Harold D. Itskovitz

Enalapril prevents stroke and kidney dysfunction in salt-loaded stroke-prone spontaneously hypertensive rats.

The influence of chronic treatment with the angiotensin I converting enzyme (ACE) inhibitor enalapril on blood pressure, kidney function, and survival was examined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP that were fed a Japanese rat chow plus a 1% NaCl drinking solution beginning at 7–8 weeks of age developed severe hypertension and stroke; 14 of 18 untreated control SHRSP died by 14 weeks of age and exhibited evidence of cerebrovascular lesions. When enalapril (15 mg/kg/day) was included in the drinking solution of 15 SHRSP, blood pressure was initially reduced by only a slight degree, whereas survival unproved markedly; only one of 10 SHRSP died before the rest were killed at 18 to 21 weeks. The remaining five enalapril-treated SHRSP lived beyond 36 weeks and on histological examination exhibited no evidence of cerebrovascular lesions. Chronic enalapril treatment also prevented the greater urinary excretion of protein and severe renal lesions observed in untreated SHRSP but did not affect urinary salt and water excretion. In anesthetized rats, glomerular filtration rate and tubular reabsorption of water were lower hi untreated control SHRSP when compared with enalapril-treated SHRSP. Mean arterial pressure was comparable in both groups. These data support a possible role for ACE inhibition in the prevention of stroke and maintenance of kidney function independent of any marked change in blood pressure of SHRSP. Whether the protective effects of ACE inhibition relate to reduced angiotensin H formation, increased tissue kinins, or another mechanism remains to be determined.

Thromboxane A2 and the development of hypertension in spontaneously hypertensive rats

Osmotic minipumps containing OKY-046 (15-20 mg/kg per day), to inhibit thromboxane (TX) A2 synthase, were implanted into 43-day-old SHR and age-matched Wistar-Kyoto rats (WKY) to study the role of TXA2 in the development of hypertension in SHR. Inhibition of TXA2 synthase with OKY-046 did not affect urine volume, sodium excretion, potassium excretion, food and water intake or body weight in either WKY or SHR during the two weeks of study. In the first week systolic blood pressure (SBP) was significantly lower in SHR receiving OKY-046 in comparison to SHR which received no OKY-046 (127 +/- 3 vs. 110 +/- 4 mm Hg, P less than 0.01). OKY-046 did not affect SBP in WKY. By the second week SBP in SHR and WKY receiving OKY-046 did not differ from their respective controls despite an 85% reduction in serum immunoreactive TXB2 (iTXB2; the stable hydrolysis product of TXA2) and a 45% reduction in urinary iTXB2 excretion. These results support a possible role for TXA2 in the developmental stage of hypertension in SHR and other factors in the sustained elevation of blood pressure.

Urinary Dopamine and Sodium Excretion in Spontaneously Hypertensive Rats

We measured urinary dopamine in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) before (days 0-6) and during high-salt diet, in the absence (days 6-10) and presence (days 10-14) of added L-dopa (2 mg/kg/day by gavage). Urinary excretion of sodium (UNaV) increased 20-fold during intake of chow containing 8% NaCl in both strains. Systolic blood pressure (SBP) of SHR increased slightly (9 +/- 4 mmHg; p < 0.05) on the high-salt diet, whereas SBP did not change in WKY. Urinary dopamine excretion was not different between strains in the basal state, and was as great or greater in SHR than WKY during high-salt intake with and without added L-dopa. SBP was unaffected by L-dopa administration and UNaV did not increase or differ between strains despite higher urinary dopamine excretion in SHR. We conclude that renal dopamine formation in vivo is not diminished in SHR, compared with WKY, on normal or high-salt diets, and that elevation of renal dopamine formation secondary to L-dopa administration is not associated with reductions in SBP or altered UNaV in these rats.

Formation of biogenic amines by isolated kidneys of spontaneously hypertensive rats

Kidneys form dopamine (DA) from L-dopa and serotonin from L-5-hydroxytryptophan (L-5-HTP) via aromatic L-amino acid decarboxylase. We compared the ability of isolated perfused kidneys from adult (20-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) to form these biogenic amines. Renal vascular resistance (RVR) was greater in perfused kidneys from SHR (n = 10) than WKY (n = 8) (p less than 0.01). Slight decreases in RVR were observed during L-dopa infusion but these were unrelated to DA formation. L-Dopa infusion was associated with greater DA output in SHR than WKY in both the renal venous and urinary effluents although the latter did not achieve statistical significance. L-5-HTP increased RVR to a greater degree in SHR than WKY kidneys. This was associated with larger quantities of serotonin in the urinary and venous effluents and greater pressor responses to exogenous serotonin in SHR than WKY kidneys; however, either parameter alone was not significantly increased. Our findings do not support a deficiency of intrarenal DA formation as a pathogenic factor for hypertension in SHR. Biogenic amine formation is as great if not greater in SHR than WKY kidneys and appears to contribute largely to the greater increases in renal resistance seen in SHR kidneys on infusion of L-5-HTP. Enhanced renal serotonin formation may elevate blood pressure, whereas enhanced renal DA formation would favor blood pressure lowering, perhaps as a compensatory mechanism.

