Insulin attenuates vasopressin-induced calcium transients and a voltage-dependent calcium response in rat vascular smooth muscle cells.

Insulin attenuates the contractile responses of vascular smooth muscle (VSM) to various agonists. Insulinopenic and insulin-resistant rats lack this normal attenuation of vascular contractile responses. To study this attenuating mechanism, the effects of insulin on calcium (Ca2+) responses of cultured VSM cells (a7r5) to arginine vasopressin (AVP) and membrane potential were investigated. Insulin (1 and 100 mU/ml) shifted AVP dose-response curves to the right, reducing relative potency of AVP by 16-fold and 220-fold, respectively. Responses to AVP were significantly attenuated within 30 min of insulin application. The AVP-elicited rise in [Ca2+]i was partially dependent upon extracellular Ca2+. AVP-elicited inward current was reduced by 90 min of insulin treatment (100 mU/ml), from a peak current of -103 +/- 27 pA (normal) to -37 +/- 15 pA (insulin treated). Peak voltage-dependent Ca(2+)-dependent inward current was unaffected by insulin; however, the current-voltage curve was shifted 16 +/-3 mV to the right by insulin. Thus, insulin may reduce VSM contractile responses by attenuating agonist-mediated rises in [Ca2+]i mediated, in part, by reductions in Ca2+ influx through both receptor- and voltage-operated channels.

Effects of insulin and IGF-I on vascular smooth muscle glucose and cation metabolism.

Data is accumulating indicating that impaired insulin action predisposes to increased vascular smooth muscle (VSM) tone, the hallmark of hypertension associated with diabetes. During the last several years, it has been established that VSM is an insulin-sensitive tissue like skeletal muscle and adipocytes. Investigators have shown that insulin regulates VSM intracellular cation metabolism through attenuating effects on inward calcium (Ca2+) currents and by direct effects on VSM cells (VSMCs) Na+, K(+)-ATPase pump expression and activity and that insulin and IGF-I stimulate glucose uptake in VSMCs. Furthermore, recent data suggest that IGF-I, like insulin, attenuates cytosolic calcium [Ca2+]i transients and vasoconstrictive responses. IGF-I, like insulin, also stimulates the production of nitric oxide from both the endothelium and VSMCs. IGF-I and insulin are structurally related, share receptors, and have similar postreceptor actions. Unlike insulin, which must transverse the endothelium before acting on VSMCs in vivo, IGF-I is synthesized by VSMCs. Thus, it is likely that IGF-I has more relevance than insulin in regulating physiological parameters in VSMCs.

Troglitazone attenuates high-glucose-induced abnormalities in relaxation and intracellular calcium in rat ventricular myocytes.

Diabetes is associated with impaired cardiac diastolic dysfunction. Isolated ventricular myocytes from diabetic animals demonstrate impaired relaxation concomitant with prolonged intracellular Ca2+ transients. We have recently shown that maintaining normal adult rat ventricular myocytes in a "diabetic-like" culture medium (low insulin and high glucose) produces abnormalities in excitation-contraction coupling similar to in vivo diabetes. Troglitazone (TRO), a novel insulin-sensitizing agent, significantly lowers blood pressure and modestly increases cardiac output in vivo, but its direct impact on cardiac function is unknown. To determine whether TRO could prevent high-glucose-induced dysfunction, normal myocytes were maintained in culture for 1-2 days in either normal medium containing 5 mmol/l glucose or high-glucose medium containing 25 mmol/l glucose. TRO (5 micromol/l) was added to both normal and high-glucose media. Mechanical properties were evaluated using a high-resolution video-edge detection system, and Ca2+ transients were recorded in fura-2-loaded myocytes. Relaxation from peak contraction was significantly longer in myocytes cultured in high glucose. Treating cells with TRO either attenuated or prevented the high-glucose effects, without changing the mechanical properties of myocytes cultured in normal medium. TRO also prevented the abnormally slow rates of Ca2+ transient decay induced by high glucose. Collectively, these data demonstrate that TRO can protect against the high-glucose-induced relaxation defects, perhaps through changes in intracellular Ca2+ handling. If TRO has both vasodilatory actions and beneficial cardiac properties (e.g., improvement of diastolic function) in the presence of hyperglycemia, this antidiabetic agent may prove to have significant salutary cardiovascular effects in type II diabetes.

