S U M M A R YThe temporal and spatial expression of transforming growth factor (TGF)-␤ 1 and connective tissue growth factor (CTGF) was assessed in the left ventricle of a myocardial infarction (MI) model of injury with and without angiotensin-converting enzyme (ACE) inhibition. Coronary artery ligated rats were killed 1, 3, 7, 28, and 180 days after MI. TGF-␤ 1 , CTGF, and procollagen ␣ 1(I) mRNA were localized by in situ hybridization, and TGF-␤ 1 and CTGF protein levels by immunohistochemistry. Collagen protein was measured using picrosirius red staining. In a separate group, rats were treated for 6 months with an ACE inhibitor. There were temporal and regional differences in the expression of TGF-␤ 1 , CTGF, and collagen after MI. Procollagen ␣ 1(I) mRNA expression increased in the border zone and scar peaking 1 week after MI, whereas collagen protein increased in all areas of the heart over the 180 days. Expression of TGF-␤ 1 mRNA and protein showed major increases in the border zone and scar peaking 1 week after MI. The major increases in CTGF mRNA and protein occurred in the viable myocardium at 180 days after MI. Long-term ACE inhibition reduced left ventricular mass and decreased fibrosis in the viable myocardium, but had no effect on cardiac TGF-␤ 1 or CTGF. TGF-␤ 1 is involved in the initial, acute phase of inflammation and repair after MI, whereas CTGF is involved in the ongoing fibrosis of the heart. The antifibrotic benefits of captopril are not mediated through a reduction in CTGF.

The precise role of vasopressin in the pathophysiology of cardiovascular disease is controversial, but this peptide hormone is important for several reasons. Firstly, circulating concentrations of vasopressin are elevated in heart failure and some forms of hypertension. Secondly, there is evidence that vasopressin is synthesized not only in the hypophysial-pituitary axis but also in peripheral tissues including the heart where it acts as a paracrine hormone. Thirdly, vasopressin has vasoconstrictor, mitogenic, hyperplastic and renal fluid retaining properties which, by analogy with angiotensin 11, may have deleterious effects when present in chronic excess. Finally, the availability of orally active non-peptide vasopressin receptor antagonists allows vasopressin receptor antagonism to be considered as a therapeutic option in cardiovascular disease. Experimental Physiology (2000) 85S, 259s-265s. VasopressinVasopressin is a major hormonal system in the body responsible for blood pressure homeostasis and for salt and water balance (Johnston, 1985; Phillips et al. 199%). Vasopressin belongs to a family of vasoactive and mitogenic peptides and has multiple actions including inhibition of diuresis, contraction of vascular smooth muscle, trophic actions, platelet aggregation, stimulation of Von Willebrand factor, liver glycogenolysis and central regulation of blood pressure and the baroreflex (Johnston, 1985; Phillips et al. 1 9 9 5~; Sampey et al. 1999). Vasopressin exerts its actions through binding to typical heptahelical transmembrane G-proteincoupled receptors with distinct second messenger systems; the V,, (vascular, hepatic) and V,, (anterior pituitary) receptors through phosphatidylinosilol hydrolysis to mobilize calcium, and the V, (kidney) receptor through adenylyl cyclase. In addition to its classical vasopressor action via the VIA receptor, vasopressin mediates vasodilatation through renal V,-like receptors (Naitoh et al. 1993; Burrell et al. 1994a). To date more than ten related complementary DNAs have been cloned and sequenced (Bichet, 1996) including rat and human vasopressin V,, receptors, human V,, receptor, rat and human V, receptors and sheep VIA receptors (Hutchins et al. 1995). These receptors are strikingly similar in both size and amino acid sequence. Vasopressin and cardiovascular disease

In CHF, blockade of vasopressin V(1a) and V(2) receptors was associated with increased water excretion, and the combination of conivaptan with ACE inhibition was the only treatment to reduce blood pressure, natriuretic peptide and pulmonary congestion. These results suggest conivaptan may be a useful addition to ACE inhibitors in the management of vasoconstriction and fluid retention that characterizes CHF.