Search

Objective: To test a recombinant human relaxin preparation, developed for potential therapeutic application, for possible hypotensive actions in near-term pregnant rhesus monkeys., Methods: Groups of four females received 1-hour intravenous infusions of 0, 0.1, or 2.0 mg recombinant human relaxin/kg on gestation day 147 (term = 165 days). Maternal heart rate, electrocardiogram, and diastolic, systolic, and mean arterial pressure; and fetal heart rate were monitored before, during, and after the infusion. After spontaneous delivery, physical, neurobehavioral, and physiologic examinations were conducted on the newborn., Results: No effects of recombinant human relaxin were detected by statistical analysis or examination of data records., Conclusion: Intravenous infusion of up to 2.0 mg recombinant human relaxin/kg in conscious pregnant rhesus monkeys had no effect on maternal cardiovascular indices or fetal heart rate.

Previous studies from our laboratory indicated that the lipoxygenase inhibitor phenidone markedly attenuates angiotensin II (AII) induced vascular contractility. Phenidone was also shown to inhibit the formation of vascular lipoxygenase products and to reduce blood pressure in the AII-dependent renovascular hypertensive rat. We have now examined the effects of phenidone in the spontaneously hypertensive rat (SHR). A single dose of phenidone lowered intraarterial systolic pressure in a dose dependent manner in both SHR and Wistar-Kyoto (WKY) [(max 74 +/- 15 and 22 +/- 3 mm Hg, respectively; P < .001)], but the effect was substantially greater in SHR. Long-term oral phenidone administration arrested the evolution of hypertension in 6 week old SHR treated over a period of 4 weeks (control 190 +/- 2 mm Hg; phenidone treated rats 164 +/- 4 mm Hg; P < .01). To assess the role of AII related mechanisms in the hypotensive effect of phenidone, the acute effect was studied in SHR on high and low sodium intake. In addition, the effect of captopril was compared to that of phenidone alone or captopril and phenidone in salt restricted SHR. While a single dose of phenidone (30 mg/kg, intraperitoneally) elicited similar maximal effects in SHR on high and low sodium intake (54 +/- 6 and 52 +/- 5 mm Hg compared to basal blood pressure, respectively), the hypotensive effect in sodium restricted rats was more sustained. Phenidone had no further hypotensive effect in captopril treated, salt restricted SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

This study investigated changes in plasma norepinephrine and the renin-angiotensin-aldosterone system during weight loss. Subjects were maintained on a hypocaloric and low sodium diet for 12 weeks. During weight loss statistically significant decreases in blood pressure, aldosterone, plasma renin activity, and norepinephrine were evident. Plasma renin substrate was suppressed from week one to eight and returned to control levels by week twelve. The data indicate that a reduction in the activity of the renin-angiotensin-aldosterone system, modulated by circulating norepinephrine and plasma renin substrate, may significantly contribute to the fall in blood pressure associated with weight loss.

To assess the potential role of the lipoxygenase (LO) pathway in the vasculature in an angiotensin II (ANG II)-dependent model of hypertension, we investigated the effect of LO pathway inhibition on blood pressure in the two-kidney, one-clip (2K,1C) Goldblatt hypertensive rat. The development of renovascular hypertension in 2K,1C rats was attenuated by oral administration of phenidone (Phe, 60 mg.kg-1.day-1), a nonselective LO inhibitor, throughout the 3 wk of observation after renal artery constriction. In contrast, the same treatment protocol had no effect on the evolution of hypertension in the deoxycorticosterone acetate-salt rat, which is considered to be an ANG II-independent form of hypertension. The hypotensive effect of Phe was not associated with changes in plasma renin or aldosterone concentration (PRC and PAC, respectively). In vitro synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE) by aortic segments was increased in 2K,1C hypertensive rats compared with sham-operated rats. In addition, the synthesis of 12-HETE was suppressed by the in vitro addition of Phe (10(-4) M) to aortic-segment incubates obtained from 2K,1C rats and sham-operated rats. Acute administration of Phe (30 or 60 mg/kg) in 2K,1C hypertensive rats produced a rapid and sustained decrease in mean blood pressure (MBP). This decrease in MBP was accompanied by a brisk rise in PRC and PAC. In contrast, bolus administration of indomethacin, a selective cyclooxygenase inhibitor, did not affect MBP, PRC, or PAC.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Hormonal and mean arterial pressure (MAP) responses to posture, isometric handgrip, angiotensin II (AII), adrenocorticotrophic hormone (ACTH), and metoclopramide (MCP), a dopamine (DA) antagonist, were examined in nine men with essential hypertension and nine age- and weight-matched normotensive men on a constant 100 mEq sodium and 80 mEq potassium intake before and after 4 days of administration of the DA agonist, bromocriptine (BEC; 2.5 mg three times a day). BEC depressed supine basal MAP in the hypertensives, and decreased MAP response to posture and isometric exercise in both groups. Hypertensives displayed greater (p less than 0.01) NE responses to posture and exercise than the normotensives. BEC decreased the NE response to 10 minutes of upright posture and exercise more in hypertensives (p less than 0.01) than in normotensives, but following BEC, the responses were similar. BEC did not affect basal PRA or PRA responses to posture and exercise in the two groups. PA responses to ACTH and MCP were similar in both groups, but the hypertensives displayed greater (p less than 0.01) PA responses to AII. BEC suppressed PA responses to AII (p less than 0.01) and to high dose ACTH (p less than 0.05) to a similar extent in both groups. The prolactin as well as the PA response to DA antagonism with MCP was similar in the two groups. These results suggest that dopaminergic control of NE secretion may be altered in essential hypertension. Blood pressure lowering effects of BEC in patients with essential hypertension may be related, in part, to depression of sympathetic nervous system activity.

