In contrast with the short research history of the enzymatic synthesis of nitric oxide (NO), the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin) is the first compound of this category. On October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning NO as a signaling molecule in the cardiovascular system. NO-mediated signaling is a recognized component in various physiologic processes (eg, smooth muscle relaxation, inhibition of platelet and leukocyte aggregation, attenuation of vascular smooth muscle cell proliferation, neurotransmission, and immune defense), to name only a few. NO has also been implicated in the pathology of many inflammatory diseases, including arthritis, myocarditis, colitis, and nephritis and a large number of pathologic conditions such as amyotrophic lateral sclerosis, cancer, diabetes, and neurodegenerative diseases. Some of these processes (eg, smooth muscle relaxation, platelet aggregation, and neurotransmission) require only a brief production of NO at low nanomolar concentrations and are dependent on the recruitment of cyclic guanosine monophosphate (cGMP)-dependent signaling. Other processes are associated with direct interaction of NO or reactive nitrogen species derived from it with target proteins and requires a more sustained production of NO at higher concentrations but do not involve the cGMP pathway.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-7176.2008.06632.x

Vascular system: role of nitric oxide in cardiovascular diseases.

—Earlier studies have demonstrated evidence for increased reactive oxygen species, enhanced NO synthase (NOS) expression, and elevated NO production in spontaneously hypertensive rats (SHR)...

Effect of Antioxidant Therapy on Blood Pressure and NO Synthase Expression in Hypertensive Rats

Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 +/- 55 nmol O(2)/min per g, WKY: 611 +/- 51 nmol O(2)/min per g, P > 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin -13.9 +/- 1.9%, enalaprilat -15.3 +/- 1.6%, amlodipine -11.9 +/- 0.7%; WKY: bradykinin -22.8 +/- 1.0%, enalaprilat -24.1 +/- 2.0%, amlodipine -20.7 +/- 2.3%; P < 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempol. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation.

Impaired Regulation of Renal Oxygen Consumption in Spontaneously Hypertensive Rats

https://www.kidney-international.org/article/S0085-2538(15)47515-5/pdf

Effect of severe aortic banding above the renal arteries on nitric oxide synthase isotype expression

—Conflicting evidence exists on the possible impairment of tonic nitric oxide (NO)–mediated vasodilation as a causative factor in the genesis of human as well as experimental hypertension. We evaluated the tonic NO-dependent vasodilation from the pressor response to NO synthesis inhibition by N G-monomethyl-l-arginine (L-NMMA) in 9 conscious, chronically instrumented spontaneously hypertensive rats (SHR) at 12 weeks of age, ie, during the early established hypertensive stage. Nine age-matched Wistar-Kyoto rats (WKY) were used as controls. The pressor responses to L-NMMA (100 mg · kg−1 IV bolus plus 1.5 mg · kg−1 · min−1 infusion for 60 minutes) as well as to non–NO-dependent pressor stimuli, namely, vasopressin (2, 4, and 8 ng · kg−1) and phenylephrine (0.5, 1, and 2 μg · kg−1) given as IV boluses, were assessed both under control conditions and during suppression of autonomic reflexes by hexamethonium (30 mg · kg−1 IV bolus+1.5 mg · kg−1 · min−1 infusion). Rather than being reduced, the pressor responses to L-NMMA were 39% and 71% larger in the control and areflexic conditions, respectively, than those observed in WKY (both P <0.01). A similar pattern was observed for the pressor responses to vasopressin (+37% and +68% in the control and areflexic conditions, respectively; both P <0.01) and phenylephrine, (+20% and +52%; both P <0.05). Additional groups of 6-week-old prehypertensive SHR (n=11) and age-matched WKY (n=11) were subjected to an identical protocol: in these animals, the pressor responses to L-NMMA were similar in each strain, as were the pressor responses to vasopressin and phenylephrine in both control and areflexic conditions. In conclusion, our observations indicate that during the developmental phase of hypertension in the SHR model, namely, during the prehypertensive as well as the early established hypertensive stage, NO-dependent vasodilation is preserved (if not enhanced) so that a putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in this experimental model.

Nitric Oxide–Dependent Vasodilation in Young Spontaneously Hypertensive Rats

Summary

1. The depressor response to sodium nitroprusside (SNP) and the pressor response to Nω-nitro-L-arginine methyl ester (L-NAME) were investigated in anaesthetized and ganglion-blocked 6 week old (young) and 20 week old (adult) spontaneously hypertensive rats (SHR), and the results were compared with those in age-matched normotensive Wistar-Kyoto (WKY) rats.



2. SNP produced a dose-dependent decrease of the mean blood pressure (BP) in both strains, and no differences in vascular sensitivity to SNP were observed between the strains.



3. L-NAME caused dose-dependent pressor responses in both strains. The sensitivity and the maximal response to L-NAME in SHR were significantly greater than those in age-matched WKY (P < 0.05 or 0.01; t-test, 13d.f. in both ages). However, there were no significant differences in the responses between ages in each strain.



4. Acute reduction of BP induced by 7-O-ethylfangchinoline did not affect the responses to SNP and L-NAME in the adult SHR.



5. These results indicate that a greater amount of NO is tonically released in SHR and that its contribution to BP control is greater in SHR than in WKY, whereas vascular sensitivity to NO does not differ between the strains. In addition, acute changes in BP do not affect the degree of dependency on NO for BP control.

Role of nitric oxide in the control of blood pressure in young and adult spontaneously hypertensive rats.

1. The antihypertensive effects of 10 mg/kg trichloromethiazide (TCM), 10 mg/kg 7-O-ethylfangchinoline (7-O-EFC) and the combination of these drugs given orally once daily for 2 weeks were investigated by measuring the blood pressure (BP), heart rate (HR) and activity in conscious, freely moving spontaneously hypertensive rats (SHR) fitted with a telemetry device. 2. Clear diurnal rhythms of the HR and activity in synchrony with the light/dark cycle were observed during therapy, whereas the BP rhythm was obscure. 3. Alone, TCM and 7-O-EFC produced slight and insignificant reductions of 24h mean BP, whereas in combination they produced an additive and significant BP reduction, compared with the vehicle-treated controls, from the third day of therapy. The BP reduction induced by the combination of these drugs during the dark phase was more marked than that during the light phase. 4. None of the drug therapies affected the HR and activity diurnal rhythms. 5. The results of the present study demonstrate that the telemetry method is useful for monitoring the antihypertensive effects of drugs in SHR under physiological conditions with minimal stress.

Antihypertensive effects, determined by a telemetry method, of trichloromethiazide and 7–o‐ethylfangchinoline, a derivative of tetrandrine, in spontaneously hypertensive rats

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Role of nitric oxide in the control of blood pressure in young and adult spontaneously hypertensive rats.

Antihypertensive effects, determined by a telemetry method, of trichloromethiazide and 7–o‐ethylfangchinoline, a derivative of tetrandrine, in spontaneously hypertensive rats