Henry W. Overbeck

Sodium pump activity in arteries of rats with Goldblatt hypertension.

Several laboratories have reported evidence suggesting abnormalities in the activity of the sarcolemmal sodium pump in vascular smooth muscle in hypertension. The present experiments were designed to investigate the relationship of such changes to the status of the renin-angiotensin-aldosterone system and body fluid volumes. We assessed sodium pump activity in vitro in sodium-loaded tail artery and thoracic aorta freshly excised from rats with chronic one-kidney, one clip, and two-kidney, one clip hypertension, and from appropriate normotensive control rats. 86Rb uptake in the absence (total uptake) and presence of 1.0 mM ouabain (ouabain-insensitive uptake) was measured, and ouabain-sensitive uptake (nmole/mg dry weight/18 min) was calculated. There were increases in plasma renin activity in the two-kidney, one clip rats only. In the hypertensive rats there were significant increases (up to +60%) in the ouabain-sensitive and total 86Rb uptakes in both tail artery and aorta. The magnitude of increases in arterial tissue uptakes in the two forms of Goldblatt hypertension, and in one-kidney, one clip hypertensive rats given 0.9% saline to drink for 2 to 3 days before sacrifice, were similar. Further sodium loading of aortas from normotensive control rats did not increase their uptake. The results of this study provide no evidence for decreases in sodium pump activity, instead indicating that there are increases in the activity of the pump in the sarcolemma or arterial smooth muscle studied in vitro. These increases in pump activity do not appear to be related to altered activity of the renin-angiotensin-aldosterone system, to changes in body fluid volumes, or to increases in intracellular concentrations of sodium. Increases in numbers or concentration of sarcolemmal pump molecules or in their turnover rate may be involved. However, in vitro 86Rb uptake by tail artery and aorta may not reflect the status of sodium pump activity in resistance vessels in vivo.

Decreased intraocular pressure in dogs with one-kidney, one wrapped hypertension.

We examined the relationship of intraocular pressure and the development of one-kidney, one wrapped (perinephritic) hypertension in the dog. Conscious femoral arterial pressure (direct arterial puncture) and intraocular pressure (Schiotz tonometer) were measured weekly before and after the surgical induction of hypertension in 11 healthy male mongrel dogs and before and after unilateral nephrectomy in 15 normotensive control dogs. Preoperative mean arterial pressure (102 +/- 5 vs 99 +/- 8 [SD] mm Hg, hypertensive vs control dogs) and intraocular pressure (18.1 +/- 2.5 vs 17.7 +/- 2.1 mm Hg, hypertensive vs control dogs) were similar in both groups. In normotensive control dogs, mean arterial pressure and intraocular pressure averaged over the postoperative period (4-8 weeks) did not differ significantly from preoperative values. In contrast, during the same period arterial pressure significantly increased and intraocular pressure significantly decreased in hypertensive dogs (arterial pressure, 163 +/- 8 mm Hg; intraocular pressure, 11.9 +/- 4.0 mm Hg; p less than 0.001 for both values compared with corresponding values in control dogs). Intraocular pressure was inversely related to arterial pressure in hypertensive dogs (r = 0.56, p less than 0.01). These observations indicate that intraocular pressure decreases with the development of canine one-kidney, one wrapped hypertension. The mechanism of this decrease may be related to abnormalities in Na+,K+-adenosine triphosphatase activity found in this form of hypertension.

Function of the sodium pump in arterial smooth muscle in experimental hypertension: role of pressure.

Several laboratories have reported evidence suggesting that in hypertension there are abnormalities in the activity of the sarcolemmal sodium pump in vascular smooth muscle. In the present study, by sampling tissue from both hypertensive and normotensive portions of the arterial tree in coarctation hypertension, we investigated the relationship of such abnormalities to the elevated intravascular pressure. Additionally, we measured plasma renin activity and body fluid volumes. We assessed sodium pump activity in vitro sodium-loaded arteries freshly excised from rats with chronic coarctation hypertension (abdominal aorta constricted above the renal arteries 4 to 5 weeks previously) and from normotensive sham-coarcted rats; these included the tail artery, the hypertensive thoracic aorta, and the normotensive portion of the abdominal aorta below the clip. The Rb uptake in the absence (total uptake) and presence (ouabain-insensitive uptake) of 1.0 mM ouabain was measured, and ouabain-sensitive uptake (nmole/mg dry weight/10 min) was calculated. In the rats with coarctation hypertension, there were significant increases in the ouabain-sensitive and total Rb uptakes in both the thoracic and abdominal aorta, but no abnormalities in Rb uptake in the tail artery. The higher uptakes in tissue from coarcted rats could not be attributed to increased levels of intracellular sodium. Plasma renin activity was elevated in the coarcted rats, but no changes in body fluid volumes were detected. This study provides evidence that increases in the activity of the sodium pump, similar to those we have observed in tissue from rats with salt-induced or Goldblatt hypertension, occur in conduit arteries of rats with coarctation hypertension studied in vitro. Because similar increases occur in vascular smooth muscle of the normotensive and hypertensive portions of the aorta, these pump abnormalities in arteries do not appear to be the direct result of increased intravascular pressure and probably are not attributable to tissue hyperplasia. Hypertension 4: 394–399, 1982)

