Transgenic mice to study the role of dopamine receptors in cardiovascular function.

Dopamine, an intrarenal regulator of sodium transport, is important in the pathogenesis of hypertension. The transduction of D1-like receptors in renal proximal tubules is defective in animal models of genetic hypertension. The defect is associated with an impaired regulation of proximal tubular sodium transport and cosegregates with hypertension in rats. Moreover, mice lacking one or both D1A receptor alleles develop hypertension. Extrasynaptic D3 receptors in renal tubules and juxtaglomerular cells may also regulate renal sodium transport and renin secretion while presynaptic D3 receptors may act as autoreceptors to inhibit neural norepinephrine release. Mice lacking one or both D3 alleles have elevated systolic blood pressure and developed diastolic hypertension. Although basal urine flow, sodium excretion, and glomerular filtration rate are similar, mice homozygous to the D3 receptor have an impaired ability to excrete an acute saline load compared to heterozygous and wild type mice. These studies suggest that abnormalities in dopamine receptor genes or their regulation may lead to the development of hypertension via different pathogenetic mechanisms.