To evaluate the role of the renin-angiotensin system and sodium depletion in the hypotensive response to 1-sarcosine-8-alanine-angiotensin II (saralasin), 15 male patients with essential hypertension were studied on a diet containing 120 mEq of sodium and 100 mEq of potassium per day. After a 5-day control period, all subjects had a mild pressor response to the saralasin infusion (p less than 0.01). After 5 days of the diuretic metolazone (5 mg/day), eight of the 15 patients had a vasodepressor response; these responders had a significantly greater increase in plasma renin activity and angiotensin II concentrations than did the non-responders. Sodium deficit differed markedly (p less than 0.001) between the two groups (361 +/- 121 mEq (SD) vs 52 +/- 26 mEq sodium, respectively). The addition of spironolactone (400 mg/day) for 5 days resulted in saralasin responsiveness in all but two patients, both of whom had small sodium deficits. Thus, variability in the natriuretic response to diuretics may affect saralasin testing and limit its clinical utility.

We have previously demonstrated that the lipoxygenase (LO) pathway has a specific role in the effect of angiotensin II (ANG II) on aldosterone secretion. To elucidate whether the LO pathway also participates in the vascular effects of ANG II, the nonselective LO inhibitor phenidone (PHE; 30 mg/kg) was administered to rats 1 h before graded dose ANG II infusion. PHE reduced the LO product 12-hydroxyeicosatetraenoic acid (12-HETE) in deendothelialized aortas by an average of 36% as determined by radiometric detection with high-performance liquid chromatography and radioimmunoassay methods. In parallel, the peak systolic pressor response to ANG II was lowered from 36.2 +/- 3.7 to 16.8 +/- 2.0 mmHg. The peak pressor responses to ANG II were also reduced by two other LO inhibitors, baicalein (30 mg/kg) and esculetin (60 mg/kg) (13.9 +/- 2.4 and 22.1 +/- 4.7 mmHg, respectively; P less than 0.01 compared with control rats for both), but not by the cyclooxygenase inhibitor indomethacin. The LO inhibitors baicalein (7.5 X 10(-5) M) and PHE (10(-4) M) markedly attenuated the in vitro contractile response to ANG II of femoral artery rings. In contrast, neither the in vivo nor in vitro constrictor responses to norepinephrine were affected by baicalein. Thus lipoxygenase blockade induces a direct and selective inhibition of ANG II-induced vasoconstriction. The LO pathway may have an important role in mediating the pressor effect of ANG II.

Some proposed mechanisms for the hypotensive effect of high calcium intake involve reduction in vascular responsivity. To assess the effect of dietary calcium on vascular responsivity, spontaneously hypertensive rats (SHR) were placed on normal (N-Ca; 0.4%) or high (H-Ca; 2.8%) casein-based synthetic diet for 4 wk. Intraarterial pressure, pressor response to graded intravenous infusion of norepinephrine (NE) and angiotensin II (ANG II), and in vitro vascular reactivity of tail artery segments to NE and transmural nerve stimulation (TNS) were studied. Urinary electrolyte excretion, plasma renin activity (PRA), aldosterone, NE, and epinephrine (EPI) were also determined. H-Ca SHR had a lower intraarterial systolic and diastolic pressure. However, H-Ca SHR had greater in vivo pressor response to both ANG II and NE. Maximal contractile force developed by tail artery segments in vitro in response to NE and TNS was slightly, but not significantly, higher in H-Ca SHR. In vitro dose-response curves to NE and TNS were not significantly different. Although H-Ca SHR had increased urinary excretion of sodium throughout the study period, PRA and aldosterone levels were similar in both groups. Plasma NE and EPI levels in the two groups were also not different. Despite lowered intra-arterial blood pressure, H-Ca SHR exhibited enhanced pressor response to ANG II and NE in vivo and a similar in vitro vascular reactivity to NE and TNS when compared with N-Ca SHR. Our results do not support a role for alterations in vascular reactivity to NE or ANG II in the hypotensive effect of high calcium intake in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)