Metformin but not glyburide prevents high glucose-induced abnormalities in relaxation and intracellular Ca2+ transients in adult rat ventricular myocytes.

We have recently demonstrated that adult rat ventricular myocytes maintained in a high glucose (HG) culture medium exhibit abnormalities in excitation-contraction coupling similar to myocytes from diabetic rats. Metformin, an insulin-sensitizing biguanide, enhances peripheral insulin action and lowers blood pressure in hyperinsulinemic animals, but its direct impact on cardiac function is not fully understood. To examine the role of metformin on HG-induced cardiac dysfunction at the cellular level, normal adult ventricular myocytes were cultured for 1 day in a serum-free insulin-containing medium with either normal glucose (5.5 mmol/l glucose) or HG (25.5 mmol/l glucose) in the presence or absence of metformin or the sulfonylurea glyburide. Mechanical properties were evaluated using a high-speed video-edge detection system, and intracellular Ca2+ transients were recorded in fura-2-loaded myocytes. As previously reported, culturing myocytes in HG depresses peak shortening, prolongs time to 90% relengthening, and slows Ca2+ transient decay. Culturing cells with metformin (50 micromol/l) prevented the HG-induced abnormalities in relaxation without ameliorating depressed peak-shortening amplitudes. Incubation of the cells with metformin also prevented slower intracellular Ca2+ clearing induced by HG. However, the HG-induced relaxation defects were not improved by glyburide (50-300 micromol/l). Interestingly, metformin also improved HG-induced relaxation abnormalities in the absence of insulin, whereas it failed to protect against HG in the presence of the tyrosine kinase inhibitor genistein (50 micromol/l). These data demonstrate that, unlike glyburide, metformin provides cardioprotection against HG-induced abnormalities in myocyte relaxation, perhaps through tyrosine kinase-dependent changes in intracellular Ca2+ handling, independent of its insulin sensitizing action.

Troglitazone reduces contraction by inhibition of vascular smooth muscle cell Ca2+ currents and not endothelial nitric oxide production.

The insulin-sensitizing compound troglitazone has evolved into a promising therapeutic agent for type II diabetes. It improves insulin sensitivity and lipoprotein metabolic profiles and lowers blood pressure in humans and rodents. Because troglitazone has insulin-like effects on a number of tissues, we hypothesized that it may reduce vascular tone through stimulation of endothelial-derived nitric oxide (NO) production or by diminution of vascular smooth muscle cell (VSMC) intracellular calcium ([Ca2+]i). Our results show that troglitazone decreases norepinephrine-induced contractile responses in the rat tail artery, an effect not reversed by the NO inhibitor L-nitroarginine methyl ester (L-NAME). In contrast, troglitazone significantly inhibited L-type Ca2+ currents in freshly dissociated rat tail artery and aortic VSMCs and in cultured VSMCs. The data suggest that troglitazone attenuates vascular contractility via a mechanism involving VSMC [Ca2+]i but independent from endothelial generation of NO. Because insulin has been shown to affect vascular tone by both of these mechanisms, troglitazone only partially mimics insulin action in this tissue.

Myocardial norepinephrine, epinephrine and dopamine concentrations after cardiac autotransplantation in dogs.

