Citations

Endothelin-1 contracts vascular smooth muscle and inhibits release of neurotransmitter from adrenergic and cholinergic neurons. Experiments were designed to investigate the interaction of these mechanisms in a blood vessel that receives both adrenergic and cholinergic innervation. Rings cut from canine left anterior descending coronary arteries were suspended in organ chambers for the measurement of isometric force. In some rings, the endothelium was removed. Endothelin-1 caused concentration-dependent increases in tension in all rings. During electrical stimulation (1 Hz, 9 V, 2 msec), the contractions to endothelin-1 were reduced significantly. In rings without endothelium, this decrease was greater in the presence of atropine (10(-6) M) and was eliminated by a combination of phentolamine (10(-5) M) and propranolol (5 x 10(-6) M). Contractions to endothelin-1 during electrical stimulation in rings with endothelium were significantly less than those without endothelium. This difference was eliminated by atropine and NG-monomethyl L-arginine (10(-4) M). The presynaptic effects of endothelin-1 were studied by measurement of tritium-labeled norepinephrine. Phasic electrical stimulation induced release of norepinephrine; this was inhibited by endothelin-1 at high concentrations (4 x 10(-7) M) in the presence of atropine. These results suggest that the major effect of endothelin-1 is postsynaptic in canine coronary arteries. However, contractions to endothelin-1 may be modulated by the level of sympathetic and parasympathetic tone. In situations in which innervation to the coronary arteries is altered, for example, in hearts used for transplantation, the contractile effects of endothelin-1 would prevail.

The objectives of the present study were to determine whether sodium-lithium countertransport contributes to predicting the probability of having hypertension and to determine whether it does so after other predictor traits have been considered. We used logistic regression to model the relation between sodium-lithium countertransport and the probability of having hypertension, estimated by the prevalence of hypertension among 172 men and 252 women, aged 47-89 years, from the Caucasian population of Rochester, Minn. When sodium-lithium countertransport was the only predictor trait considered, it made a statistically significant contribution to prediction both in men (model chi(2)1df = 20.50, p < 0.001) and in women (model chi(2)1df = 16.69, p < 0.001). For each standard deviation increase in sodium-lithium counter-transport, the expected odds of having hypertension increased 2.25 times in men (95% confidence interval [CI], 1.44-3.51) and 1.77 times in women (95% CI, 1.32-2.37). When sodium-lithium countertransport was not considered, the other traits identified as predictors were age, body mass index, and plasma apolipoprotein CII and CII squared; plasma apolipoprotein AI was an additional predictor in women but not in men. When sodium-lithium countertransport was added to models that included the other predictors, it improved prediction both in men (increase in model chi(2)1df = 12.29, p < 0.001) and in women (increase in model chi(2)1df = 4.86, p < 0.027). Based on these complete models, when the other predictors remained at their mean values, each standard deviation increase in sodium-lithium countertransport increased the expected odds of having hypertension 2.06 times in men (95% CI, 1.31-3.22) and 1.48 times in women (95% CI, 1.04-2.21). These results establish that sodium-lithium countertransport provides information that is helpful in predicting the probability of having hypertension and is not reflected in other identified predictor traits.

