Smoking is associated with albuminuria and abnormal renal function. However, these associations are less pronounced or absent in former smokers.

Abstract-The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiotensin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1-7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1-7) up to 100%, with an IC 50 of 3.0 and 4.0 mol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro 11 ,D-Ala 12 ]-angiotensin I were antagonized by angiotensin-(1-7) (10 Ϫ5 mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro 10 ]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) only inhibits ACE. These results show that angiotensin-(1-7) may be an important modulator of the human renin-angiotensin system. (Hypertension. 1999;34:296-301.)

1 Increased vascular resistance in chronic heart failure (CHF) has been attributed to stimulated neurohumoral systems. However, local mechanisms may also importantly contribute to set arterial tone. Our aim, therefore, was to test whether pressure-induced myogenic constriction of resistance arteries in vitro -devoid of acute effects of circulating factors -is increased in CHF and to explore underlying mechanisms. 2 At 12 weeks after coronary ligation-induced myocardial infarction or SHAM-operations in rats, we studied isolated mesenteric arteries for myogenic constriction, determined as the active constriction (% of passive diameter) in response to stepwise increase in intraluminal pressure (20 -160 mmHg), in the absence and presence of inhibitors of potentially involved modulators of myogenic constriction. 3 We found that myogenic constriction in mesenteric arteries from CHF rats was markedly increased compared to SHAM over the whole pressure range, the difference being most pronounced at 60 mmHg (2472 versus 473%, respectively, Po0.001). 4 Both removal of the endothelium as well as inhibition of NO production (l-N G -monomethylarginine, 100 mm) significantly increased myogenic constriction ( þ 16 and þ 25%, respectively), the increase being similar in CHF-and SHAM-arteries (P ¼ NS). Neither endothelin type A (ET A )-receptor blockade (BQ123, 1 mm) nor inhibition of perivascular (sympathetic) nerve conduction (tetrodotoxin, 100 nm) affected the myogenic response in either group. 5 Interestingly, increased myogenic constriction in CHF was fully reversed after angiotensin II type I (AT 1 )-receptor blockade (candesartan, 100 nm; losartan, 10 mm), which was without effect in SHAM. In contrast, neither angiotensin-converting enzyme (ACE) inhibition (lisinopril, 1 mm; captopril, 10 mm) or AT 2 -receptor blockade (PD123319, 1 mm), nor inhibition of superoxide production (superoxide dismutase, 50 U ml À1 ), TXA 2 -receptor blockade (SQ29,548, 1 mm) or inhibition of cyclooxygenase-derived prostaglandins (indomethacin, 10 mm) affected myogenic constriction. 6 Sensitivity of mesenteric arteries to angiotensin II (10 nm -100 mm) was increased (Po0.05) in CHF (pD 2 7.170.4) compared to SHAM (pD 2 6.270.3), while the sensitivity to KCl and phenylephrine was not different. 7 Our results demonstrate increased myogenic constriction in small mesenteric arteries of rats with CHF, potentially making it an important target for therapy in counteracting increased vascular resistance in CHF. Our results further suggest active and instantaneous participation of AT 1 -receptors in increased myogenic constriction in CHF, involving increased sensitivity of AT 1 -receptors rather than apparent ACE-mediated local angiotensin II production.

The first human studies using relatively high-doses of ANF revealed similar effects as observed in the preceding animal reports, including effects on systemic vasculature (blood pressure fall, decrease in intravascular volume), renal vasculature (rise in GFR, fall in renal blood flow), renal electrolyte excretion (rises in many electrolytes), and changes in release of a number of different hormones. Whether all these changes are the result of direct ANF effects or secondary to a (single) primary event of the hormone remains to be determined. Certainly, it has been proven that more physiological doses of ANF fail to induce short-term changes in many of these parameters leaving only a rise in hematocrit, natriuresis and an inhibition of the RAAS as important detectable ANF effects in humans. This leads us to hypothesize that ANF is a "natriuretic" hormone with physiological significance. The primary function in humans is to regulate sodium homeostasis in response to changes in intravascular volume (cardiac atrial stretch). Induction of excess renal sodium excretion and extracellular volume shift appear to be the effector mechanisms. The exact mechanism of the natriuresis in humans still needs to be resolved. It appears however, that possibly a small rise in GFR, a reduction in proximal and distal tubular sodium reabsorption, as well as an ensuing medullary washout, are of importance. The pathophysiological role of ANF in human disease is unclear. One may find elevated plasma irANF levels and/or decreased responses to exogenous ANF in some disease states. Whether these findings are secondary to the disease state rather than the cause of the disease remains to be resolved. Therapeutic applications for ANF, or drugs that intervene in its production or receptor-binding, seem to be multiple. Most important could be the antihypertensive effect, although areas such as congestive heart failure, renal failure, liver cirrhosis and the nephrotic syndrome cannot be excluded. Although the data that have been gathered to date allowed us to draw some careful conclusions as to the (patho)physiological role of ANF, the exact place of ANF in sodium homeostatic control must still be better defined. To achieve this, we will need more carefully designed low-dose ANF infusion, as well as ANF-breakdown inhibitor studies. Even more promising, however, is the potential area of studies open to us when ANF-receptor (ant)agonists become available for human use.

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