Myocardial norepinephrine is markedly reduced after cardiac transplantation because of interruption of postganglionic cardiac sympathetic nerves. There are also substantial stores of dopamine in the myocardium, but the influence of cardiac denervation on dopamine remains unknown. The effect of cardiac transplantation was determined and, thus, the effect of denervation on myocardial norepinephrine, dopamine and epinephrine. Myocardial catecholamines were measured with high-performance liquid chromatography with electrochemical detection in five dogs 6 to 8 weeks and in four dogs 8 to 12 years after cardiac autotransplantation and in six sham-operated dogs with intact cardiac innervation. Norepinephrine, dopamine and epinephrine levels were determined from samples obtained from the right and left atria and ventricles. Samples from the left ventricular apex and base were analyzed separately. There was a striking depletion of norepinephrine in all cardiac chambers after short-term autotransplantation. The norepinephrine content of the left atrium in sham-operated dogs (1,659 +/- 219 ng/g) was significantly higher than that of dogs with long-term autotransplanted hearts (754 +/- 372 ng/g). Sham-operated dogs and dogs with long-term autotransplanted hearts had statistically significant (p less than 0.05) differences in norepinephrine content in the left ventricular apex (480 +/- 197 versus 294 +/- 198 ng/g), left ventricular base (876 +/- 2204 versus 654 +/- 156 ng/g) and right ventricle (766 +/- 133 versus 247 +/- 29 ng/g). In contrast to norepinephrine, dopamine concentrations were relatively preserved in the short-term group despite the virtual depletion of myocardial norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus and diabetes-associated vascular disease.

Diabetes-related cardiovascular disease remains the leading cause of death in patients with type 2 diabetes. Hypertension is common among diabetics and has the same pathogenetic mechanisms as insulin resistance, in which the activated renin-angiotensin system contributes to the emerging high blood pressure and hyperglycemia. Hyperglycemia is one of the triggering factors for vascular dysfunction and clotting abnormalities and, therefore, for accelerated atherosclerosis in diabetes. Glycated hemoglobin levels, as a reflection of the degree of glycemia, are strongly associated with the risk of cardiovascular disease in diabetics and in the general population. Tight glycemic control, the treatment of dyslipidemia and raised blood pressure, in addition to the use of antiplatelet therapy, all powerfully reduce the risks associated with diabetes. Furthermore, angiotensin-converting enzyme inhibitors might offer additional cardioprotection to diabetics above that provided by blood pressure reduction.

Diabetes mellitus and cardiovascular disease in women.

BACKGROUND: Coronary heart disease (CHD) is the leading cause of morbidity and mortality in women in the United States. Although CHD is less common in premenopausal women than in men, this difference begins to disappear after the onset of menopause, presumably related to reduced levels of female sex hormones. RESULTS: An association between both a postmenopausal increase in blood pressure and CHD that coincide with loss of ovarian function suggests that estrogen and/or progesterone may be protective against hypertension and CHD. Diabetes removes the normal sex difference in the prevalence of CHD. Increased mortality in women with CHD and diabetes compared with women without diabetes has been observed in epidemiological studies. CONCLUSIONS: Diabetes appears to obviate the protective effects of female sex hormones. Possible reasons for this catastrophic effect of diabetes in women are discussed.

An update on perioperative management of diabetes.

Surgery in the patient with diabetes mellitus is relatively common, as the numbers of persons with diabetes is increasing and diabetes predisposes to medical conditions that require surgical intervention. An estimated 25% of diabetic patients will require surgery, and advances in perioperative care of these patients allow them to safely undergo the most complicated surgical procedures. We will review issues of preoperative, intraoperative, and postoperative care of diabetic patients.

Hypertensive disorders of pregnancy in southwestern Navajo Indians.

BACKGROUND: The Navajos are the largest Native American tribe. They, like other Native Americans, appear to be in an "epidemiologic transition" and are accordingly experiencing increased rates of hypertension, diabetes, and obesity. METHODS: A retrospective chart review of all pregnancies in 1991 at the Crownpoint Indian Health Service Facility in Crownpoint, NM, was conducted to determine the prevalence of hypertensive disorders of pregnancy in this Navajo population. RESULTS: Seventy-five (12.6%) of 594 pregnancies were associated with a hypertensive disorder. There were 18 individuals who developed gestational hypertension and 10 individuals with chronic hypertension that persisted during pregnancy. There were 46 women (7.7%) who developed preeclampsia and one woman (0.3%) who developed eclampsia. Eight women (1.4%) with chronic hypertension developed superimposed preeclampsia during pregnancy. Thus, 12.3% of these pregnancies in Navajo women were associated with the development of, or worsening, hypertension, and there was a prevalence of preeclampsia of 9.1%. CONCLUSION: The Navajos exhibit a high prevalence of pregnancy-related hypertension and preeclampsia.