We investigated whether blood pressures are higher in normotensive offspring of hypertensive parents than in normotensive offspring of normotensive parents outside the physician's office and, if so, whether these higher blood pressures are dependent on the level of dietary sodium intake. We compared 24-hour ambulatory blood pressure profiles between 11 normotensive sons of two hypertensive parents and 11 normotensive sons of two normotensive parents; profiles were recorded after 1 week of a low sodium diet (10 meq/day) and after 1 week of a high sodium diet (200 meq/day). The sons of hypertensive parents were on average 6 years older than the sons of normotensive parents (47 +/- 5 [SD] versus 41 +/- 4 years, p < 0.05). The shift from low to high sodium diet did not significantly change the magnitude of differences in office or ambulatory blood pressures between the groups (i.e., no group-by-diet interaction); thus, we assessed group effects by contrasting blood pressure means for each group pooled across diets. Age-adjusted office blood pressure was higher in sons of hypertensive parents than in sons of normotensive parents (116 +/- 7/80 +/- 6 versus 111 +/- 7/75 +/- 6 mm Hg; p = 0.020 for systolic and p = 0.003 for diastolic blood pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine evokes the simultaneous release of endothelium-derived relaxing and contracting factors in aortas from spontaneously hypertensive rats. Only relaxing factors are released in aortas from normotensive controls. Experiments were designed to determine whether inhibitors of endothelium-dependent relaxations modify endothelium-dependent contractions. Rings of thoracic aortas of normotensive and spontaneously hypertensive rats, with and without endothelium, were suspended in organ chambers for isometric tension recording. Oxyhemoglobin (a scavenger of endothelium-derived relaxing factor) and NG-monomethyl L-arginine (an inhibitor of nitric oxide formation) augmented the contractions to acetylcholine. Methylene blue (an inhibitor of soluble guanylate cyclase) and superoxide dismutase (a scavenger of superoxide anions) did not modify these contractions. The contractions in the presence of oxyhemoglobin or NG-monomethyl L-arginine, like those in untreated rings, were endothelium-dependent; they only occurred in aortas from spontaneously hypertensive rats and were abolished by indomethacin. The contractions to acetylcholine in the presence of oxyhemoglobin were not affected by superoxide dismutase or deferoxamine. These data suggest that endothelium-derived relaxing factor inhibits endothelium-dependent contractions to acetylcholine in the spontaneously hypertensive rat aorta, probably by chemical inactivation of the endothelium-derived contracting factor rather than by stimulation of guanylate cyclase or scavenging of oxygen-derived free radicals.

The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender, age, body size, and plasma lipids. We studied 543 men and 589 women from the population of Rochester, Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370 +/- 147 [mean +/- SD] versus 315 +/- 110 mumol/l red blood cells [RBC]/hr, p less than 0.001) and in women (339 +/- 114 versus 269 +/- 92 mumol/l RBC/hr, p less than 0.001). Interindividual differences in plasma triglycerides, body mass index (wt/[ht]2), and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p less than 0.001) and 20.2% in women (p less than 0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides, body mass index, and plasma total cholesterol did not differ between diagnostic groups in men (p = 0.31) or in women (p = 0.29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates, mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354 +/- 139 versus 319 +/- 104 mumol/l RBC/hr, p less than 0.01) and in women (311 +/- 103 versus 278 +/- 83 mumol/l RBC/hr, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Studies of normotensive offspring of hypertensive parents offer the potential to identify inherited abnormalities that contribute to essential hypertension. We compared renal and systemic hemodynamic responses to saline infusion between normotensive sons of two hypertensive parents (SOHT) and sons of two normotensive parents (SONT) selected from the general population of Rochester, Minn. Hemodynamic measurements were performed after a week of low sodium intake (10 meq/day) and were repeated after a week of high sodium intake (200 meq/day). Despite being in the normotensive range, blood pressures in SOHT were higher than those in SONT during low sodium (124 +/- 3/85 +/- 3 versus 118 +/- 2/71 +/- 2 mm Hg, p less than 0.01) and high sodium (122 +/- 3/80 +/- 3 versus 112 +/- 2/70 +/- 2 mm Hg, p less than 0.05) conditions. Higher pressures in SOHT were associated with elevated systemic and renal vascular resistance. After a high sodium diet, renal vascular resistance in SOHT rose further during acute saline infusion, whereas systemic vascular resistance did not change. After a low sodium diet, this renal vasoconstrictor response to saline infusion in SOHT was not present, and renal vascular resistance fell to levels not different from SONT. Plasma renin activity, aldosterone, and atrial natriuretic peptide did not differ between SONT and SOHT. Circulating levels of norepinephrine were higher in SOHT. These data demonstrate a renal vasoconstrictor response to saline infusion in normotensive SOHT, which depends on prior sodium intake. This alteration in renal hemodynamics may represent an inherited abnormality related to the development of hypertension.

