Treatment of hypertension by renal vascular delivery of guanethidine

Abstract

Sympathetic nerves run through the adventitia surrounding renal arteries and are critical in the modulation of systemic hypertension. Hyperactivity of these nerves can cause renal hypertension, a disease prevalent in 30-40% of the adult population. Hypertension can be treated with neuromodulating agents (such as angiotensin converting enzyme inhibitors, angiotensin II inhibitors, or aldosterone receptor blockers), but requires adherence to strict regimens and often does not reach target blood pressure threshold to reduce risk of major cardiovascular events. A minimally invasive solution is presented here to reduce the activity of the sympathetic nerves surrounding the renal artery by locally delivering neurotoxic or sympathetic nerve-blocking agents into the adventitia. Extended elution of these agents may also be accomplished in order to tailor the therapy to the patient.

1 . A method for treating hypertension in a patient, said method comprising the delivering of an amount of a therapeutic agent composition to the nerves surrounding a blood vessel,
 wherein the delivering comprises injecting the therapeutic agent composition into tissue bound on the inside by the external elastic lamina of said blood vessel and bound on the outside by the outer extent of the adventitial and perivascular connective tissues that surround the blood vessel,   wherein the amount of the therapeutic agent composition delivered is effective to reduce release of norepinephrine from sympathetic nerve terminals of the nerves surrounding the blood vessel.   
     
     
         2 . The method of  claim 1 , wherein the reduction of release of norepinephrine from the sympathetic nerve terminals of the nerves surrounding the blood vessels is sufficient to lower systemic blood pressure by a therapeutically beneficial amount. 
     
     
         3 . The method of  claim 1 , wherein the therapeutic agent composition comprises guanethidine. 
     
     
         4 . The method of  claim 1 , wherein the therapeutic agent composition comprises a neuromodulating agent. 
     
     
         5 . The method of  claim 1 , wherein the therapeutic agent composition comprises a heated fluid. 
     
     
         6 . The method of  claim 1 , wherein the therapeutic agent composition comprises ethanol. 
     
     
         7 . The method of  claim 1 , wherein the therapeutic agent composition comprises a hydrogel. 
     
     
         8 . The method of  claim 1 , wherein the therapeutic agent composition comprises a contrast agent. 
     
     
         9 . The method of  claim 1 , wherein the amount of therapeutic agent composition is delivered to a renal artery. 
     
     
         10 . The method of  claim 9 , wherein norepinephrine levels in a renal cortex is reduced by at least 86% at least 28 days after the delivering of the amount of the therapeutic agent composition. 
     
     
         11 . The method of  claim 1 , wherein the delivering of the amount of the therapeutic agent composition further comprises positioning a needle through a wall of the blood vessel so that an aperture of the needle is positioned beyond the external elastic lamina of blood vessel. 
     
     
         12 . The method of  claim 1 , wherein the delivering of the amount of the therapeutic agent composition further comprises confirming that the therapeutic agent composition is being delivered to the tissue by imaging either the therapeutic agent composition which is mixed with a diagnostic agent or by the delivery of a diagnostic agent prior to the delivery of the therapeutic agent composition. 
     
     
         13 . The method of  claim 1 , wherein the amount of therapeutic agent composition is delivered to an artery. 
     
     
         14 . The method of  claim 1 , wherein the amount of therapeutic agent composition is delivered to a vein. 
     
     
         15 . The method of  claim 1 , wherein one delivery of a dosage of the therapeutic agent composition is effective to lower systemic blood pressure by a therapeutically beneficial amount. 
     
     
         16 . The method of  claim 1 , wherein the amount of the therapeutic agent composition delivered is effective to reduce release of norepinephrine by at least 86%. 
     
     
         17 . The method of  claim 1 , wherein the patient is human. 
     
     
         18 . The method of  claim 4 , wherein the neuromodulating agent is a neurotoxin or a fragment thereof. 
     
     
         19 . The method of  claim 18 , wherein the neurotoxin is botulinum neurotoxin or a fragment thereof. 
     
     
         20 . The method of  claim 5 , wherein the heated fluid is effective in heating nerves of the tissue from 42° C. to 50° C.