Morris E. Berger

Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries

To investigate the long-term influence of insulin resistance and hyperinsulinemia on vascular reactivity, both muscarinic and alpha2-receptor-mediated relaxations and the contribution of nitric oxide to these mechanisms were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n = 6) or normal chow (CNT, n = 6) for 40 weeks. Systolic blood pressure was measured by tail-cuff method. A 3-mm segment of mesenteric artery was excised, cannulated and pressurized, pretreated with prazosin (10(-6) mol/L) and propranolol (3 x 10(-6) mol/L), then precontracted with serotonin (10(-6) mol/L). Endothelium dependent relaxation was induced by addition of acetylcholine (10(-9) to 10(-4) mol/L), or a selective alpha2-agonist B-HT 920 (10(-9) to 10(-5) mol/L), with or without the nitric oxide synthase inhibitor L-NAME (10(-4) mol/L). Systolic blood pressure was significantly higher in FFR at the early period; however, there was no difference at the end of 40 weeks compared to CNT. Fasting plasma insulin was much higher in FFR than in CNT (110+/-62 v 41+/-11 microU/mL, P < .05), whereas plasma glucose was not different. Maximum relaxation to acetylcholine was attained at 10(-6) mol/L in FFR but at 3 x 10(-7) mol/L in CNT. The degree of maximum relaxation attained with acetylcholine was similar in FFR and CNT (89+/-9 and 94+/-4% of precontraction), although attenuated (P < .01) by the addition of L-NAME only in FFR (to 34+/-22%, P < .05) but not in CNT (to 82+/-25%). The half-maximal relaxation dose of acetylcholine was greater in FFR (P < .01) compared with CNT and was significantly increased (P < .05) by L-NAME in both groups. B-HT 920 at 10(-5) mol/L induced a greater relaxation in CNT (36+/-10% of serotonin constriction) than in FFR (19+/-14%, P < .05). These responses were significantly blunted by L-NAME. Thus, muscarinic receptor-mediated vascular relaxation is less sensitive and more nitric oxide dependent in FFR versus CNT. Alpha2-adrenergic-mediated relaxation, predominantly mediated by nitric oxide, is also impaired in FFR. It is possible that prolonged insulin resistance and hyperinsulinemia in FFR could alter endothelial-dependent vasodilatory mechanisms, thereby contributing to the increase in blood pressure seen in this model.

Altered vascular responses in cyclosporine-treated rats

Administration of cyclosporine to allograft recipients and patients with immunologically mediated disorders is associated with a high incidence of the development of hypertension. We studied the effect of CsA on blood pressure and on the in vitro tail artery contractile response to transmural nerve stimulation (TNS) and exogenous norepinephrine (NE) in the spontaneously hypertensive rat (SHR). Fourteen days of p.o. administration of CsA 5 mg/kg/day (CsA5) or CsA 20 mg/kg/day (CsA20) resulted in significant increases in blood pressure. The effective level of TNS that resulted in a 50% of maximal response (ED50) was significantly (P < 0.05) decreased in the CsA5 and CsA20 animals compared to controls. The values for controls (n = 7), CsA5 (n = 10), and CsA20 (n = 9) were 4.3±0.3, 3.2±0.3, and 3.1±0.4 pulses/sec, respectively. In the CsA20 group, the doseresponse curve to NE was significantly shifted to the left, and the ED50 was significantly (P < 0.01) decreased compared to controls (5.7 ± 0.8×10−5 mol/L, n = 11, vs. 8.9±0.6×10−5 mol/L, n = 12). We conclude that the in vitro contractile response to nerve stimulation is augmented by CsA. Some of the increase may be related to an enhancement of NE response, but a direct effect on neurovascular function is also suggested. This effect of CsA may be important in the development of hypertension and the changes in neurovascular tone seen with the clinical administration of this immunosuppressant.

PROSTAGLANDIN AND ANGIOTENSIN CONVERTING ENZYME INHIBITION: EFFECTS ON BLOOD PRESSURE, RENIN ACTIVITY AND RENAL FUNCTION IN HEMORRHAGED CONSCIOUS RABBITS