Endothelium-dependent contractions to acetylcholine and endothelium-independent contractions to oxygen-derived free radicals in the aorta of the spontaneously hypertensive rat (SHR) are mediated by an unidentified product of the cyclooxygenase pathway of arachidonic acid metabolism. To determine the role of thromboxane A2 (TXA2) or prostaglandin H2 (PGH2) in these contractions, rings of the thoracic aorta of SHR were suspended in organ chambers for measurement of isometric force. Acetylcholine caused endothelium-dependent contractions in quiescent rings from SHR aortas. Oxygen-derived free radicals generated with xanthine plus xanthine oxidase caused contractions in rings without endothelium. Dazoxiben (thromboxane synthetase inhibitor) did not affect contractions evoked by acetylcholine. AH 23,848, SQ 29,548, or R 68,070 (TXA2/PGH2 receptor antagonists) inhibited contractions to U 46,619 (a TXA2/PGH2 receptor agonist), acetylcholine, and oxygen-derived free radicals. Acetylcholine stimulated the release of prostacyclin from Wistar-Kyoto (WKY) rat and SHR aortas but not the release of other prostaglandins (PGE2, PGF2 alpha, TXA2). Oxygen-derived free radicals did not stimulate the release of prostaglandins from either SHR or WKY rat aortas. These results demonstrate that stimulation of TXA2/PGH2 receptors probably by PGH2 might be involved in endothelium-dependent contractions. Oxygen-derived free radicals, which might be an endothelium-derived contracting factor or factors, ultimately cause contraction by stimulation of TXA2/PGH2 receptors.

Intrarenal infusion of acetylcholine in meclofenamate-treated dogs significantly increased renal blood flow, diuresis, and natriuresis. Intrarenal infusions of either NG-monomethyl-L-arginine (inhibitor of endothelium-derived relaxing factor formation), or L-arginine (precursor of endothelium-derived relaxing factor formation) did not modify basal levels of those parameters. However, the infusion of NG-monomethyl-L-arginine inhibited the acetylcholine-induced increases in renal blood flow and diuresis without affecting natriuresis, which increased significantly. The infusion of L-arginine failed to further enhance hemodynamic and excretory effects elicited by acetylcholine. The concomitant infusion of L-arginine and NG-monomethyl-L-arginine did not change renal blood flow, urine flow, or sodium excretion rate. L-Arginine administration prevented the inhibitory effect of NG-monomethyl-L-arginine on acetylcholine-induced renal vasodilatation and diuresis. Glomerular filtration rate and mean arterial pressure did not change throughout the experiment. The results indicate that the vasodilatory and diuretic responses to intrarenal acetylcholine in meclofenamate-treated dogs are largely dependent on endothelium-derived relaxing factor.

To determine if oxygen-derived free radicals are mediators of endothelium-dependent contractions to acetylcholine in the aorta of spontaneously hypertensive rats (SHR), the mechanism of contraction to xanthine plus xanthine oxidase was studied. Rings, with and without endothelium, of thoracic aorta from normotensive Wistar-Kyoto (WKY) rats and SHR were suspended in organ chambers for isometric tension recording. Oxygen-derived free radicals caused concentration-dependent contractions; these contractions were twice as large in the aortas of SHR than in WKY rats. Deferoxamine reversed the response to xanthine oxidase to a small relaxation. Either allopurinol, superoxide dismutase, or catalase, or the combination of superoxide dismutase plus catalase reduced the contractions. Diltiazem inhibited the response to xanthine oxidase; in contrast, phentolamine plus propranolol did not affect it. Indomethacin and meclofenamate, but not tranylcypromine or dazoxiben blocked the contractions. Endothelium-dependent contractions to acetylcholine in aortas from the SHR were not affected by deferoxamine or superoxide dismutase plus catalase. These data suggest that hydroxyl radicals cause contractions in the rat aorta, which are dependent on extracellular calcium and mediated by activation of the cyclooxygenase in the vascular smooth muscle. The augmented contractions in the hypertensive strain are due to an increased reactivity of the smooth muscle to oxygen-derived free radicals. However, the lack of effect of the scavengers on endothelium-dependent contractions to acetylcholine suggests that the endothelium-derived contracting factor is chemically different from oxygen-derived free radicals.

The response of isolated blood vessels to a variety of vasoactive agonists is modulated by the presence of endothelial cells. Indeed, these cells can release both dilator and constrictor substances. The major endothelium-derived relaxing factor may be nitric oxide, which activates soluble guanylate cyclase in the smooth muscle, although the endothelial cells also secrete an unidentified hyperpolarizing factor. Among the natural stimuli for the release of endothelium-derived relaxing factors are circulating hormones, platelet products, thrombin, shear stress, and certain autacoids. Endothelium-derived relaxing factors may contribute to the regulation of the release of atrial natriuretic factor and renin. The endothelial cells can also release constricting factors; among the likely candidates are superoxide anions or the peptide endothelin. In hypertensive blood vessels, the ability to release endothelium-derived relaxing factors but not endothelium-derived contracting factors is blunted.