;2) To determine the properties of single KATP channels in membrane patches from isolated vascular smooth muscle cells derived from hypertensive and normotensive rats; 3) To prevent the rise in or lower blood pressure in hypertensive rats by pharmacological means or arterial obstruction and then determine the effect of such treatment on:a) the actions of specific agonists and antagonists of the KATP channel on basal and agonist-stimulated contractile responses in vascular smooth muscle from hypertensive and normotensive rats,b) the properties of single KATP channels in membrane patches from isolated vascular smooth muscle cells derived from hypertensive and normotensive rats; 5) To determine if the properties of single KATP channels are altered when vascular smooth muscle cells from hypertensive and normotensive rats are grown in primary cell culture; 6) To determine whether the sensitivity of the KATP channel to ATP is altered in a non-genetic model of hypertension; 7) To determine whether the change in ATP sensitivity of the KATP channel is associated with a change in the membrane environment (posttranslational effect) or whether the change represents the expression of a different form of this channel (pretranslational effect). The proposed experiments will be performed on isolated blood vessel segments and cells (carotid, tail, mesenteric and coronary arteries) from the stroke-prone strain of the spontaneously hypertensive rat and normotensive Wistar-Kyoto rats using standard muscle bath technique and the patch clamp technique. The expression of vascular smooth muscle cell mRNA in frog oocytes will indicate whether the genetic expression of the KATP channel is altered in hypertension. Elucidation of the relationship between the greater potency of KATP channel agonists and the altered properties of this channel in hypertension may lead a better understanding of the phenomenon of vascular hypertrophy and to the development of more effective and better tolerated pharmacological agents for the treatment of this disease.