The interaction of the prostaglandin and renin-angiotensin systems on blood pressure and renal function was studied in conscious rabbits following mild (6 ml/kg) or moderate (15 ml/kg) hemorrhage. One hour following the injection of the prostaglandin synthetase inhibitor indomethacin (Indo) plasma renin activity (PRA) was significantly lower than the values in control animals. Two hours following hemorrhage, the increase in PRA was very similar in the Indo and control animals. Renal plasma flow (RPF) was not affected by Indo. Glomerular filtration rate (GFR) was significantly lower in the Indo group following moderate hemorrhage. Interruption of the renin-angiotensin system with the converting enzyme inhibitor (CEI), captopril, resulted in similar hypotensive responses in the Indo and non-Indo groups. The marked PRA increase induced by this agent also was not influenced by Indo. The CEI increased RPF and decreased renal vascular resistance (RVR) in the mild hemorrhage animals. However, in the moderate hemorrhage group the RPF changes were variable and RVR tended to increase, especially in the Indo group. GFR fell significantly following captopril in both Indo and non-Indo animals after moderate hemorrhage. The results indicate that prostaglandin inhibition lowers basal PRA levels but that the renin response to hemorrhage and captopril are not prevented. Indo also did not alter the hypotensive response to CEI, suggesting that prostaglandins do not play a major role in this effect. The magnitude of the hemorrhagic stress influences the renal responses to inhibition of the prostaglandin or renin-angiotensin systems in the conscious rabbit.

Decreased vascular reactivity to nonrepinephrine in fischer rats with neoplasia-induced hypercalcemia

The effect of a hypercalcemia-producing Leydig cell tumor on vascular reactivity in Fischer rats was studied. Seven to eight days after tumor implantation, there was no difference between tumor (T) and control (C) animals in serum calcium, serum phosphate, plasma catecholamine levels, mean arterial pressure (MAP), or blood pressure responses to norepinephrine (NE) infusion. At day 12-13 of tumor growth, the serum calcium in the tumor-bearing rats was significantly higher (12.2 +/- 0.8 vs. 9.7 +/- 0.3 mg%, P less than .01) and their serum phosphate significantly lower (4.5 +/- 0.3 vs. 5.7 +/- 0.4 mg%, P less than .01) than controls. Plasma epinephrine (E) (497 +/- 154 vs. 62 +/- 13 pg/ml, P less than .05), and norepinephrine (NE) (686 +/- 85 vs. 329 +/- 75 pg/ml, P less than .01) were markedly elevated in the tumor rats. MAP and the blood pressure responses to graded NE infusions were significantly lower in tumor animals at Day 12-13, whereas there was no change in sensitivity to angiotensin II (AII) infusions. In vitro contractile responses of tail artery segments to transmural nerve stimulation (TNS) in animals with tumors were lower than in controls but there were no differences in sensitivity to exogenous NE in vitro. These results suggest that the tumor stimulates production of a circulating factor which desensitizes NE receptors and that this tumor also decreases neurovascular function by an undefined mechanism.

Rapid Hypertensinogenic Effect of Lead: Studies in the Spontaneously Hypertensive Rat

Chronic lead exposure may cause hypertension in normotensive rats. This hypertensinogenic effect has been attributed to perturbations in the renin-angiotensin axis, the contractile resporase of the vascular smooth muscle, or the intracellular Ca2+ homeostasis as a consequence of the inhibition of Na+-K+-ATPase activity. In this study we examined the short-term effect of lead exposure on blood pressure, plasma renin activity, vascular contractility, and renal Na+-K+-ATPase activity and abundance in the spontaneously hypertensive rat. Our data indicate that modest lead exposure caused blood pressure elevation within two weeks in this rat strain that is genetically susceptible to the development of hypertension. This rapid blood pressure-elevating effect did not appear to depend on the mechanisms described in hypertension associated with more chronic lead exposure listed above. This acute model provides an additional approach to the study of lead-induced hypertension.

The role of prostaglandins in the renin, catecholamine, and blood pressure responses to hemorrhage and captopril in conscious rabbits

Abstract The plasma renin activity (PRA) increases and blood pressure changes seen following mild (6 ml/kg) hemorrhage and angiotensin converting enzyme inhibition (captopril, 1 mg/kg bolus followed by 0.6 mg/kg/hr infusion) were studied in conscious rabbits. Two protocols were followed to evaluate the role of fatty acid cyclooxygenase products and beta-adrenergic receptors. In the first, the effect of indomethacin (I) (n=8) (4mg/kg/d in drinking water for five days and 10 mg/kg intravenous bolus followed by 2 mg/kg/h infusion on day of study) was compared to control (C) (n=8) receiving I diluent. In the second protocol, the combination of propranolol (P) (5 mg/kg/d in drinking water for five days and 0.5 mg/kg bolus followed by 2.4 mg/kg/hr infusion) plus I (n=7) was compared to P alone (n=7). After oral I, immunoassayable prostaglandin E (PGE) excretion was 46% less than control (p p