UC San Diego

The overall objective of our studies is to determine the underlying mechanisms of cell and organ failure in hypertension. We proposed recently a new "autodigestion hypothesis" postulating that there may be elevated levels of unchecked degrading proteases in hypertensive patients, not present in healthy controls. These uncontrolled extracellular proteases cause receptor cleavage that destroys membrane receptors involved in arterial constriction/dilation and consequently the higher blood pressure. We investigate these mechanisms in a model of human hypertension, the spontaneously hypertensive rats (SHR). These rats have elevated protease activity in their plasma. The goal of the current study is to determine the source of the uncontrolled enzymatic activity and its leakage mechanism into the bloodstream. The enzymatic activity of SHR pancreas, since it is a major source of digestive enzymes, and plasma paired with normotensive (WKY rat) controls was measured with zymography. The results showed that SHR has significantly higher enzymatic activity than WKY in the venous blood, pancreas, and pancreatic venules (p<0.05). These enzymes were identified to be possibly trypsin and chymotrypsin. Furthermore, by introduction of an 18 hour fasting period with reduction of these digestive enzyme levels in the pancreas there is a small but significant reduction in systolic blood pressure in SHR but not in its normotensive control. These results provide the first time a lead for the origin of uncontrolled enzymes in the SHR. The evidence suggests leakage of highly degrading enzymes from the pancreas into the circulation through its venules leading to receptor cleavage and hypertension