Elevated Arterial Pressure, Vascular Wall “Waterlogging,” and Impaired Cardiac Growth in Rats Chronically Receiving Digoxin

Abstract Decreased activity of the sarcolemmal sodium pump may account, in part, for the elevated arterial pressure and also for the vascular wall “waterlogging” in certain forms of hypertension. To further test this hypothesis, digoxin, 120 or 240 mg/kg/day, was administered orally to 4-week-old rats and continued for 6-7 weeks in Group A rats. After 5 weeks of similar administration, digoxin was stopped in Group B rats. Group C control rats never received digoxin. Measured serum digoxin levels in Group A rats ranged from 204 to 660 ng/ml. In rats receiving digoxin, tail systolic arterial pressures measured three times per week were slightly (6%) but significantly (P <0.001) higher than in control rats. At age 12 weeks, tail systolic pressures (mm Hg; M ± SEM) were 128.2 ± 1.1, 118.4 ± 0.7, and 118.0 ± 0.3 in Groups A, B, and C. At age 12-13 weeks, water content of the thoracic vena cava in digoxin-treated rats of Group A was increased by 3-5% (P <0.05). An additional finding was that left ventricular weight and LV weight/body wt in Group A rats were decreased by 4-9% (P <0.05). These data indicate that, in rats, chronic inhibition of the membrane sodium pump in the cardiovascular muscle by digitalis is associated with increased arterial pressure and vascular wall waterlogging. Thus, pump inhibition may play a role in similar abnormalities occurring in hypertension. Digoxin administration also impaired cardiac growth in these young rats.

Vascular Smooth Muscle Membrane Potential in Rats with Early and Chronic One-Kidney, One-Clip Hypertension

Abstract It has been suggested that the cell membrane of vascular smooth muscle in one-kidney, one-clip hypertension, and other forms of volume-dependent, low-renin hypertension, is partially depolarized due to the effects of a circulating ouabain-like factor, and that this depolarization is an important mechanism of the hypertension. Levels of circulating ouabain-like factors in early stages of volume-dependent hypertension are reported equal to, or greater than, those in chronic hypertension. Therefore, we measured intracellular membrane potentials (E m ) in vitro (37 °C, physiological salt solution) in vascular smooth muscle of the caudal artery from normotensive control rats (1K) and rats in the early and chronic stages of one-kidney, one-clip hypertension (1K1C). In 20 chronic 1K1C (4-6 weeks of systolic pressure > 140 mm Hg) the resting E ms (M ± SEM) were −46.7 ± 0.7 mV, compared to −50.9 ± 0.6 for 20 1K (P < 0.01). The ΔE m due to 1 mM ouabain was attenuated in 10 1K1C compared to 11 1K (+5.4 ± 0.9 and +10.0 ± 0.7 mV, respectively; P < 0.01). The E ms of the two groups after ouabain were the same. In contrast, in 16 early 1K1C rats (<7 days hypertension, average 3 days) compared to 15 appropriate 1K, there were no significant alterations in resting E m (-50.1 ± 0.4 mV, compared to −50.5 ± 0.5, respectively) and there were no differences in ouabain response. These results suggest a temporal dissociation between levels of humoral inhibitors and depolarization, and between depolarization and hypertension, and thus fail to support the hypotheses that there are causal relationships between these variables in volume-dependent, low-renin hypertension.

Aortic hypertrophy and "waterlogging" in the development of coarctation hypertension.

To study the mechanisms and roles of vascular structural changes during the development of hypertension, we coarcted or sham-coarcted the abdominal aorta of rats. At intervals of 3 to 56 days later, we obtained standardized segments of thoracic and abdominal aortas for measurement of dry weight, water content, and amino acid content. Carotid arterial pressure was elevated by day 5 in coarcted rats and remained elevated. Femoral and tail arterial pressures remained normal. Cardiac ventricular weight and dry weight of the thoracic aorta, normalized for body weight, rose rapidly over 3–10 days in coarcted rats, remaining constant at 50–60% above levels in sham-coarcted rats thereafter. In contrast, water content of thoracic aorta in coarcted rats peaked at 123% of control values on day 7 (p < 0.001), falling rapidly thereafter to levels about half of peak. Increments in dry weight and water content of the normotenslve abdominal aortic segments were of far lesser magnitude and occurred 1 to 2 weeks later, probably reflecting the effects of initial hypotension of the hindquarters. Percent hydroxyproline of intima-media segments of the thoracic aorta remained normal during the 8-week period, indicating that increases in aortic dry weight did not represent disproportional fibrosis and thus are attributable to muscular hypertrophy. These results provide support for the hypothesis that arterial wall “waterlogging” is primarily an early manifestation of the hypertensive process. The greatest magnitude of waterlogging coincides with the rapid early increase in aortic dry weight, representing hypertrophy, which suggests common mechanisms, such as activation of Na+-H+ antiport.