Carotid plaque associations among hypertensive patients.

OBJECTIVE: To assess the relationship between cardiovascular risk factors and carotid plaque. DESIGN: Hypertensive patients were screened for randomization into the Multicenter Isradipine Diuretic Atherosclerosis Study, a trial intended to determine if blood pressure control by isradipine as compared with hydrochlorothiazide will blunt the progression of carotid plaque (intima plus media thickness, 1.3 to 3.5 mm) in patients with serum cholesterol levels of less than 6.85 mmol/L (265 mg/dL) without insulin-dependent diabetes mellitus or estrogen therapy. Demographics of those who underwent B-mode ultrasound evaluations at common, bifurcation, and internal carotid artery sites to detect plaque were assessed from a southern and a northern site. SETTING: Participants were from ambulatory outpatient clinics associated with medical schools. PATIENTS: The initial screening included 1823 hypertensive volunteer patients who were between 40 and 83 years of age who had a diastolic pressure of 90 to 114 mm Hg (or < 90 mm Hg with treatment). OUTCOME MEASURES: Complete data were collected on the variables of age, cholesterol, cigarette smoking, race, gender, and the presence of carotid plaque in 1126 patients. RESULTS: All variables were significantly associated with carotid plaque (intima plus media thickness, > or = 1.3 mm). The adjusted percentage with plaque was 66.4% +/- 3.4% for blacks and 70.1% +/- 2.3% for whites at the southern site and 42.7% +/- 4.5% for blacks and 61.3% +/- 3.2% for whites at the northern site. The rate of plaque was 75.8% among cigarette smokers, despite a mildly elevated cholesterol level. CONCLUSIONS: Although these 1126 cases do not constitute a random sample of patients, these data suggest that there may be regional differences in racial tendencies toward plaque among blacks.

A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks.

A double-blind, positively controlled, forced dose titration study comparing the efficacy and safety of atenolol, captopril, and verapamil sustained release as single agents in the treatment of black patients with mild to moderate hypertension (diastolic blood pressure, 95 to 114 mm Hg) was conducted. A total of 394 patients were randomized to one of the three therapies. Mean blood pressures during a 2- to 4-week placebo treatment period (baseline) ranged from 100.4 to 100.7 mm Hg diastolic and 151.7 to 152.5 mm Hg systolic for the three groups. Of the patients, 355 (of whom 345 had assessable data) completed the first treatment period, which consisted of therapy with either 50 mg/d of atenolol, 25 mg every 12 hours of captopril, or 240 mg/d of verapamil sustained release. During the second 4-week treatment period, which 319 patients completed (307 assessable), half of the patients had their antihypertensive medication increased and the other half continued the same dose. Goal blood pressure was defined as a supine diastolic pressure of less than 90 mm Hg or a 10-mm Hg or greater drop in supine diastolic blood pressure from pretreatment levels. Atenolol, captopril, and verapamil sustained release therapy was associated with goal blood pressure achievement during the first treatment period 55.1%, 43.8%, and 65.2% of the time, respectively, and during the second treatment period 59.6%, 57.1%, and 73.0% of the time. Side effects were minimal and comparable for all three drugs.

Plasma antithrombin III and thrombin generation time: correlation with hemoglobin A1 and fasting serum glucose in young diabetic women.

