May 6, 1998 ATHENS, Ga. -- When it comes to blood vessels, all people are not created equal. Blacks have more problems with cardiovascular disease than whites. Males die from heart attacks far more often than females. Women suffer from migraine headaches more often than men. The reasons are complex, and only now are scientists discovering why.
A new discovery by researchers at the University of Georgia may help explain one aspect of the tangled problem. Using small pieces of left-over saphenous vein tissue from heart bypass surgeries, they compared the veins of white men and women and discovered a startling difference between them. They demonstrated for the first time dramatic differences in the density of receptors for a powerful and naturally occurring blood-borne substance called endothelin-1. And it's more bad news for white males.
"We won't entirely know the relevance of this study until we do the same experiments with arterial tissue, but it's an important first step," said Dr.Adviye Ergul of the University of Georgia's department of biochemistry and molecular biology. Collaborating with Ergul on the research were Dr. David Puett of the same department and Dr. Randall Tackett of the University of Georgia College of Pharmacy.
Results of the study were published this week in the May issue of the Journal of Pharmacology and Experimental Therapeutics.
Endothelin-1 (ET-1) is produced by cells that line the blood vessels and is a potent vasoconstrictor -- that is, a compound which causes vessels to contract. Ergul and Puett showed in 1996 that hypertensive blacks have four times as much endothelin-1 in their blood streams as hypertensive whites, and that hypertensive blacks have eight times more circulating ET-1 than blacks with normal blood pressure. The current study is the first to examine gender differences in ET-1.
ET-1 by itself can't do much in the human body. It needs receptor sites in the veins to mediate its effects, and medical researchers had previously discovered two different kinds of receptors: ETA, which causes vessels to constrict, is located in the vascular smooth muscle, and ETB, located in the endothelium, usually causes vasodilation, depending on the species and tissue location. The current study showed that males had a 75-25 ratio of ETA receptors to ETB, while in females the numbers were closer to 50-50. Males also had five times more total receptors than females.
The saphenous vein tissue used in the study was obtained from patients at the Medical College of Georgia in Augusta who were undergoing coronary artery bypass. Ages of males were from 51-83 and females (all postmenopausal and not receiving estrogen-replacement therapy) from 55-69.
"Our findings clearly demonstrate that saphenous veins from males contain a greater number of ETA receptors than those of females," said Tackett.
Not only do males have more of these receptors involved in vein constriction, the contractile response of men to ET-1 is twice as high as that of females. All this means that these veins are far more likely to constrict -- causing problems with blood flow -- in men than in women. The vastly greater number of ETA receptors in men than women could also help explain why men have far more reoccurrences of clotting problems (often at the suture line) and graft failures after heart bypass surgery than women. Since ET-1 was first discovered, researchers have focused on its potential role in the maintenance of blood pressure and its role in hypertension due to its ability to make vessels contract. Elevated plasma ET-1 levels have been discovered in many medical conditions, from chronic heart failure to atherosclerosis. It remains unclear, however, just how ET-1 works in the body, and this study is the first to indicate gender differences
There's another reason to understand these receptors, though. Drugs that block the binding of ET-1 to its receptor sites have been shown in animals to be useful in treating congestive heart failure and pulmonary hypertension. In humans, these blocking drugs, called antagonists, have also proved important. Medical researchers have discovered that ETA receptor antagonists may be useful as vasodilator agents in chronic heart failure and hypertension.
"The gender differences observed in this study raise interesting questions with regard to our understanding of the gender-related differences in cardiovascular disease reported in epidemiological studies," said Puett.
One immediate concern is that the efficacy of the potential ET receptor antagonist may not be the same in men and women. Clearly, the larger number of ETA receptors in males is consistent with a higher rate of observed vascular disease. The researchers point out the need for a corroborating study of receptor sites in arterial tissue, especially since post-menopausal women are know to be at a higher risk for cardiovascular disease than pre-menopausal women.
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