Serotonin and 5-hydroxytryptophan on blood pressure and renal blood flow in anesthetized rats

The effects of exogenous (injected) serotonin on mean blood pressure and renal blood flow in male Sprague-Dawley rats were compared with the effects of enhanced endogenous serotonin, accomplished by injections of 5-hydroxytryptophan (5-HTP). Responses were evaluated with and without carbidopa, which blocks peripheral conversion of 5-HTP to serotonin, and with and without indomethacin to assess the contribution of prostanoids. Both serotonin (0.25-1.0 micrograms) and 5-HTP (50-200 micrograms) decreased blood pressure and renal blood flow and increased renal vascular resistance in dose-dependent fashion. Hypotensive responses with both agents were greater after arterial injections into the aortic arch than after intravenous injections (into the jugular vein). Carbidopa had no significant effects on responses to serotonin but ablated the ability of 5-HTP to increase renal vascular resistance and decrease renal blood flow. Carbidopa did not alter the hypotensive action of 5-HTP. Indomethacin had no significant effect on responses to serotonin or 5-HTP. These results support a direct renal vasoconstrictor effect for exogenous and endogenously formed serotonin and a hypotensive effect probably arising in the central nervous system.

5-Hydroxytryptophan and carbidopa in spontaneously hypertensive rats.

Serial measurements of blood pressure, body weight, food and water intake, and salt and water excretion were compared in two groups of spontaneously hypertensive rats (SHR) over a 12-day period: control SHR (n = 11) and a group (n = 9) which received supplementary 5-hydroxytryptophan (5-HTP; 2 mg/ml) in its drinking water. During the final 4 days of study, both groups received additional oral carbidopa (50 mg/kg twice a day) to inhibit peripheral, but not brain aromatic L-amino-acid decarboxylase (LAAD), an enzyme necessary to the formation of 5-hydroxytryptamine (5-HT, serotonin) from 5-HTP. 5-Hydroxytryptophan increased urinary 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) markedly; following carbidopa, urinary 5-HT, and to a lesser degree urinary 5-HIAA, decreased, whereas brain 5-HT and 5-HIAA increased. Spontaneously hypertensive rats treated with 5-HTP plus carbidopa had significantly lower blood pressure levels, lower pulse rates, reductions in food and water intake, salt and water excretion, and a loss of body weight, when compared with the control SHR. These data indicate that enhanced brain formation of 5-HT can give rise to metabolic and circulatory responses with a resultant lowering of blood pressure.

Enhanced vasodilatory responses to bradykinin in stroke-prone spontaneously hypertensive rats

Vasodilatory responses to bradykinin (BK) and acetylcholine (ACh) were compared in phenylephrine preconstricted perfused kidneys from 30-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Responses to ACh did not differ between kidneys from SHRSP and WHY. BK-induced dilatation was greater in kidneys from SHRSP relative to WHY and was not affected by indomethacin or captopril. These results indicate that renal vasodilatory responsiveness to bradykinin is enhanced in SHRSP with established hypertension.

The long-term antihypertensive effects of prazosin and atenolol

The efficacy and tolerability of the alpha-blocker prazosin was compared with that of atenolol, a beta-blocker, in the long-term treatment of uncomplicated, essential hypertension. Twelve patients were randomly assigned to prazosin treatment and 15 to treatment with atenolol. Drug therapy was titrated to reduce diastolic blood pressure by 10 mm Hg or to below 89 mm Hg, whichever was lower. If monotherapy with either study drug failed to do this, hydrochlorothiazide was added to the regimen. Once blood pressure control was established, patients received maintenance therapy at that dosage and were followed for up to 12 months. Blood pressure, side effects, and plasma lipid levels were monitored during this period. Seventy-five percent of patients receiving prazosin monotherapy attained blood pressure goals, compared with 60 percent of patients given atenolol monotherapy. With the addition of low-dose hydrochlorothiazide, those patients not having an adequate response to monotherapy attained blood pressure control. Blood pressure reductions were maintained without dosage adjustment throughout the maintenance period; patient acceptance was good, and there was no evidence of tolerance. Treatment with atenolol produced slight increases in plasma triglyceride levels and little change in total or low-density lipoprotein cholesterol. In contrast, patients treated with prazosin demonstrated no adverse effects with regard to lipid levels. Although a higher percentage of patients reached goal blood pressure with prazosin monotherapy than with atenolol, the response rates were comparable when hydrochlorothiazide was added to the regimens.