Three parameters of coagulability--thrombin generation time (TGT), antithrombin III (AT III), and activated partial thromboplastin time (ATPP)--and two parameters of diabetic control--serial measurements of fasting serum glucose (FG) and hemoglobin A1(HbA1)--were used to study the relationship between diabetic control and hypercoagulability. Four groups of females were studied consisting of 10 young normal, 10 young insulin-dependent diabetic, 10 pregnant nondiabetic, and 8 first-trimester, insulin-dependent, pregnant diabetic subjects. Fasting serum glucose values and HbA1 were higher (P < 0.005) in nonpregnant diabetic subjects (193.1 +/- 29.1 mg/dl, 12.9 +/- 1.1%) and pregnant diabetic subjects (111.0 +/- 13.6 mg/dl, 8.2 +/- 1.7%) than in controls (64.8 +/- 4.4 mg/dl, 5.9 +/- 0.1%) and the nondiabetic pregnant females (71.6 +/- 3.8 mg/dl, 6.1 +/- 0.2%). Young diabetic females, pregnant females, and pregnant diabetic subjects had a shorter (P < 0.01) TGT than did the controls. AT III was greater (P < 0.01) for controls (99.7 +/- 2.7%) than for pregnant nondiabetic (83.2 +/- 3.8%), diabetic (79.5 +/- 2.5%), and pregnant diabetic subjects (76.2 +/- 4.4%). There was a positive correlation (r = 0.88, P < 0.005) between HbA1 and FG in the 10 young diabetic and in the 8 pregnant diabetic subjects (r = 0.74, P < 0.05). In the 10 diabetic females there was a negative correlation between AT III and FG (r = -0.76, P < 0.01) and between AT III and HbA1 (r = -0.79, P < 0.01). Thus, AT III is depressed in both diabetes and pregnancy, with pregnant diabetic subjects displaying the lowest AT III levels. Our observation that depression of AT III levels in young diabetic females was closely correlated with elevations of fasting serum glucose and HbA1 suggests that strict diabetic control may help prevent hypercoagulability in diabetes.

Isradipine in prediabetic hypertensive subjects.

OBJECTIVE: Investigators from the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) previously reported that the isradipine group had a higher incidence of cardiovascular disease (CVD) events than the diuretic group. The ultimate objective of the analyses presented here was to assess how indices of glycemia (specifically, serum glucose, serum insulin, and HbA1c) might have influenced the effects of the two agents on blood pressure control and CVD events. RESEARCH DESIGN AND METHODS: Inclusion criteria included men and women > or = 40 years of age with ultrasonographically confirmed carotid atherosclerosis and a diastolic blood pressure of > 90 mmHg. Although insulin-dependent diabetic patients were excluded, the three glycemia indices had wide enough ranges to include patients who may be classified as prediabetic. A total of 883 patients were randomized either to the dihydropyridine calcium antagonist (CA) isradipine (2.5-5 mg twice a day) or to the diuretic hydrochlorothiazide (12.5-25 mg twice a day) and followed in double-blind fashion for 3 years. RESULTS: Both treatment groups had achieved comparable control of diastolic blood pressure, and there were no statistically significant differences in any of the glycemia indices, either at baseline or during follow-up. However, the excess isradipine events were noted to be clustered among those patients with elevated baseline levels of HbA1c who also experienced greater blood pressure reductions during follow-up. CONCLUSIONS: The increased cardiovascular risk associated with dihydropyridine CAs in prediabetic patients may be an explanation for the overall CA debate.

Insulin attenuation of vasopressin-induced calcium responses in arterial smooth muscle from Zucker rats.

