Our data suggests an important in vivo mechanism of calcium antagonist peripheral vascular pharmacodynamic effect is via indirect blockade of angiotensin II (AII) and endothelin-1 (E-1) vasoconstrictor effect. Furthermore it supports a close interrelationship between AII and E-1 mediated vasoconstriction. The present proposal will confirm and extend these observations to better understand the effects of aging hypertension on this aspect of calcium antagonist pharmacodynamics and will explore in vivo mechanisms for the observed interrelationship between AII and E-1 mediated vasoconstriction. Hypothesis#1: Calcium antagonists block vascular contractile responses to AII and E-1 and this effect is maintained and/or accentuated in aging hypertension.
Specific Aim#I : Determine and compare the reversal of AII and E-1 mediated vasoconstriction by calcium antagonists in younger and older hypertensive patients.
Specific Aim#2 : Establish that this is a sustained effect during chronic calcium antagonist antihypertensive treatment. Hypothesis#2: Vascular contractile responses of E-1 are partially dependent on the activity of an intact local and systemic renin angiotensin system (RAS) and partially independent of an intact renin angiotensin system. Calcium antagonists block both of these components while angiotensin converting enzyme inhibition blocks only the RAS dependent component.
Specific Aim#3 : Determine the E1 contractile response in the presence of local forearm blockade of AII formation. Compare this to the E-1 contractile response in the presence of calcium antagonists.
Aim#4 : Establish the in vivo mechanisms by which AII and/or angiotensin converting enzyme inhibition and E-1 mediated vasoconstriction are related. Hypothesis#3: E-1 contractile responses are the summation of direct stimulation of vascular smooth muscle and indirect effects via the vascular endothelium. Impaired endothelial function in aging hypertension enhances in vivo E-1 contractile response, and calcium antagonists remain effective in blocking the contractile response irrespective of age.
Specific Aim#5 : In vivo endothelial function will be compared between younger and older hypertensive patients. In individual patients the determined endothelial function will be evaluated as a source of variance for the interindividual E1 contractile response.
Specific Aim#6 : Calcium antagonist reversal of E-1 contractile response in the same individuals will be determined with the expectation that individuals with the greatest impairment in in vivo endothelial function will have the greatest E-1 contractile response and the greatest proportional reversal of this response by calcium antagonists. These studies will extend understanding of the mechanisms of in vivo vasorelaxant effects of calcium antagonist drugs in aging hypertensive patients. Furthermore they will define the effects of calcium channel blockade on the most potent vasoconstrictor hormones known, AII and E-1, in aging hypertension.
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