Insulin attenuates agonist-induced vascular contractility of aortic rings and decreases vasopressin (AVP)-elicited increases in vascular smooth muscle cell (VSMC) intracellular calcium ([Ca2+]i). To determine if insulin's effects on AVP-induced [Ca2+]i responses are altered in an insulin-resistant and hypertensive state, we studied vascular smooth muscle calcium responses in VSMC derived from Zucker lean and obese rats. AVP concentration-response experiments revealed that VSMC derived from obese animals exhibited exaggerated [Ca2+]i responses over the range of 1 x 10(-10) to 1 x 10(-7) M AVP compared to lean controls (P < 0.05, by multiple analysis of variance). Insulin treatment (7 x 10(-7) M) decreased the [Ca2+]i response to 1 nM AVP by 66 +/- 8% and 71 +/- 9% in lean and obese VSMC, respectively. Similar decreases were observed with the 10 nM AVP stimulus (41 +/- 9% and 61 +/- 7%, for lean and obese, respectively). AVP receptor binding studies revealed that exaggerated [Ca2+]i responses in obese VSMC were not due to alterations in AVP-binding properties (no significant differences in ID50, Kd, or binding capacity in lean and obese VSMC preparations). In addition, insulin treatment (1 x 10(-7) M) resulted in no differences in AVP receptor-binding properties in either cell line. Therefore, exaggerated [Ca2+]i responses in obese VSMC are most likely due to a postreceptor abnormality. These abnormalities in VSMC [Ca2+]i metabolism preceed and may play a role in the development of hypertension in the Zucker obese rat. Although insulin resistance in Zucker obese rats has been demonstrated in several tissues, VSMC [Ca2+]i responses to AVP are, nonetheless, similarly attenuated by insulin in obese and lean VSMC preparations.

Effects of metoclopramide on plasma corticosteroid levels in sheep.

This study investigated the role of dopaminergic mechanisms in modulation of corticosteroid secretion in sheep. Administration of the dopamine antagonist metoclopramide (200 micrograms/kg iv) in six mature sheep resulted in rapid and parallel rises in plasma cortisol, corticosterone, 18-hydroxycorticosterone, and aldosterone. Treatment of the sheep with 4 mg dexamethasone im every 6 h for 4 days abolished the response of all four corticosteroids to metoclopramide in the six sheep. These observations suggest that metoclopramide may stimulate corticosteroid secretion in sheep via nonspecific stressor effects.

Dopaminergic modulation of aldosterone secretion in the rhesus monkey: evidence that dopamine affects the late pathway of aldosterone biosynthesis by inhibiting the conversion of corticosterone to 18-hydroxycorticosterone.

This study was designed to investigate the role of dopaminergic mechanisms in the control of aldosterone secretion. Six rhesus monkeys received metoclopramide (1.25 mg, iv), with 5% dextrose (vehicle) or with dopamine (4 micrograms/kg . min) infusions begun 60 min before the administration of the dopamine antagonists. Metoclopramide, in the presence of vehicle, increased plasma aldosterone concentrations from 4.5 +/- 0.5 ng/dl to a maximum of 26 +/- 4.1 ng/dl and PRL concentrations from 8.1 +/- 1.3 ng/ml to a maximum of 118.4 +/- 7.6 ng/ml. Dopamine infusion inhibited the aldosterone and PRL responses to metoclopramide. The administration of metoclopramide resulted in a rise in plasma 18-hydroxycorticosterone from 10.4 +/- 1.5 ng/dl to a maximum concentration of 41 +/- 4.2 ng/dl. The aldosterone and 18-hydroxycorticosterone responses displayed a parallel time course, with significant responses of both occurring 5 min after metoclopramide administration. Plasma concentrations of electrolytes, PRA, plasma cortisol, 11-deoxycorticosterone, corticosterone, and 18-hydroxy-11-deoxycorticosterone were not altered by metoclopramide. The results of this investigation demonstrate that aldosterone and PRL responses to metoclopramide are mediated by their antagonist activities at dopamine receptors. Rather than simply affecting secretion, dopaminergic mechanisms appear to modulate the late pathway of adrenal glomerulosa biosynthesis of aldosterone. A parallel time course of stimulation of 18-hydroxycorticosterone and aldosterone secretion, with no change in other aldosterone precursors, strongly suggests that dopamine modulates the activity of the glomerulosa 18-hydroxylase enzyme.

Dopaminergic modulation of aldosterone secretion is independent of alterations in renin secretion.

This study was designed to determine if dopaminergic modulation of aldosterone secretion is mediated through the renin-angiotensin system. In rats, intraarterial administration of metoclopramide (MCP), a dopamine antagonist, resulted in a significant elevation of plasma aldosterone (PA) 5 min after administration and a peak response 10 min after administration. Pretreatment with L-dopa (30 mg/kg) 30 min before administration of MCP suppressed the early PA response to MCP. PRA after MCP showed no change at 5 min but increased significantly at 10 min, with peak responses occurring at 30 min. Preadministration of L-dopa blunted and delayed the PRA response to MCP. Preadministration of the angiotensin-converting enzyme inhibitor, SQ 14,225 (1 mg/kg), did not inhibit the PA response to MCP. Infusion of the angiotensin II antagonist, saralasin (10 micrograms/kg min-1), begun 30 min before MCP, depressed basal levels of PA slightly but did not significantly alter the PA response to MCP. Rats studied 36 h after bilateral nephrectomy displayed intact PA responses to MCP, but there was no PRA response to MCP. The results indicate that dopaminergic modulation of PA secretion occurs independently of alterations in renin secretion.

Sodium-potassium ATPase in deoxycorticosterone-salt hypertension: opposing effects of sodium load and mineralocorticoids.

Previous studies of the sodium-potassium pump in the deoxycorticosterone (DOC)-salt (DS) model of hypertension yielded contrasting results, some investigators reporting increased and others finding decreased pump activity. To test the possibility that the net pump activity in the DS rats results from separate effects of sodium overload and mineralocorticoid activity, we compared the Na+-K+-ATPase pump in DS rats with that in other experimental models in which these potential determinants do not coincide. Renocortical and myocardial ATPase activities were measured in control rats; adrenalectomized-saline-repleted rats; adrenalectomized aldosterone- or dexamethasone-repleted rats; uninephrectomized, saline-drinking rats; and uninephrectomized, saline-drinking, DOC- and salt-treated rats. DOC- and salt-treated rats had higher (P less than 0.001) blood pressures and lower (P less than 0.05) serum potassium levels than control rats. Renocortical and myocardial ATPase activities were considerably (P less than 0.01) decreased in adrenalectomized, saline-repleted rats, but could be at least partially restituted by either aldosterone or dexamethasone therapy. Uninephrectomized, saline-drinking rats had reduced (P less than 0.01) renocortical and myocardial ATPase activities compared with control rats. In uninephrectomized, saline-drinking rats treated with DOC, renocortical and myocardial ATPase activities were not different from control values. The results of this study suggest that the Na+-K+-ATPase pump in DOC- and salt-treated rats is modulated by the opposing effects of sodium overload-associated suppression and DOC-mediated stimulation.

Insulin-like growth factor I diminishes in vivo and in vitro vascular contractility: role of vascular nitric oxide.

Although most insulin-like growth factor I (IGF-I) in the circulation is generated by the liver, the hormone is also produced locally by the vasculature, suggesting its potential importance in regulation of regional blood flow. Accordingly, we studied the effects of in vivo exposure to IGF-I (5.1 nmol, i.v.) as well as in vitro incubation (100 nM) on endothelium-intact rat tail artery contractile responses to KCl and norepinephrine (NE). Systemic administration of IGF-I resulted in transient lowering of blood pressure, with maximal reduction occurring at 15 min and a return to baseline by 60 min. Maximal contractility of rings removed from animals 90 min after a bolus injection of IGF-I, when blood pressure had returned to normal, was significantly reduced for both KCl (58%) and NE (51%) without a change in sensitivity. Similar data were obtained when rings from untreated animals were preincubated in vitro for 90 min; maximal contractility in response to KCl was decreased by 31% and that to NE by 22%. L-Nitroarginine methyl ester, an inhibitor of nitric oxide (NO) production, administered in vivo before IGF-I or added to the bath buffer reversed the attenuation. The nearly identical in vivo and in vitro results suggest that the observed diminution in contractility is a direct effect of IGF-I on the vasculature, probably mediated in large part by the release of NO. This idea is supported by our observation that IGF-I stimulates NO production in intact vessels. Further, the latency required indicates that rather complex mechanisms involving actions common on both receptor- and nonreceptor-mediated events are initiated by IGF-I and/or NO.